Upregulation of RGS2: a new mechanism for pirfenidone amelioration of pulmonary fibrosis.

PubMed

Xie, Yan; Jiang, Haihong; Zhang, Qian; Mehrotra, Suneet; Abel, Peter W; Toews, Myron L; Wolff, Dennis W; Rennard, Stephen; Panettieri, Reynold A; Casale, Thomas B; Tu, Yaping

2016-08-22

Pirfenidone was recently approved for treatment of idiopathic pulmonary fibrosis. However, the therapeutic dose of pirfenidone is very high, causing side effects that limit its doses and therapeutic effectiveness. Understanding the molecular mechanisms of action of pirfenidone could improve its safety and efficacy. Because activated fibroblasts are critical effector cells associated with the progression of fibrosis, this study investigated the genes that change expression rapidly in response to pirfenidone treatment of pulmonary fibroblasts and explored their contributions to the anti-fibrotic effects of pirfenidone. We used the GeneChip microarray to screen for genes that were rapidly up-regulated upon exposure of human lung fibroblast cells to pirfenidone, with confirmation for specific genes by real-time PCR and western blots. Biochemical and functional analyses were used to establish their anti-fibrotic effects in cellular and animal models of pulmonary fibrosis. We identified Regulator of G-protein Signaling 2 (RGS2) as an early pirfenidone-induced gene. Treatment with pirfenidone significantly increased RGS2 mRNA and protein expression in both a human fetal lung fibroblast cell line and primary pulmonary fibroblasts isolated from patients without or with idiopathic pulmonary fibrosis. Pirfenidone treatment or direct overexpression of recombinant RGS2 in human lung fibroblasts inhibited the profibrotic effects of thrombin, whereas loss of RGS2 exacerbated bleomycin-induced pulmonary fibrosis and mortality in mice. Pirfenidone treatment reduced bleomycin-induced pulmonary fibrosis in wild-type but not RGS2 knockout mice. Endogenous RGS2 exhibits anti-fibrotic functions. Upregulated RGS2 contributes significantly to the anti-fibrotic effects of pirfenidone.

Proceedings of the First Joint NASA Cardiopulmonary Workshop

NASA Technical Reports Server (NTRS)

Fortney, Suzanne M. (Editor); Hargens, Alan R. (Editor)

1991-01-01

The topics covered include the following: flight echocardiography, pulmonary function, central hemodynamics, glycerol hyperhydration, spectral analysis, lower body negative pressure countermeasures, orthostatic tolerance, autonomic function, cardiac deconditioning, fluid and renal responses to head-down tilt, local fluid regulation, endocrine regulation during bed rest, autogenic feedback, and chronic cardiovascular measurements. The program ended with a general discussion of weightlessness models and countermeasures.

Leptin as regulator of pulmonary immune responses: Involvement in respiratory diseases

PubMed Central

Vernooy, Juanita H.J.; Ubags, Niki D.J.; Brusselle, Guy G.; Tavernier, Jan; Suratt, Benjamin T.; Joos, Guy F.; Wouters, Emiel F.M.; Bracke, Ken R.

2014-01-01

Leptin is an adipocyte-derived hormone, recognized as a critical mediator of the balance between food intake and energy expenditure by signalling through its functional receptor (Ob-Rb) in the hypothalamus. Structurally, leptin belongs to the long-chain helical cytokine family, and is now known to have pleiotropic functions in both innate and adaptive immunity. The presence of the functional leptin receptor in the lung together with evidence of increased airspace leptin levels arising during pulmonary inflammation, suggests an important role for leptin in lung development, respiratory immune responses and eventually pathogenesis of inflammatory respiratory diseases. The purpose of this article is to review our current understanding of leptin and its functional role on the different resident cell types of the lung in health as well as in the context of three major respiratory conditions being chronic obstructive pulmonary disease (COPD), asthma, and pneumonia. PMID:23542720

TRPV4 channels: physiological and pathological role in cardiovascular system.

PubMed

Randhawa, Puneet Kaur; Jaggi, Amteshwar Singh

2015-11-01

TRPV4 channels are non-selective cation channels permeable to Ca(2+), Na(+), and Mg(2+) ions. Recently, TRPV4 channels have received considerable attention as these channels are widely expressed in the cardiovascular system including endothelial cells, cardiac fibroblasts, vascular smooth muscles, and peri-vascular nerves. Therefore, these channels possibly play a pivotal role in the maintenance of cardiovascular homeostasis. TRPV4 channels critically regulate flow-induced arteriogenesis, TGF-β1-induced differentiation of cardiac fibroblasts into myofibroblasts, and heart failure-induced pulmonary edema. These channels also mediate hypoxia-induced increase in proliferation and migration of pulmonary artery smooth muscle cells and progression of pulmonary hypertension. These channels also maintain flow-induced vasodilation and preserve vascular function by directly activating Ca(2+)-dependent KCa channels. Furthermore, these may also induce vasodilation and maintain blood pressure indirectly by evoking the release of NO, CGRP, and substance P. The present review discusses the evidences and the potential mechanisms implicated in diverse responses including arteriogenesis, cardiac remodeling, congestive heart failure-induced pulmonary edema, pulmonary hypertension, flow-induced dilation, regulation of blood pressure, and hypoxic preconditioning.

Emodin suppresses silica-induced lung fibrosis by promoting Sirt1 signaling via direct contact.

PubMed

Yang, Tian; Wang, Jinyuan; Pang, Yamei; Dang, Xiaomin; Ren, Hui; Liu, Ya; Chen, Mingwei; Shang, Dong

2016-11-01

Pulmonary silicosis is characterized by lung fibrosis, which leads to impairment of pulmonary function; the specific mechanism remains to be fully elucidated Emodin shows antifibrotic effects in several organs with fibrosis, however, it has not been investigated in pulmonary silicosis. In the present study, the possible mechanism of lung fibrosis and the antifibrotic effect of emodin in silica inhalation‑induced lung fibrosis were investigated. Pulmonary silica particle inhalation was used to induce lung fibrosis in mice. Emodin and or the sirtuin 1 (Sirt1) inhibitor, nicotinamide, were used to treat the modeled animals. Pulmonary function was assessed using an occlusion method. The deposition of collagen I and α‑smooth muscle actin (SMA) in the lung tissue were detected using fluorescence staining; transforming growth factor‑β1 (TGF‑β1) in the bronchoalveolar lavage fluid (BALF) was examined using an enzyme‑linked immunosorbent assay; TGF-β1/Sirt1/small mothers against decapentaplegic (Smad) signaling activation in lung tissue was also examined. The molecular contacts between emodin were evaluated using liquid chromatography‑mass spectrometry analysis. The deposition of collagen I and α‑SMA in lung tissues were found to be elevated following silica exposure, however, this was relieved by emodin treatment. The pulmonary function of the animals was impaired by silica inhalation, and this was improved by emodin administration. However, the therapeutic effects of emodin on lung fibrosis were impaired by nicotinamide administration. The levels of TGF‑β1 in the BALF and lung tissue were elevated by silica inhalation, however, they were not affected by either emodin or nicotinamide treatment. Additionally, emodin was found to increase the expression level of Sirt1, which decreased the level of deacetylated Smad3 to attenuate collagen deposition. Furthermore, the data suggested that there was direct binding between emodin and Sirt1. Sirt1‑regulated TGF‑β1/Smad signaling was involved in silica inhalation‑induced lung fibrosis. Emodin attenuated this lung fibrosis to improve pulmonary function by targeting Sirt1, which regulated TGF-β1/Smad fibrotic signaling.

Emodin suppresses silica-induced lung fibrosis by promoting Sirt1 signaling via direct contact

PubMed Central

Yang, Tian; Wang, Jinyuan; Pang, Yamei; Dang, Xiaomin; Ren, Hui; Liu, Ya; Chen, Mingwei; Shang, Dong

2016-01-01

Pulmonary silicosis is characterized by lung fibrosis, which leads to impairment of pulmonary function; the specific mechanism remains to be fully elucidated Emodin shows antifibrotic effects in several organs with fibrosis, however, it has not been investigated in pulmonary silicosis. In the present study, the possible mechanism of lung fibrosis and the antifibrotic effect of emodin in silica inhalation-induced lung fibrosis were investigated. Pulmonary silica particle inhalation was used to induce lung fibrosis in mice. Emodin and or the sirtuin 1 (Sirt1) inhibitor, nicotinamide, were used to treat the modeled animals. Pulmonary function was assessed using an occlusion method. The deposition of collagen I and α-smooth muscle actin (SMA) in the lung tissue were detected using fluorescence staining; transforming growth factor-β1 (TGF-β1) in the bronchoalveolar lavage fluid (BALF) was examined using an enzyme-linked immunosorbent assay; TGF-β1/Sirt1/small mothers against decapentaplegic (Smad) signaling activation in lung tissue was also examined. The molecular contacts between emodin were evaluated using liquid chromatography-mass spectrometry analysis. The deposition of collagen I and α-SMA in lung tissues were found to be elevated following silica exposure, however, this was relieved by emodin treatment. The pulmonary function of the animals was impaired by silica inhalation, and this was improved by emodin administration. However, the therapeutic effects of emodin on lung fibrosis were impaired by nicotinamide administration. The levels of TGF-β1 in the BALF and lung tissue were elevated by silica inhalation, however, they were not affected by either emodin or nicotinamide treatment. Additionally, emodin was found to increase the expression level of Sirt1, which decreased the level of deacetylated Smad3 to attenuate collagen deposition. Furthermore, the data suggested that there was direct binding between emodin and Sirt1. Sirt1-regulated TGF-β1/Smad signaling was involved in silica inhalation-induced lung fibrosis. Emodin attenuated this lung fibrosis to improve pulmonary function by targeting Sirt1, which regulated TGF-β1/Smad fibrotic signaling. PMID:27748907

Pulmonary inflammation-induced loss and subsequent recovery of skeletal muscle mass require functional poly-ubiquitin conjugation.

PubMed

Ceelen, Judith J M; Schols, Annemie M W J; Thielen, Nathalie G M; Haegens, Astrid; Gray, Douglas A; Kelders, Marco C J M; de Theije, Chiel C; Langen, Ramon C J

2018-05-02

Pulmonary inflammation in response to respiratory infections can evoke muscle wasting. Increased activity of the ubiquitin (Ub)-proteasome system (UPS) and the autophagy lysosome pathway (ALP) have been implicated in inflammation-induced muscle atrophy. Since poly-Ub conjugation is required for UPS-mediated proteolysis and has been implicated in the ALP, we assessed the effect of impaired ubiquitin conjugation on muscle atrophy and recovery following pulmonary inflammation, and compared activation and suppression of these proteolytic systems to protein synthesis regulation. Pulmonary inflammation was induced in mice by an intratracheal instillation of LPS. Proteolysis (UPS and ALP) and synthesis signaling were examined in gastrocnemius muscle homogenates. Ub-conjugation-dependency of muscle atrophy and recovery was addressed using Ub-K48R (K48R) mice with attenuated poly-ubiquitin conjugation, and compared to UBWT control mice. Pulmonary inflammation caused a decrease in skeletal muscle mass which was accompanied by a rapid increase in expression of UPS and ALP constituents and reduction in protein synthesis signaling acutely after LPS. Muscle atrophy was attenuated in K48R mice, while ALP and protein synthesis signaling were not affected. Muscle mass recovery starting 72 h post LPS, correlated with reduced expression of UPS and ALP constituents and restoration of protein synthesis signaling. K48R mice however displayed impaired recovery of muscle mass. Pulmonary inflammation-induced muscle atrophy is in part attributable to UPS-mediated proteolysis, as activation of ALP- and suppression of protein synthesis signaling occur independently of poly-Ub conjugation during muscle atrophy. Recovery of muscle mass following pulmonary inflammation involves inverse regulation of proteolysis and protein synthesis signaling, and requires a functional poly-Ub conjugation.

Dextromethorphan mediated bitter taste receptor activation in the pulmonary circuit causes vasoconstriction.

PubMed

Upadhyaya, Jasbir D; Singh, Nisha; Sikarwar, Anurag S; Chakraborty, Raja; Pydi, Sai P; Bhullar, Rajinder P; Dakshinamurti, Shyamala; Chelikani, Prashen

2014-01-01

Activation of bitter taste receptors (T2Rs) in human airway smooth muscle cells leads to muscle relaxation and bronchodilation. This finding led to our hypothesis that T2Rs are expressed in human pulmonary artery smooth muscle cells and might be involved in regulating the vascular tone. RT-PCR was performed to reveal the expression of T2Rs in human pulmonary artery smooth muscle cells. Of the 25 T2Rs, 21 were expressed in these cells. Functional characterization was done by calcium imaging after stimulating the cells with different bitter agonists. Increased calcium responses were observed with most of the agonists, the largest increase seen for dextromethorphan. Previously in site-directed mutational studies, we have characterized the response of T2R1 to dextromethorphan, therefore, T2R1 was selected for further analysis in this study. Knockdown with T2R1 specific shRNA decreased mRNA levels, protein levels and dextromethorphan-induced calcium responses in pulmonary artery smooth muscle cells by up to 50%. To analyze if T2Rs are involved in regulating the pulmonary vascular tone, ex vivo studies using pulmonary arterial and airway rings were pursued. Myographic studies using porcine pulmonary arterial and airway rings showed that stimulation with dextromethorphan led to contraction of the pulmonary arterial and relaxation of the airway rings. This study shows that dextromethorphan, acting through T2R1, causes vasoconstrictor responses in the pulmonary circuit and relaxation in the airways.

In Vitro Study of Flow Regulation for Pulmonary Insufficiency

PubMed Central

Camp, T. A.; Stewart, K. C.; Figliola, R. S.; McQuinn, T.

2007-01-01

Given the tolerance of the right heart circulation to mild regurgitation and gradient, we study the potential of using motionless devices to regulate the pulmonary circulation. In addition, we document the flow performance of two mechanical valves. A motionless diode, a nozzle, a mechanical bileaflet valve, and a tilting disk valve were tested in a pulmonary mock circulatory system over the normal human range of pulmonary vascular resistance (PVR). For the mechanical valves, regurgitant fractions (RFs) and transvalvular pressure gradients were found to be weak functions of PVR. On the low end of normal PVR, the bileaflet and tilting disk valves fluttered and would not fully close. Despite this anomaly, the regurgitant fraction of either valve did not change significantly. The values for RF and transvalvular gradient measured varied from 4 to 7% and 4 to 7 mm Hg, respectively, at 5 lpm for all tests. The diode valve was able to regulate flow with mild regurgitant fraction and trivial gradient but with values higher than either mechanical valve tested. Regurgitant fraction ranged from 2 to 17% in tests extending from PVR values of 1 to 4.5 mm Hg/lpm at 5 lpm and with concomitant increases in gradient up to 17 mm Hg. The regurgitant fraction for the nozzle increased from 2 to 23% over the range of PVR with gradients increasing to 18 mm Hg. The significant findings were: (1) the mechanical valves controlled regurgitation at normal physiological cardiac output and PVR even though they failed to close at some normal values of PVR and showed leaflet flutter; and (2) it may be possible to regulate the pulmonary circulation to tolerable levels using a motionless pulmonary valve device. PMID:17408334

Identification and Functional Characterization of Hypoxia-Induced Endoplasmic Reticulum Stress Regulating lncRNA (HypERlnc) in Pericytes.

PubMed

Bischoff, Florian C; Werner, Astrid; John, David; Boeckel, Jes-Niels; Melissari, Maria-Theodora; Grote, Phillip; Glaser, Simone F; Demolli, Shemsi; Uchida, Shizuka; Michalik, Katharina M; Meder, Benjamin; Katus, Hugo A; Haas, Jan; Chen, Wei; Pullamsetti, Soni S; Seeger, Werner; Zeiher, Andreas M; Dimmeler, Stefanie; Zehendner, Christoph M

2017-08-04

Pericytes are essential for vessel maturation and endothelial barrier function. Long noncoding RNAs regulate many cellular functions, but their role in pericyte biology remains unexplored. Here, we investigate the effect of hypoxia-induced endoplasmic reticulum stress regulating long noncoding RNAs (HypERlnc, also known as ENSG00000262454) on pericyte function in vitro and its regulation in human heart failure and idiopathic pulmonary arterial hypertension. RNA sequencing in human primary pericytes identified hypoxia-regulated long noncoding RNAs, including HypERlnc. Silencing of HypERlnc decreased cell viability and proliferation and resulted in pericyte dedifferentiation, which went along with increased endothelial permeability in cocultures consisting of human primary pericyte and human coronary microvascular endothelial cells. Consistently, Cas9-based transcriptional activation of HypERlnc was associated with increased expression of pericyte marker genes. Moreover, HypERlnc knockdown reduced endothelial-pericyte recruitment in Matrigel assays ( P <0.05). Mechanistically, transcription factor reporter arrays demonstrated that endoplasmic reticulum stress-related transcription factors were prominently activated by HypERlnc knockdown, which was confirmed via immunoblotting for the endoplasmic reticulum stress markers IRE1α ( P <0.001), ATF6 ( P <0.01), and soluble BiP ( P <0.001). Kyoto encyclopedia of genes and gene ontology pathway analyses of RNA sequencing experiments after HypERlnc knockdown indicate a role in cardiovascular disease states. Indeed, HypERlnc expression was significantly reduced in human cardiac tissue from patients with heart failure ( P <0.05; n=19) compared with controls. In addition, HypERlnc expression significantly correlated with pericyte markers in human lungs derived from patients diagnosed with idiopathic pulmonary arterial hypertension and from donor lungs (n=14). Here, we show that HypERlnc regulates human pericyte function and the endoplasmic reticulum stress response. In addition, RNA sequencing analyses in conjunction with reduced expression of HypERlnc in heart failure and correlation with pericyte markers in idiopathic pulmonary arterial hypertension indicate a role of HypERlnc in human cardiopulmonary disease. © 2017 American Heart Association, Inc.

High Altitude Pulmonary Hypertension: Role of K+ and Ca2+ Channels

PubMed Central

Remillard, Carmelle V.; Yuan, Jason X.-J.

2006-01-01

Global alveolar hypoxia, as experienced at high-altitude living, has a serious impact on vascular physiology, particular on the pulmonary vasculature. The effects of sustained hypoxia on pulmonary arteries include sustained vasoconstriction and enhanced medial hypertrophy. As the major component of the vascular media, pulmonary artery smooth muscle cells (PASMC) are the main effectors of the physiological response(s) induced during or following hypoxic exposure. Endothelial cells, on the other hand, can sense humoral and haemodynamic changes incurred by hypoxia, triggering their production of vasoactive and mitogenic factors that then alter PASMC function and growth. Transmembrane ion flux through channels in the plasma membrane not only modulates excitation-contraction coupling in PASMC, but also regulates cell volume, apoptosis, and proliferation. In this review, we examine the roles of K+ and Ca2+ channels in the pulmonary vasoconstriction and vascular remodeling observed during chronic hypoxia-induced pulmonary hypertension. PMID:16060848

Redox Signaling and Persistent Pulmonary Hypertension of the Newborn.

PubMed

Sharma, Megha; Afolayan, Adeleye J

2017-01-01

Reactive oxygen species (ROS) are redox-signaling molecules that are critically involved in regulating endothelial cell functions, host defense, aging, and cellular adaptation. Mitochondria are the major sources of ROS and important sources of redox signaling in pulmonary circulation. It is becoming increasingly evident that increased mitochondrial oxidative stress and aberrant signaling through redox-sensitive pathways play a direct causative role in the pathogenesis of many cardiopulmonary disorders including persistent pulmonary hypertension of the newborn (PPHN). This chapter highlights redox signaling in endothelial cells, antioxidant defense mechanism, cell responses to oxidative stress, and their contributions to disease pathogenesis.

Impairment of Immunoproteasome Function by Cigarette Smoke and in Chronic Obstructive Pulmonary Disease.

PubMed

Kammerl, Ilona E; Dann, Angela; Mossina, Alessandra; Brech, Dorothee; Lukas, Christina; Vosyka, Oliver; Nathan, Petra; Conlon, Thomas M; Wagner, Darcy E; Overkleeft, Hermen S; Prasse, Antje; Rosas, Ivan O; Straub, Tobias; Krauss-Etschmann, Susanne; Königshoff, Melanie; Preissler, Gerhard; Winter, Hauke; Lindner, Michael; Hatz, Rudolf; Behr, Jürgen; Heinzelmann, Katharina; Yildirim, Ali Ö; Noessner, Elfriede; Eickelberg, Oliver; Meiners, Silke

2016-06-01

Patients with chronic obstructive pulmonary disease (COPD) and in particular smokers are more susceptible to respiratory infections contributing to acute exacerbations of disease. The immunoproteasome is a specialized type of proteasome destined to improve major histocompatibility complex (MHC) class I-mediated antigen presentation for the resolution of intracellular infections. To characterize immunoproteasome function in COPD and its regulation by cigarette smoke. Immunoproteasome expression and activity were determined in bronchoalveolar lavage (BAL) and lungs of human donors and patients with COPD or idiopathic pulmonary fibrosis (IPF), as well as in cigarette smoke-exposed mice. Smoke-mediated alterations of immunoproteasome activity and MHC I surface expression were analyzed in human blood-derived macrophages. Immunoproteasome-specific MHC I antigen presentation was evaluated in spleen and lung immune cells that had been smoke-exposed in vitro or in vivo. Immunoproteasome and MHC I mRNA expression was reduced in BAL cells of patients with COPD and in isolated alveolar macrophages of patients with COPD or IPF. Exposure of immune cells to cigarette smoke extract in vitro reduced immunoproteasome activity and impaired immunoproteasome-specific MHC I antigen presentation. In vivo, acute cigarette smoke exposure dynamically regulated immunoproteasome function and MHC I antigen presentation in mouse BAL cells. End-stage COPD lungs showed markedly impaired immunoproteasome activities. We here show that the activity of the immunoproteasome is impaired by cigarette smoke resulting in reduced MHC I antigen presentation. Regulation of immunoproteasome function by cigarette smoke may thus alter adaptive immune responses and add to prolonged infections and exacerbations in COPD and IPF.

Deficiency of Akt1, but not Akt2, attenuates the development of pulmonary hypertension

PubMed Central

Tang, Haiyang; Chen, Jiwang; Fraidenburg, Dustin R.; Song, Shanshan; Sysol, Justin R.; Drennan, Abigail R.; Offermanns, Stefan; Ye, Richard D.; Bonini, Marcelo G.; Minshall, Richard D.; Garcia, Joe G. N.; Machado, Roberto F.; Makino, Ayako

2014-01-01

Pulmonary vascular remodeling, mainly attributable to enhanced pulmonary arterial smooth muscle cell proliferation and migration, is a major cause for elevated pulmonary vascular resistance and pulmonary arterial pressure in patients with pulmonary hypertension. The signaling cascade through Akt, comprised of three isoforms (Akt1–3) with distinct but overlapping functions, is involved in regulating cell proliferation and migration. This study aims to investigate whether the Akt/mammalian target of rapamycin (mTOR) pathway, and particularly which Akt isoform, contributes to the development and progression of pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension (HPH). Compared with the wild-type littermates, Akt1−/− mice were protected against the development and progression of chronic HPH, whereas Akt2−/− mice did not demonstrate any significant protection against the development of HPH. Furthermore, pulmonary vascular remodeling was significantly attenuated in the Akt1−/− mice, with no significant effect noted in the Akt2−/− mice after chronic exposure to normobaric hypoxia (10% O2). Overexpression of the upstream repressor of Akt signaling, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), and conditional and inducible knockout of mTOR in smooth muscle cells were also shown to attenuate the rise in right ventricular systolic pressure and the development of right ventricular hypertrophy. In conclusion, Akt isoforms appear to have a unique function within the pulmonary vasculature, with the Akt1 isoform having a dominant role in pulmonary vascular remodeling associated with HPH. The PTEN/Akt1/mTOR signaling pathway will continue to be a critical area of study in the pathogenesis of pulmonary hypertension, and specific Akt isoforms may help specify therapeutic targets for the treatment of pulmonary hypertension. PMID:25416384

Investigations of Pulmonary Epithelial Cell Damage due to Air-Liquid Interfacial Stresses in a Microgravity Environment

NASA Technical Reports Server (NTRS)

Gaver, Donald P., III; Bilek, A. M.; Kay, S.; Dee, K. C.

2004-01-01

Pulmonary airway closure is a potentially dangerous event that can occur in microgravity environments and may result in limited gas exchange for flight crew during long-term space flight. Repetitive airway collapse and reopening subjects the pulmonary epithelium to large, dynamic, and potentially injurious mechanical stresses. During ventilation at low lung volumes and pressures, airway instability leads to repetitive collapse and reopening. During reopening, air must progress through a collapsed airway, generating stresses on the airway walls, potentially damaging airway tissues. The normal lung can tolerate repetitive collapse and reopening. However, combined with insufficient or dysfunctional pulmonary surfactant, repetitive airway collapse and reopening produces severe lung injury. Particularly at risk is the pulmonary epithelium. As an important regulator of lung function and physiology, the degree of pulmonary epithelial damage influences the course and outcome of lung injury. In this paper we present experimental and computational studies to explore the hypothesis that the mechanical stresses associated with airway reopening inflict injury to the pulmonary epithelium.

Rejuvenating cellular respiration for optimizing respiratory function: targeting mitochondria.

PubMed

Agrawal, Anurag; Mabalirajan, Ulaganathan

2016-01-15

Altered bioenergetics with increased mitochondrial reactive oxygen species production and degradation of epithelial function are key aspects of pathogenesis in asthma and chronic obstructive pulmonary disease (COPD). This motif is not unique to obstructive airway disease, reported in related airway diseases such as bronchopulmonary dysplasia and parenchymal diseases such as pulmonary fibrosis. Similarly, mitochondrial dysfunction in vascular endothelium or skeletal muscles contributes to the development of pulmonary hypertension and systemic manifestations of lung disease. In experimental models of COPD or asthma, the use of mitochondria-targeted antioxidants, such as MitoQ, has substantially improved mitochondrial health and restored respiratory function. Modulation of noncoding RNA or protein regulators of mitochondrial biogenesis, dynamics, or degradation has been found to be effective in models of fibrosis, emphysema, asthma, and pulmonary hypertension. Transfer of healthy mitochondria to epithelial cells has been associated with remarkable therapeutic efficacy in models of acute lung injury and asthma. Together, these form a 3R model--repair, reprogramming, and replacement--for mitochondria-targeted therapies in lung disease. This review highlights the key role of mitochondrial function in lung health and disease, with a focus on asthma and COPD, and provides an overview of mitochondria-targeted strategies for rejuvenating cellular respiration and optimizing respiratory function in lung diseases. Copyright © 2016 the American Physiological Society.

AMD3100 treatment attenuates pulmonary angiogenesis by reducing the c-kit (+) cells and its pro-angiogenic activity in CBDL rat lungs.

PubMed

Shen, Cheng-Cheng; Chen, Bing; Gu, Jian-Teng; Ning, Jiao-Lin; Zeng, Jing; Yi, Bin; Lu, Kai-Zhi

2018-03-01

Recent studies have shown that pulmonary angiogenesis is an important pathological process in the development of hepatopulmonary syndrome (HPS), and growing evidence has indicated that Stromal cell-derived factor 1/C-X-C chemokine receptor type 4 (SDF-1/CXCR4) axis is involved in pulmonary vascular disease by mediating the accumulation of c-kit+ cells. This study aimed to test the effect of AMD3100, an antagonist of CXCR4, in HPS pulmonary angiogenesis. Common bile duct ligation (CBDL) rats were used as experimental HPS model and were treated with AMD3100 (1.25mg/kg/day, i.p.) or 0.9% saline for 3weeks. The sham rats underwent common bile duct exposure without ligation. The c-kit+ cells accounts and its angiogenic-related functions, prosurvival signals, pulmonary angiogenesis and arterial oxygenation were analysed in these groups. Our results showed that pulmonary SDF-1/CXCR4, Akt, Erk and VEGF/VEGFR2 were significantly activated in CBDL rats, and the numbers of circulating and pulmonary c-kit+ cells were increased in CBDL rats compared with control rats. Additionally, the angiogenic-related functions of c-kit+ cells and pulmonary microvessel counts were also elevated in CBDL rats. CXCR4 inhibition reduced pulmonary c-kit+ cells and microvessel counts and improved arterial oxygenation within 3weeks in CBDL rats. The pulmonary prosurvival signals and pro-angiogenic activity of c-kit+ cells were also down-regulated in AMD3100-treated rats. In conclusion, AMD3100 treatment attenuated pulmonary angiogenesis in CBDL rats and prevented the development of HPS via reductions in pulmonary c-kit+ cells and inhibition of the prosurvival signals. Our study provides new insights in HPS treatment. Copyright © 2017. Published by Elsevier B.V.

16S rDNA analysis of the effect of fecal microbiota transplantation on pulmonary and intestinal flora.

PubMed

Liu, Tianhao; Yang, Zhongshan; Zhang, Xiaomei; Han, Niping; Yuan, Jiali; Cheng, Yu

2017-12-01

This study aims to explore the effect of FMT on regulations of dysbacteriosis of pulmonary and intestinal flora in rats with 16S rDNA sequencing technology. A total of 27 SPF rats (3-4 weeks old) were randomly divided into three groups: normal control group (K), model control group (MX), and fecal microbiota transplantation group (FMT); each group contained nine rats. The OTU values of the pulmonary and intestinal flora of the MX group decreased significantly compared with the normal control group. After FMT, the OTU value of pulmonary flora increased, while the value of OTU in intestinal flora declined. At the phylum level, FMT down-regulated Proteobacteria , Firmicutes , and Bacteroidetes in the pulmonary flora. At the genus level, FMT down-regulated Pseudomonas , Sphingobium , Lactobacillus , Rhizobium , and Acinetobacter , thus maintaining the balance of the pulmonary flora. Moreover, FMT could change the structure and diversity of the pulmonary and intestinal flora by positively regulating the pulmonary flora and negatively regulating intestinal flora. This study may provide a scientific basis for FMT treatment of respiratory diseases.

Imbalance of caveolin-1 and eNOS expression in the pulmonary vasculature of experimental diaphragmatic hernia.

PubMed

Hofmann, Alejandro; Gosemann, Jan-Hendrik; Takahashi, Toshiaki; Friedmacher, Florian; Duess, Johannes W; Puri, Prem

2014-08-01

Caveolin-1 (Cav-1) exerts major regulatory functions on intracellular signaling pathways originating at the plasma membrane. Cav-1 is a key regulator in adverse lung remodeling and the development of pulmonary hypertension (PH) regulating vasomotor tone through its ability to reduce nitric oxide (NO) production. This low-output endothelial NO synthase (eNOS) derived NO maintains normal pulmonary vascular homeostasis. Cav-1 deficiency leads to increased bioavailability of NO, which has been linked to increased nitrosative stress. Inhibition of eNOS reduced oxidant production and reversed PH, supporting the concept that Cav-1 regulation of eNOS activity is crucial to endothelial homeostasis in lungs. We designed this study to investigate the hypothesis that expression of Cav-1 is downregulated while eNOS expression is upregulated by the pulmonary endothelium in the nitrofen-induced congenital diaphragmatic hernia (CDH). Pregnant rats were exposed to nitrofen or vehicle on day 9.5 (D9.5). Fetuses were sacrificed on D21 and divided into nitrofen and control groups. Quantitative real-time polymerase chain reaction, Western blotting, and confocal immunofluorescence were performed to determine pulmonary gene expression levels and protein expression of Cav-1 and eNOS. Pulmonary Cav-1 gene expression levels were significantly decreased, while eNOS gene expression was significantly increased in nitrofen-induced CDH(+). Western blotting and confocal microscopy revealed decreased pulmonary Cav-1 protein expression, while eNOS protein expression was increased in CDH(+) compared to controls. The striking evidence of markedly decreased gene and protein expression of Cav-1 with concurrently increased eNOS gene and protein expression in the pulmonary vasculature suggests that activation of eNOS secondary to Cav-1 deficiency may play an important role in the pathogenesis of PH in the nitrofen-induced CDH. © 2014 Wiley Periodicals, Inc.

Dysregulated expression of microRNAs and mRNAs in pulmonary artery remodeling in ascites syndrome in broiler chickens

PubMed Central

Zhuang, Yu; Xiao, Qingyang; Cao, Huabin; Zhang, Caiying; Wang, Tiancheng; Lin, Huayuan; Guo, Xiaoquan; Hu, Guoliang

2017-01-01

Ascites syndrome (AS), also known as pulmonary artery hypertension, remains a challenging disease that severely affects both humans and broiler chickens. Pulmonary artery remodeling presents a key step in the development of AS. In this study, we obtained pulmonary artery tissues from broilers with and without AS to perform miRNA sequencing analysis, miRNA-mRNA association analysis and pathological examinations. 29 significantly differentially expressed miRNAs were found both in known and novel miRNAs with 18 up-regulated and 11 down-regulated miRNAs. Their predicted potential targets were involved in a wide range of functional clusters as indicated via GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analyses. The upregulation of miR-155, miR-23b-3p, miR-146b-5p and miR-146b-3p were found closely associated with the pathogenesis of pulmonary artery remodeling in AS progression. The association analysis for the miRNAs-mRNAs showed that these 29 significantly differentially expressed miRNAs regulate 162 differentially expressed target genes. Among them, 20 miRNAs correlated with 18 predicted target genes that appear to be involved in pulmonary artery remodeling, mainly in three broad physiological processes: the hypoxia sensing response (HIF1a, NHE1, STAT5 and STAT3), endothelial permeability dysfunction (CD44, TRAF2, CDK2AP1, LZTFL1, JAZF1, PEBP1, LRP1B, RPS14 and THBS2) and inflammation (MEOX2, STAT5, STAT3, IRF8, MAP3K8, IL-1BETA and TNFRSF1B). Pathological pulmonary artery remodeling in the AS broilers was consistently observed in the present study. Taken together, the current analysis further illuminates the molecular mechanism of pulmonary artery remodeling underlying AS progression. PMID:27791988

Hydrogen-rich saline inhibits tobacco smoke-induced chronic obstructive pulmonary disease by alleviating airway inflammation and mucus hypersecretion in rats.

PubMed

Liu, Zibing; Geng, Wenye; Jiang, Chuanwei; Zhao, Shujun; Liu, Yong; Zhang, Ying; Qin, Shucun; Li, Chenxu; Zhang, Xinfang; Si, Yanhong

2017-09-01

Chronic obstructive pulmonary disease induced by tobacco smoke has been regarded as a great health problem worldwide. The purpose of this study is to evaluate the protective effect of hydrogen-rich saline, a novel antioxidant, on chronic obstructive pulmonary disease and explore the underlying mechanism. Sprague-Dawley rats were made chronic obstructive pulmonary disease models via tobacco smoke exposure for 12 weeks and the rats were treated with 10 ml/kg hydrogen-rich saline intraperitoneally during the last 4 weeks. Lung function testing indicated hydrogen-rich saline decreased lung airway resistance and increased lung compliance and the ratio of forced expiratory volume in 0.1 s/forced vital capacity in chronic obstructive pulmonary disease rats. Histological analysis revealed that hydrogen-rich saline alleviated morphological impairments of lung in tobacco smoke-induced chronic obstructive pulmonary disease rats. ELISA assay showed hydrogen-rich saline lowered the levels of pro-inflammatory cytokines (IL-8 and IL-6) and anti-inflammatory cytokine IL-10 in bronchoalveolar lavage fluid and serum of chronic obstructive pulmonary disease rats. The content of malondialdehyde in lung tissue and serum was also determined and the data indicated hydrogen-rich saline suppressed oxidative stress reaction. The protein expressions of mucin MUC5C and aquaporin 5 involved in mucus hypersecretion were analyzed by Western blot and ELISA and the data revealed that hydrogen-rich saline down-regulated MUC5AC level in bronchoalveolar lavage fluid and lung tissue and up-regulated aquaporin 5 level in lung tissue of chronic obstructive pulmonary disease rats. In conclusion, these results suggest that administration of hydrogen-rich saline exhibits significant protective effect on chronic obstructive pulmonary disease through alleviating inflammation, reducing oxidative stress and lessening mucus hypersecretion in tobacco smoke-induced chronic obstructive pulmonary disease rats. Impact statement This study was designed to evaluate protective effect of hydrogen-rich saline, a novel antioxidant, on tobacco smoke (TS)-induced chronic obstructive pulmonary disease (COPD) in rats and explore the underlying mechanism. Our results suggest that administration of hydrogen-rich saline improves lung function and alleviates morphological impairments of lung through alleviating inflammation, reducing oxidative stress and lessening mucus hypersecretion in TS-induced COPD rats.

Guards at the gate: physiological and pathological roles of tissue-resident innate lymphoid cells in the lung.

PubMed

Cheng, Hang; Jin, Chengyan; Wu, Jing; Zhu, Shan; Liu, Yong-Jun; Chen, Jingtao

2017-12-01

The lung is an important open organ and the primary site of respiration. Many life-threatening diseases develop in the lung, e.g., pneumonia, asthma, chronic obstructive pulmonary diseases (COPDs), pulmonary fibrosis, and lung cancer. In the lung, innate immunity serves as the frontline in both anti-irritant response and anti-tumor defense and is also critical for mucosal homeostasis; thus, it plays an important role in containing these pulmonary diseases. Innate lymphoid cells (ILCs), characterized by their strict tissue residence and distinct function in the mucosa, are attracting increased attention in innate immunity. Upon sensing the danger signals from damaged epithelium, ILCs activate, proliferate, and release numerous cytokines with specific local functions; they also participate in mucosal immune-surveillance, immune-regulation, and homeostasis. However, when their functions become uncontrolled, ILCs can enhance pathological states and induce diseases. In this review, we discuss the physiological and pathological functions of ILC subsets 1 to 3 in the lung, and how the pathogenic environment affects the function and plasticity of ILCs.

Receptor for advanced glycation endproducts (RAGE) maintains pulmonary structure and regulates the response to cigarette smoke.

PubMed

Wolf, Lisa; Herr, Christian; Niederstraßer, Julia; Beisswenger, Christoph; Bals, Robert

2017-01-01

The receptor for advanced glycation endproducts (RAGE) is highly expressed in the lung but its physiological functions in this organ is still not completely understood. To determine the contribution of RAGE to physiological functions of the lung, we analyzed pulmonary mechanics and structure of wildtype and RAGE deficient (RAGE-/-) mice. RAGE deficiency spontaneously resulted in a loss of lung structure shown by an increased mean chord length, increased respiratory system compliance, decreased respiratory system elastance and increased concentrations of serum protein albumin in bronchoalveolar lavage fluids. Pulmonary expression of RAGE was mainly localized on alveolar epithelial cells and alveolar macrophages. Primary murine alveolar epithelial cells isolated from RAGE-/- mice revealed an altered differentiation and defective barrier formation under in vitro conditions. Stimulation of interferone-y (IFNy)-activated alveolar macrophages deficient for RAGE with Toll-like receptor (TLR) ligands resulted in significantly decreased release of proinflammatory cytokines and chemokines. Exposure to chronic cigarette smoke did not affect emphysema-like changes in lung parenchyma in RAGE-/- mice. Acute cigarette smoke exposure revealed a modified inflammatory response in RAGE-/- mice that was characterized by an influx of macrophages and a decreased keratinocyte-derived chemokine (KC) release. Our data suggest that RAGE regulates the differentiation of alveolar epithelial cells and impacts on the development and maintenance of pulmonary structure. In cigarette smoke-induced lung pathology, RAGE mediates inflammation that contributes to lung damage.

The Role of Mitochondrial DNA in Mediating Alveolar Epithelial Cell Apoptosis and Pulmonary Fibrosis

PubMed Central

Kim, Seok-Jo; Cheresh, Paul; Jablonski, Renea P.; Williams, David B.; Kamp, David W.

2015-01-01

Convincing evidence has emerged demonstrating that impairment of mitochondrial function is critically important in regulating alveolar epithelial cell (AEC) programmed cell death (apoptosis) that may contribute to aging-related lung diseases, such as idiopathic pulmonary fibrosis (IPF) and asbestosis (pulmonary fibrosis following asbestos exposure). The mammalian mitochondrial DNA (mtDNA) encodes for 13 proteins, including several essential for oxidative phosphorylation. We review the evidence implicating that oxidative stress-induced mtDNA damage promotes AEC apoptosis and pulmonary fibrosis. We focus on the emerging role for AEC mtDNA damage repair by 8-oxoguanine DNA glycosylase (OGG1) and mitochondrial aconitase (ACO-2) in maintaining mtDNA integrity which is important in preventing AEC apoptosis and asbestos-induced pulmonary fibrosis in a murine model. We then review recent studies linking the sirtuin (SIRT) family members, especially SIRT3, to mitochondrial integrity and mtDNA damage repair and aging. We present a conceptual model of how SIRTs modulate reactive oxygen species (ROS)-driven mitochondrial metabolism that may be important for their tumor suppressor function. The emerging insights into the pathobiology underlying AEC mtDNA damage and apoptosis is suggesting novel therapeutic targets that may prove useful for the management of age-related diseases, including pulmonary fibrosis and lung cancer. PMID:26370974

Early Growth Response-1 Plays an Important Role in Ischemia-Reperfusion Injury in Lung Transplants by Regulating Polymorphonuclear Neutrophil Infiltration.

PubMed

Yamamoto, Sumiharu; Yamane, Masaomi; Yoshida, Osamu; Waki, Naohisa; Okazaki, Mikio; Matsukawa, Akihiro; Oto, Takahiro; Miyoshi, Shinichiro

2015-11-01

Early growth response-1 (Egr-1) has been shown to be a trigger-switch transcription factor that is involved in lung ischemia-reperfusion injury (IRI). Mouse lung transplants were performed in wild-type (WT) C57BL/6 and Egr1-knockout (KO) mice in the following donor → recipient combinations: WT → WT, KO → WT, WT → KO, and KO → KO to determine whether the presence of Egr-1 in the donor or recipient is the most critical factor for IRI. Pulmonary grafts were retrieved after 18 hours of ischemia after 4 hours of reperfusion. We analyzed graft function by analyzing arterial blood gas and histology in each combination and assessed the effects of Egr1 depletion on inflammatory cytokines that are regulated by Egr-1 as well on polymorphonuclear neutrophil (PMN) infiltration. Deletion of Egr1 improved pulmonary graft function in the following order of donor → recipient combinations: WT → WT < WT → KO < KO → WT < KO → KO. Polymerase chain reaction assays for Il1B, Il6, Mcp1, Mip2, Icam1, and Cox2 showed significantly lower expression levels in the KO → KO group than in the other groups. Immunohistochemistry demonstrated clear Egr-1 expression in the nuclei of pulmonary artery endothelial cells and PMN cytoplasm in the WT grafts. Flow cytometry analysis showed that Egr1 deletion reduced PMN infiltration and that the extent of reduction correlated with graft function. Both graft and recipient Egr-1 played a role in lung IRI, but the graft side contributed more to this phenomenon through regulation of PMN infiltration. Donor Egr-1 expression in pulmonary artery endothelial cells may play an important role in PMN infiltration, which results in IRI after lung transplantation.

Pulmonary stromal cells induce the generation of regulatory DC attenuating T-cell-mediated lung inflammation.

PubMed

Li, Qian; Guo, Zhenhong; Xu, Xiongfei; Xia, Sheng; Cao, Xuetao

2008-10-01

The tissue microenvironment may affect the development and function of immune cells such as DC. Whether and how the pulmonary stromal microenvironment can affect the development and function of lung DC need to be investigated. Regulatory DC (DCreg) can regulate T-cell response. We wondered whether such regulatory DC exist in the lung and what is the effect of the pulmonary stromal microenvironment on the generation of DCreg. Here we demonstrate that murine pulmonary stromal cells can drive immature DC, which are regarded as being widely distributed in the lung, to proliferate and differentiate into a distinct subset of DCreg, which express high levels of CD11b but low levels of MHC class II (I-A), CD11c, secrete high amounts of IL-10, NO and prostaglandin E2 (PGE2) and suppress T-cell proliferation. The natural counterpart of DCreg in the lung with similar phenotype and regulatory function has been identified. Pulmonary stroma-derived TGF-beta is responsible for the differentiation of immature DC to DCreg, and DCreg-derived PGE2 contributes to their suppression of T-cell proliferation. Moreover, DCreg can induce the generation of CD4+CD25+Foxp3+ Treg. Importantly, infusion with DCreg attenuates T-cell-mediated eosinophilic airway inflammation in vivo. Therefore, the pulmonary microenvironment may drive the generation of DCreg, thus contributing to the maintenance of immune homoeostasis and the control of inflammation in the lung.

Heterozygous Null Bone Morphogenetic Protein Receptor Type 2 Mutations Promote SRC Kinase-dependent Caveolar Trafficking Defects and Endothelial Dysfunction in Pulmonary Arterial Hypertension*

PubMed Central

Prewitt, Allison R.; Ghose, Sampa; Frump, Andrea L.; Datta, Arumima; Austin, Eric D.; Kenworthy, Anne K.; de Caestecker, Mark P.

2015-01-01

Hereditary pulmonary arterial hypertension (HPAH) is a rare, fatal disease of the pulmonary vasculature. The majority of HPAH patients inherit mutations in the bone morphogenetic protein type 2 receptor gene (BMPR2), but how these promote pulmonary vascular disease is unclear. HPAH patients have features of pulmonary endothelial cell (PEC) dysfunction including increased vascular permeability and perivascular inflammation associated with decreased PEC barrier function. Recently, frameshift mutations in the caveolar structural protein gene Caveolin-1 (CAV-1) were identified in two patients with non-BMPR2-associated HPAH. Because caveolae regulate endothelial function and vascular permeability, we hypothesized that defects in caveolar function might be a common mechanism by which BMPR2 mutations promote pulmonary vascular disease. To explore this, we isolated PECs from mice carrying heterozygous null Bmpr2 mutations (Bmpr2+/−) similar to those found in the majority of HPAH patients. We show that Bmpr2+/− PECs have increased numbers and intracellular localization of caveolae and caveolar structural proteins CAV-1 and Cavin-1 and that these defects are reversed after blocking endocytosis with dynasore. SRC kinase is also constitutively activated in Bmpr2+/− PECs, and localization of CAV-1 to the plasma membrane is restored after treating Bmpr2+/− PECs with the SRC kinase inhibitor 3-(4-chlorophenyl)-1-(1,1-dimethylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (PP2). Late outgrowth endothelial progenitor cells isolated from HPAH patients show similar increased activation of SRC kinase. Moreover, Bmpr2+/− PECs have impaired endothelial barrier function, and barrier function is restored after treatment with PP2. These data suggest that heterozygous null BMPR2 mutations promote SRC-dependent caveolar trafficking defects in PECs and that this may contribute to pulmonary endothelial barrier dysfunction in HPAH patients. PMID:25411245

Pulmonary Hypertension in Wild Type Mice and Animals with Genetic Deficit in KCa2.3 and KCa3.1 Channels

PubMed Central

Sadda, Veeranjaneyulu; Nielsen, Gorm; Hedegaard, Elise Røge; Mogensen, Susie; Köhler, Ralf; Simonsen, Ulf

2014-01-01

Objective In vascular biology, endothelial KCa2.3 and KCa3.1 channels contribute to arterial blood pressure regulation by producing membrane hyperpolarization and smooth muscle relaxation. The role of KCa2.3 and KCa3.1 channels in the pulmonary circulation is not fully established. Using mice with genetically encoded deficit of KCa2.3 and KCa3.1 channels, this study investigated the effect of loss of the channels in hypoxia-induced pulmonary hypertension. Approach and Result Male wild type and KCa3.1−/−/KCa2.3T/T(+DOX) mice were exposed to chronic hypoxia for four weeks to induce pulmonary hypertension. The degree of pulmonary hypertension was evaluated by right ventricular pressure and assessment of right ventricular hypertrophy. Segments of pulmonary arteries were mounted in a wire myograph for functional studies and morphometric studies were performed on lung sections. Chronic hypoxia induced pulmonary hypertension, right ventricular hypertrophy, increased lung weight, and increased hematocrit levels in either genotype. The KCa3.1−/−/KCa2.3T/T(+DOX) mice developed structural alterations in the heart with increased right ventricular wall thickness as well as in pulmonary vessels with increased lumen size in partially- and fully-muscularized vessels and decreased wall area, not seen in wild type mice. Exposure to chronic hypoxia up-regulated the gene expression of the KCa2.3 channel by twofold in wild type mice and increased by 2.5-fold the relaxation evoked by the KCa2.3 and KCa3.1 channel activator NS309, whereas the acetylcholine-induced relaxation - sensitive to the combination of KCa2.3 and KCa3.1 channel blockers, apamin and charybdotoxin - was reduced by 2.5-fold in chronic hypoxic mice of either genotype. Conclusion Despite the deficits of the KCa2.3 and KCa3.1 channels failed to change hypoxia-induced pulmonary hypertension, the up-regulation of KCa2.3-gene expression and increased NS309-induced relaxation in wild-type mice point to a novel mechanism to counteract pulmonary hypertension and to a potential therapeutic utility of KCa2.3/KCa3.1 activators for the treatment of pulmonary hypertension. PMID:24858807

Regulation of the pulmonary circulation

PubMed Central

Lee, G. de J.

1971-01-01

Factors regulating pressure and flow in the lungs are reviewed with particular emphasis on their role in regulating blood flow velocity and distribution within the lung capillaries. The behaviour of the pulmonary arterial, system, alveolar capillaries, and pulmonary venous system are considered individually. The effect of heart disease on lung capillary blood flow is examined. PMID:4929437

MicroRNA-124 Controls the Proliferative, Migratory, and Inflammatory Phenotype of Pulmonary Vascular Fibroblasts

PubMed Central

Wang, Daren; Zhang, Zhang; Li, Min; Frid, Maria G.; Flockton, Amanda R.; McKeon, B. Alexandre; Yeager, Michael E.; Fini, Mehdi A.; Morrell, Nicholas W.; Pullamsetti, Soni S.; Velegala, Sivareddy; Seeger, Werner; McKinsey, Timothy A.; Sucharov, Carmen C.; Stenmark, Kurt R.

2014-01-01

Rationale Pulmonary hypertensive remodeling is characterized by excessive proliferation, migration, and proinflammatory activation of adventitial fibroblasts. In culture, fibroblasts maintain a similar activated phenotype. The mechanisms responsible for generation/maintenance of this phenotype remain unknown. Objective We hypothesized that aberrant expression of microRNA-124 (miR-124) regulates this activated fibroblast phenotype and sought to determine the signaling pathways through which miR-124 exerts effects. Methods and Results We detected significant decreases in miR-124 expression in fibroblasts isolated from calves and humans with severe pulmonary hypertension. Overexpression of miR-124 by mimic transfection significantly attenuated proliferation, migration, and monocyte chemotactic protein-1 expression of hypertensive fibroblasts, whereas anti–miR-124 treatment of control fibroblasts resulted in their increased proliferation, migration, and monocyte chemotactic protein-1 expression. Furthermore, the alternative splicing factor, polypyrimidine tract–binding protein 1, was shown to be a direct target of miR-124 and to be upregulated both in vivo and in vitro in bovine and human pulmonary hypertensive fibroblasts. The effects of miR-124 on fibroblast proliferation were mediated via direct binding to the 3′ untranslated region of polypyrimidine tract–binding protein 1 and subsequent regulation of Notch1/phosphatase and tensin homolog/FOXO3/p21Cip1 and p27Kip1 signaling. We showed that miR-124 directly regulates monocyte chemotactic protein-1 expression in pulmonary hypertension/idiopathic pulmonary arterial hypertension fibroblasts. Furthermore, we demonstrated that miR-124 expression is suppressed by histone deacetylases and that treatment of hypertensive fibroblasts with histone deacetylase inhibitors increased miR-124 expression and decreased proliferation and monocyte chemotactic protein-1 production. Conclusions Stable decreases in miR-124 expression contribute to an epigenetically reprogrammed, highly proliferative, migratory, and inflammatory phenotype of hypertensive pulmonary adventitial fibroblasts. Thus, therapies directed at restoring miR-124 function, including histone deacetylase inhibitors, should be investigated. PMID:24122720

Matrix Remodeling in Pulmonary Fibrosis and Emphysema

PubMed Central

O’Reilly, Philip; Antony, Veena B.; Gaggar, Amit

2016-01-01

Pulmonary fibrosis and emphysema are chronic lung diseases characterized by a progressive decline in lung function, resulting in significant morbidity and mortality. A hallmark of these diseases is recurrent or persistent alveolar epithelial injury, typically caused by common environmental exposures such as cigarette smoke. We propose that critical determinants of the outcome of the injury-repair processes that result in fibrosis versus emphysema are mesenchymal cell fate and associated extracellular matrix dynamics. In this review, we explore the concept that regulation of mesenchymal cells under the influence of soluble factors, in particular transforming growth factor-β1, and the extracellular matrix determine the divergent tissue remodeling responses seen in pulmonary fibrosis and emphysema. PMID:26741177

Inhibition of nuclear factor of activated T cells (NFAT) c3 activation attenuates acute lung injury and pulmonary edema in murine models of sepsis

PubMed Central

Karpurapu, Manjula; Lee, Yong Gyu; Qian, Ziqing; Wen, Jin; Ballinger, Megan N.; Rusu, Luiza; Chung, Sangwoon; Deng, Jing; Qian, Feng; Reader, Brenda F.; Nirujogi, Teja Srinivas; Park, Gye Young; Pei, Dehua; Christman, John W.

2018-01-01

Specific therapies targeting cellular and molecular events of sepsis induced Acute Lung Injury (ALI) pathogenesis are lacking. We have reported a pivotal role for Nuclear Factors of Activated T cells (NFATc3) in regulating macrophage phenotype during sepsis induced ALI and subsequent studies demonstrate that NFATc3 transcriptionally regulates macrophage CCR2 and TNFα gene expression. Mouse pulmonary microvascular endothelial cell monolayer maintained a tighter barrier function when co-cultured with LPS stimulated NFATc3 deficient macrophages whereas wild type macrophages caused leaky monolayer barrier. More importantly, NFATc3 deficient mice showed decreased neutrophilic lung inflammation, improved alveolar capillary barrier function, arterial oxygen saturation and survival benefit in lethal CLP sepsis mouse models. In addition, survival of wild type mice subjected to the lethal CLP sepsis was not improved with broad-spectrum antibiotics, whereas the survival of NFATc3 deficient mice was improved to 40–60% when treated with imipenem. Passive adoptive transfer of NFATc3 deficient macrophages conferred protection against LPS induced ALI in wild type mice. Furthermore, CP9-ZIZIT, a highly potent, cell-permeable peptide inhibitor of Calcineurin inhibited NFATc3 activation. CP9-ZIZIT effectively reduced sepsis induced inflammatory cytokines and pulmonary edema in mice. Thus, this study demonstrates that inhibition of NFATc3 activation by CP9-ZIZIT provides a potential therapeutic option for attenuating sepsis induced ALI/pulmonary edema. PMID:29535830

miR-34a Inhibits Lung Fibrosis by Inducing Lung Fibroblast Senescence.

PubMed

Cui, Huachun; Ge, Jing; Xie, Na; Banerjee, Sami; Zhou, Yong; Antony, Veena B; Thannickal, Victor J; Liu, Gang

2017-02-01

Cellular senescence has been implicated in diverse pathologies. However, there is conflicting evidence regarding the role of this process in tissue fibrosis. Although dysregulation of microRNAs is a key mechanism in the pathogenesis of lung fibrosis, it is unclear whether microRNAs function by regulating cellular senescence in the disease. In this study, we found that miR-34a demonstrated greater expression in the lungs of patients with idiopathic pulmonary fibrosis and in mice with experimental pulmonary fibrosis, with its primary localization in lung fibroblasts. More importantly, miR-34a was up-regulated significantly in both human and mouse lung myofibroblasts. We found that mice with miR-34a ablation developed more severe pulmonary fibrosis than did wild-type animals after fibrotic lung injury. Mechanistically, we found that miR-34a induced a senescent phenotype in lung fibroblasts because this microRNA increased senescence-associated β-galactosidase activity, enhanced expression of senescence markers, and decreased cell proliferative capacities. Consistently, we found that primary lung fibroblasts from fibrotic lungs of miR-34a-deficient mice had a diminished senescent phenotype and enhanced resistance to apoptosis as compared with those from wild-type animals. We also identified multiple miR-34a targets that likely mediated its activities in inducing senescence in lung fibroblasts. In conclusion, our data suggest that miR-34a functions through a negative feedback mechanism to restrain fibrotic response in the lungs by promoting senescence of pulmonary fibroblasts.

Hfe Deficiency Impairs Pulmonary Neutrophil Recruitment in Response to Inflammation

PubMed Central

Benesova, Karolina; Vujić Spasić, Maja; Schaefer, Sebastian M.; Stolte, Jens; Baehr-Ivacevic, Tomi; Waldow, Katharina; Zhou, Zhe; Klingmueller, Ursula; Benes, Vladimir; Mall, Marcus A.; Muckenthaler, Martina U.

2012-01-01

Regulation of iron homeostasis and the inflammatory response are tightly linked to protect the host from infection. Here we investigate how imbalanced systemic iron homeostasis in a murine disease model of hereditary hemochromatosis (Hfe−/− mice) affects the inflammatory responses of the lung. We induced acute pulmonary inflammation in Hfe−/− and wild-type mice by intratracheal instillation of 20 µg of lipopolysaccharide (LPS) and analyzed local and systemic inflammatory responses and iron-related parameters. We show that in Hfe−/− mice neutrophil recruitment to the bronchoalveolar space is attenuated compared to wild-type mice although circulating neutrophil numbers in the bloodstream were elevated to similar levels in Hfe−/− and wild-type mice. The underlying molecular mechanisms are likely multifactorial and include elevated systemic iron levels, alveolar macrophage iron deficiency and/or hitherto unexplored functions of Hfe in resident pulmonary cell types. As a consequence, pulmonary cytokine expression is out of balance and neutrophils fail to be recruited efficiently to the bronchoalveolar compartment, a process required to protect the host from infections. In conclusion, our findings suggest a novel role for Hfe and/or imbalanced iron homeostasis in the regulation of the inflammatory response in the lung and hereditary hemochromatosis. PMID:22745741

Astaxanthin prevents pulmonary fibrosis by promoting myofibroblast apoptosis dependent on Drp1-mediated mitochondrial fission

PubMed Central

Zhang, Jinjin; Xu, Pan; Wang, Youlei; Wang, Meirong; Li, Hongbo; Lin, Shengcui; Mao, Cuiping; Wang, Bingsi; Song, Xiaodong; Lv, Changjun

2015-01-01

Promotion of myofibroblast apoptosis is a potential therapeutic strategy for pulmonary fibrosis. This study investigated the antifibrotic effect of astaxanthin on the promotion of myofibroblast apoptosis based on dynamin-related protein-1 (Drp1)-mediated mitochondrial fission in vivo and in vitro. Results showed that astaxanthin can inhibit lung parenchymal distortion and collagen deposition, as well as promote myofibroblast apoptosis. Astaxanthin demonstrated pro-apoptotic function in myofibroblasts by contributing to mitochondrial fission, thereby leading to apoptosis by increasing the Drp1 expression and enhancing Drp1 translocation into the mitochondria. Two specific siRNAs were used to demonstrate that Drp1 is necessary to promote astaxanthin-induced mitochondrial fission and apoptosis in myofibroblasts. Drp1-associated genes, such as Bcl-2-associated X protein, cytochrome c, tumour suppressor gene p53 and p53-up-regulated modulator of apoptosis, were highly up-regulated in the astaxanthin group compared with those in the sham group. This study revealed that astaxanthin can prevent pulmonary fibrosis by promoting myofibroblast apoptosis through a Drp1-dependent molecular pathway. Furthermore, astaxanthin provides a potential therapeutic value in pulmonary fibrosis treatment. PMID:26119034

MicroRNA-27b plays a role in pulmonary arterial hypertension by modulating peroxisome proliferator-activated receptor γ dependent Hsp90-eNOS signaling and nitric oxide production

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bi, Rui; Bao, Chunrong; Jiang, Lianyong

Pulmonary artery endothelial dysfunction is associated with pulmonary arterial hypertension (PAH). Based on recent studies showing that microRNA (miR)-27b is aberrantly expressed in PAH, we hypothesized that miR-27b may contribute to pulmonary endothelial dysfunction and vascular remodeling in PAH. The effect of miR-27b on pulmonary endothelial dysfunction and the underlying mechanism were investigated in human pulmonary artery endothelial cells (HPAECs) in vitro and in a monocrotaline (MCT)-induced model of PAH in vivo. miR-27b expression was upregulated in MCT-induced PAH and inversely correlated with the levels of peroxisome proliferator-activated receptor (PPAR)-γ, and miR-27b inhibition attenuated MCT-induced endothelial dysfunction and remodeling and prevented PAHmore » associated right ventricular hypertrophy and systolic pressure in rats. PPARγ was confirmed as a direct target of miR-27b in HPAECs and shown to mediate the effect of miR-27b on the disruption of endothelial nitric oxide synthase (eNOS) coupling to Hsp90 and the suppression of NO production associated with the PAH phenotype. We showed that miR-27b plays a role endothelial function and NO release and elucidated a potential mechanism by which miR-27b regulates Hsp90-eNOS and NO signaling by modulating PPARγ expression, providing potential therapeutic targets for the treatment of PAH. - Highlights: • miR-27b plays a role in endothelial function and NO release. • miR-27b inhibition ameliorates MCT-induced endothelial dysfunction and PAH. • miR-27b targets PPARγ in HPAECs. • miR-27b regulates PPARγ dependent Hsp90-eNOS and NO signaling.« less

SH2 domain-containing protein tyrosine phosphatase 2 and focal adhesion kinase protein interactions regulate pulmonary endothelium barrier function.

PubMed

Chichger, Havovi; Braza, Julie; Duong, Huetran; Harrington, Elizabeth O

2015-06-01

Enhanced protein tyrosine phosphorylation is associated with changes in vascular permeability through formation and dissolution of adherens junctions and regulation of stress fiber formation. Inhibition of the protein tyrosine phosphorylase SH2 domain-containing protein tyrosine phosphatase 2 (SHP2) increases tyrosine phosphorylation of vascular endothelial cadherin and β-catenin, resulting in disruption of the endothelial monolayer and edema formation in the pulmonary endothelium. Vascular permeability is a hallmark of acute lung injury (ALI); thus, enhanced SHP2 activity offers potential therapeutic value for the pulmonary vasculature in diseases such as ALI, but this has not been characterized. To assess whether SHP2 activity mediates protection against edema in the endothelium, we assessed the effect of molecular activation of SHP2 on lung endothelial barrier function in response to the edemagenic agents LPS and thrombin. Both LPS and thrombin reduced SHP2 activity, correlated with decreased focal adhesion kinase (FAK) phosphorylation (Y(397) and Y(925)) and diminished SHP2 protein-protein associations with FAK. Overexpression of constitutively active SHP2 (SHP2(D61A)) enhanced baseline endothelial monolayer resistance and completely blocked LPS- and thrombin-induced permeability in vitro and significantly blunted pulmonary edema formation induced by either endotoxin (LPS) or Pseudomonas aeruginosa exposure in vivo. Chemical inhibition of FAK decreased SHP2 protein-protein interactions with FAK concomitant with increased permeability; however, overexpression of SHP2(D61A) rescued the endothelium and maintained FAK activity and FAK-SHP2 protein interactions. Our data suggest that SHP2 activation offers the pulmonary endothelium protection against barrier permeability mediators downstream of the FAK signaling pathway. We postulate that further studies into the promotion of SHP2 activation in the pulmonary endothelium may offer a therapeutic approach for patients suffering from ALI.

MicroRNA-138 and MicroRNA-25 Down-regulate Mitochondrial Calcium Uniporter, Causing the Pulmonary Arterial Hypertension Cancer Phenotype

PubMed Central

Hong, Zhigang; Chen, Kuang-Hueih; DasGupta, Asish; Potus, Francois; Dunham-Snary, Kimberly; Bonnet, Sebastien; Tian, Lian; Fu, Jennifer; Breuils-Bonnet, Sandra; Provencher, Steeve; Wu, Danchen; Mewburn, Jeffrey; Ormiston, Mark L.

2017-01-01

Rationale: Pulmonary arterial hypertension (PAH) is an obstructive vasculopathy characterized by excessive pulmonary artery smooth muscle cell (PASMC) proliferation, migration, and apoptosis resistance. This cancer-like phenotype is promoted by increased cytosolic calcium ([Ca2+]cyto), aerobic glycolysis, and mitochondrial fission. Objectives: To determine how changes in mitochondrial calcium uniporter (MCU) complex (MCUC) function influence mitochondrial dynamics and contribute to PAH’s cancer-like phenotype. Methods: PASMCs were isolated from patients with PAH and healthy control subjects and assessed for expression of MCUC subunits. Manipulation of the pore-forming subunit, MCU, in PASMCs was achieved through small interfering RNA knockdown or MCU plasmid-mediated up-regulation, as well as through modulation of the upstream microRNAs (miRs) miR-138 and miR-25. In vivo, nebulized anti-miRs were administered to rats with monocrotaline-induced PAH. Measurements and Main Results: Impaired MCUC function, resulting from down-regulation of MCU and up-regulation of an inhibitory subunit, mitochondrial calcium uptake protein 1, is central to PAH’s pathogenesis. MCUC dysfunction decreases intramitochondrial calcium ([Ca2+]mito), inhibiting pyruvate dehydrogenase activity and glucose oxidation, while increasing [Ca2+]cyto, promoting proliferation, migration, and fission. In PAH PASMCs, increasing MCU decreases cell migration, proliferation, and apoptosis resistance by lowering [Ca2+]cyto, raising [Ca2+]mito, and inhibiting fission. In normal PASMCs, MCUC inhibition recapitulates the PAH phenotype. In PAH, elevated miRs (notably miR-138) down-regulate MCU directly and also by decreasing MCU’s transcriptional regulator cAMP response element–binding protein 1. Nebulized anti-miRs against miR-25 and miR-138 restore MCU expression, reduce cell proliferation, and regress established PAH in the monocrotaline model. Conclusions: These results highlight miR-mediated MCUC dysfunction as a unifying mechanism in PAH that can be therapeutically targeted. PMID:27648837

PPARδ agonist GW501516 inhibits PDGF-stimulated pulmonary arterial smooth muscle cell function related to pathological vascular remodeling.

PubMed

Liu, Guangjie; Li, Xuan; Li, Yan; Tang, Xin; Xu, Jie; Li, Ran; Hao, Peng; Sun, Yongchang

2013-01-01

Pulmonary arterial hypertension (PAH) is a severe and progressive disease, a key feature of which is pulmonary vascular remodeling. Growth factors, cytokines, and lipid mediators are involved in this remodeling process. Recent reports suggest that the peroxisome proliferator-activated receptors (PPARs) play important roles in the regulation of cell growth and differentiation as well as tissue wounding and repair. In this study, we examined the role of PPAR δ in the regulation of proliferation, migration, collagen synthesis, and chemokine production in human pulmonary arterial smooth muscle cells (HPASMCs). The data showed that PPAR δ was the most abundant isoform in HPASMCs. PPAR δ was upregulated in HPASMCs treated with PDGF, which is the major mediator in pulmonary vascular remodeling. Activation of PPAR δ by GW501516, a specific PPAR δ ligand, significantly inhibited PDGF-induced proliferation in HPASMCs. The inhibitory effect of GW501516 on HPASMCs was associated with decreased expression of cyclin D1, cyclin D3, CDK2, and CDK4 as well as increased expression of the cell cycle inhibitory genes G0S2 and P27(kip1). Pretreatment of HPASMCs with GW501516 significantly inhibited PDGF-induced cell migration and collagen synthesis. GW501516 also significantly attenuated TNF-mediated expression of MCP-1. These results suggest that PPAR δ may be a potential therapeutic target against the progression of vascular remodeling in PAH.

PPARδ Agonist GW501516 Inhibits PDGF-Stimulated Pulmonary Arterial Smooth Muscle Cell Function Related to Pathological Vascular Remodeling

PubMed Central

Liu, Guangjie; Li, Xuan; Li, Yan; Tang, Xin; Xu, Jie; Li, Ran; Hao, Peng; Sun, Yongchang

2013-01-01

Pulmonary arterial hypertension (PAH) is a severe and progressive disease, a key feature of which is pulmonary vascular remodeling. Growth factors, cytokines, and lipid mediators are involved in this remodeling process. Recent reports suggest that the peroxisome proliferator-activated receptors (PPARs) play important roles in the regulation of cell growth and differentiation as well as tissue wounding and repair. In this study, we examined the role of PPARδ in the regulation of proliferation, migration, collagen synthesis, and chemokine production in human pulmonary arterial smooth muscle cells (HPASMCs). The data showed that PPARδ was the most abundant isoform in HPASMCs. PPARδ was upregulated in HPASMCs treated with PDGF, which is the major mediator in pulmonary vascular remodeling. Activation of PPARδ by GW501516, a specific PPARδ ligand, significantly inhibited PDGF-induced proliferation in HPASMCs. The inhibitory effect of GW501516 on HPASMCs was associated with decreased expression of cyclin D1, cyclin D3, CDK2, and CDK4 as well as increased expression of the cell cycle inhibitory genes G0S2 and P27kip1. Pretreatment of HPASMCs with GW501516 significantly inhibited PDGF-induced cell migration and collagen synthesis. GW501516 also significantly attenuated TNF-mediated expression of MCP-1. These results suggest that PPARδ may be a potential therapeutic target against the progression of vascular remodeling in PAH. PMID:23607100

circHIPK2-mediated σ-1R promotes endoplasmic reticulum stress in human pulmonary fibroblasts exposed to silica.

PubMed

Cao, Zhouli; Xiao, Qingling; Dai, Xiaoniu; Zhou, Zewei; Jiang, Rong; Cheng, Yusi; Yang, Xiyue; Guo, Huifang; Wang, Jing; Xi, Zhaoqing; Yao, Honghong; Chao, Jie

2017-12-13

Silicosis is characterized by fibroblast accumulation and excessive deposition of extracellular matrix. Although the roles of SiO 2 -induced chemokines and cytokines released from alveolar macrophages have received significant attention, the direct effects of SiO 2 on protein production and functional changes in pulmonary fibroblasts have been less extensively studied. Sigma-1 receptor, which has been associated with cell proliferation and migration in the central nervous system, is expressed in the lung, but its role in silicosis remains unknown. To elucidate the role of sigma-1 receptor in fibrosis induced by silica, both the upstream molecular mechanisms and the functional effects on cell proliferation and migration were investigated. Both molecular biological assays and pharmacological techniques, combined with functional experiments, such as migration and proliferation, were applied in human pulmonary fibroblasts from adults to analyze the molecular and functional changes induced by SiO 2 . SiO 2 induced endoplasmic reticulum stress in association with enhanced expression of sigma-1 receptor. Endoplasmic reticulum stress promoted migration and proliferation of human pulmonary fibroblasts-adult exposed to SiO 2 , inducing the development of silicosis. Inhibition of sigma-1 receptor ameliorated endoplasmic reticulum stress and fibroblast functional changes induced by SiO 2 . circHIPK2 is involved in the regulation of sigma-1 receptor in human pulmonary fibroblasts-adult exposed to SiO 2 . Our study elucidated a link between SiO 2 -induced fibrosis and sigma-1 receptor signaling, thereby providing novel insight into the potential use of sigma-1 receptor/endoplasmic reticulum stress in the development of novel therapeutic strategies for silicosis treatment.

Mitochondrial iron chelation ameliorates cigarette-smoke induced bronchitis and emphysema in mice

PubMed Central

Cloonan, Suzanne M.; Glass, Kimberly; Laucho-Contreras, Maria E.; Bhashyam, Abhiram R.; Cervo, Morgan; Pabón, Maria A.; Konrad, Csaba; Polverino, Francesca; Siempos, Ilias I.; Perez, Elizabeth; Mizumura, Kenji; Ghosh, Manik C.; Parameswaran, Harikrishnan; Williams, Niamh C.; Rooney, Kristen T.; Chen, Zhi-Hua; Goldklang, Monica P.; Yuan, Guo-Cheng; Moore, Stephen C.; Demeo, Dawn L.; Rouault, Tracey A.; D’Armiento, Jeanine M.; Schon, Eric A.; Manfredi, Giovanni; Quackenbush, John; Mahmood, Ashfaq; Silverman, Edwin K.; Owen, Caroline A.; Choi, Augustine M.K.

2015-01-01

Chronic obstructive pulmonary disease (COPD) is linked to both cigarette smoking and genetic determinants. We have previously identified iron-responsive element binding protein 2 (IRP2) as an important COPD susceptibility gene, with IRP2 protein increased in the lungs of individuals with COPD. Here we demonstrate that mice deficient in Irp2 were protected from cigarette smoke (CS)-induced experimental COPD. By integrating RIP-Seq, RNA-Seq, gene expression and functional enrichment clustering analysis, we identified IRP2 as a regulator of mitochondrial function in the lung. IRP2 increased mitochondrial iron loading and cytochrome c oxidase (COX), which led to mitochondrial dysfunction and subsequent experimental COPD. Frataxin-deficient mice with higher mitochondrial iron loading had impaired airway mucociliary clearance (MCC) and higher pulmonary inflammation at baseline, whereas synthesis of cytochrome c oxidase (Sco2)-deficient mice with reduced COX were protected from CS-induced pulmonary inflammation and impairment of MCC. Mice treated with a mitochondrial iron chelator or mice fed a low-iron diet were protected from CS-induced COPD. Mitochondrial iron chelation also alleviated CS-impairment of MCC, CS-induced pulmonary inflammation and CS-associated lung injury in mice with established COPD, suggesting a critical functional role and potential therapeutic intervention for the mitochondrial-iron axis in COPD. PMID:26752519

SRC-mediated EGF Receptor Activation Regulates Ozone-induced Interleukin 8 Expression in Human Bronchial Epithelial Cells

EPA Science Inventory

BACKGROUND: Human exposure to ozone (03) results in pulmonary function decrements and airway inflammation. The mechanisms underlying these adverse effects remain unclear. Epidermal growth factor receptor (EGFR) plays an important role in the pathogenesis of lung inflammation. ...

Role for phospholipid acyl chains and cholesterol in pulmonary infections and inflammation

PubMed Central

Shaikh, Saame Raza; Fessler, Michael B.

2016-01-01

Bacterial and viral respiratory tract infections result in millions of deaths worldwide and are currently the leading cause of death from infection. Acute inflammation is an essential element of host defense against infection, but can be damaging to the host when left unchecked. Effective host defense requires multiple lipid mediators, which collectively have proinflammatory and/or proresolving effects on the lung. During pulmonary infections, phospholipid acyl chains and cholesterol can be chemically and enzymatically oxidized, as well as truncated and modified, producing complex mixtures of bioactive lipids. We review recent evidence that phospholipids and cholesterol and their derivatives regulate pulmonary innate and adaptive immunity during infection. We first highlight data that oxidized phospholipids generated in the lung during infection stimulate pattern recognition receptors, such as TLRs and scavenger receptors, thereby amplifying the pulmonary inflammatory response. Next, we discuss evidence that oxidation of endogenous pools of cholesterol during pulmonary infections produces oxysterols that also modify the function of both innate and adaptive immune cells. Last, we conclude with data that n-3 polyunsaturated fatty acids, both in the form of phospholipid acyl chains and through enzymatic processing into endogenous proresolving lipid mediators, aid in the resolution of lung inflammation through distinct mechanisms. Unraveling the complex mechanisms of induction and function of distinct classes of bioactive lipids, both native and modified, may hold promise for developing new therapeutic strategies for improving pulmonary outcomes in response to infection. PMID:27286794

Astaxanthin prevents pulmonary fibrosis by promoting myofibroblast apoptosis dependent on Drp1-mediated mitochondrial fission.

PubMed

Zhang, Jinjin; Xu, Pan; Wang, Youlei; Wang, Meirong; Li, Hongbo; Lin, Shengcui; Mao, Cuiping; Wang, Bingsi; Song, Xiaodong; Lv, Changjun

2015-09-01

Promotion of myofibroblast apoptosis is a potential therapeutic strategy for pulmonary fibrosis. This study investigated the antifibrotic effect of astaxanthin on the promotion of myofibroblast apoptosis based on dynamin-related protein-1 (Drp1)-mediated mitochondrial fission in vivo and in vitro. Results showed that astaxanthin can inhibit lung parenchymal distortion and collagen deposition, as well as promote myofibroblast apoptosis. Astaxanthin demonstrated pro-apoptotic function in myofibroblasts by contributing to mitochondrial fission, thereby leading to apoptosis by increasing the Drp1 expression and enhancing Drp1 translocation into the mitochondria. Two specific siRNAs were used to demonstrate that Drp1 is necessary to promote astaxanthin-induced mitochondrial fission and apoptosis in myofibroblasts. Drp1-associated genes, such as Bcl-2-associated X protein, cytochrome c, tumour suppressor gene p53 and p53-up-regulated modulator of apoptosis, were highly up-regulated in the astaxanthin group compared with those in the sham group. This study revealed that astaxanthin can prevent pulmonary fibrosis by promoting myofibroblast apoptosis through a Drp1-dependent molecular pathway. Furthermore, astaxanthin provides a potential therapeutic value in pulmonary fibrosis treatment. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

PPAR-γ Regulates Carnitine Homeostasis and Mitochondrial Function in a Lamb Model of Increased Pulmonary Blood Flow

PubMed Central

Rafikov, Ruslan; Kumar, Sanjiv; Hou, Yali; Oishi, Peter E.; Datar, Sanjeev A.; Raff, Gary; Fineman, Jeffrey R.; Black, Stephen M.

2012-01-01

Objective Carnitine homeostasis is disrupted in lambs with endothelial dysfunction secondary to increased pulmonary blood flow (Shunt). Our recent studies have also indicated that the disruption in carnitine homeostasis correlates with a decrease in PPAR-γ expression in Shunt lambs. Thus, this study was carried out to determine if there is a causal link between loss of PPAR-γ signaling and carnitine dysfunction, and whether the PPAR-γ agonist, rosiglitazone preserves carnitine homeostasis in Shunt lambs. Methods and Results siRNA-mediated PPAR-γ knockdown significantly reduced carnitine palmitoyltransferases 1 and 2 (CPT1 and 2) and carnitine acetyltransferase (CrAT) protein levels. This decrease in carnitine regulatory proteins resulted in a disruption in carnitine homeostasis and induced mitochondrial dysfunction, as determined by a reduction in cellular ATP levels. In turn, the decrease in cellular ATP attenuated NO signaling through a reduction in eNOS/Hsp90 interactions and enhanced eNOS uncoupling. In vivo, rosiglitazone treatment preserved carnitine homeostasis and attenuated the development of mitochondrial dysfunction in Shunt lambs maintaining ATP levels. This in turn preserved eNOS/Hsp90 interactions and NO signaling. Conclusion Our study indicates that PPAR-γ signaling plays an important role in maintaining mitochondrial function through the regulation of carnitine homeostasis both in vitro and in vivo. Further, it identifies a new mechanism by which PPAR-γ regulates NO signaling through Hsp90. Thus, PPAR-γ agonists may have therapeutic potential in preventing the endothelial dysfunction in children with increased pulmonary blood flow. PMID:22962578

Impaired pulmonary function after treatment for tuberculosis: the end of the disease?

PubMed Central

Chushkin, Mikhail Ivanovich; Ots, Oleg Nikolayevich

2017-01-01

ABSTRACT Objective: To evaluate the prevalence of pulmonary function abnormalities and to investigate the factors affecting lung function in patients treated for pulmonary tuberculosis. Methods: A total of 214 consecutive patients (132 men and 82 women; 20-82 years of age), treated for pulmonary tuberculosis and followed at a local dispensary, underwent spirometry and plethysmography at least one year after treatment. Results: Pulmonary impairment was present in 102 (47.7%) of the 214 patients evaluated. The most common functional alteration was obstructive lung disease (seen in 34.6%). Of the 214 patients, 60 (28.0%) showed reduced pulmonary function (FEV1 below the lower limit of normal). Risk factors for reduced pulmonary function were having had culture-positive pulmonary tuberculosis in the past, being over 50 years of age, having recurrent tuberculosis, and having a lower level of education. Conclusions: Nearly half of all tuberculosis patients evolve to impaired pulmonary function. That underscores the need for pulmonary function testing after the end of treatment. PMID:28380187

Genetic variation in the functional ENG allele inherited from the non-affected parent associates with presence of pulmonary arteriovenous malformation in hereditary hemorrhagic telangiectasia 1 (HHT1) and may influence expression of PTPN14.

PubMed

Letteboer, Tom G W; Benzinou, Michael; Merrick, Christopher B; Quigley, David A; Zhau, Kechen; Kim, Il-Jin; To, Minh D; Jablons, David M; van Amstel, Johannes K P; Westermann, Cornelius J J; Giraud, Sophie; Dupuis-Girod, Sophie; Lesca, Gaetan; Berg, Jonathan H; Balmain, Allan; Akhurst, Rosemary J

2015-01-01

HHT shows clinical variability within and between families. Organ site and prevalence of arteriovenous malformations (AVMs) depend on the HHT causative gene and on environmental and genetic modifiers. We tested whether variation in the functional ENG allele, inherited from the unaffected parent, alters risk for pulmonary AVM in HHT1 mutation carriers who are ENG haploinsufficient. Genetic association was found between rs10987746 of the wild type ENG allele and presence of pulmonary AVM [relative risk = 1.3 (1.0018-1.7424)]. The rs10987746-C at-risk allele associated with lower expression of ENG RNA in a panel of human lymphoblastoid cell lines (P = 0.004). Moreover, in angiogenically active human lung adenocarcinoma tissue, but not in uninvolved quiescent lung, rs10987746-C was correlated with expression of PTPN14 (P = 0.004), another modifier of HHT. Quantitative TAQMAN expression analysis in a panel of normal lung tissues from 69 genetically heterogeneous inter-specific backcross mice, demonstrated strong correlation between expression levels of Eng, Acvrl1, and Ptpn14 (r2 = 0.75-0.9, P < 1 × 10(-12)), further suggesting a direct or indirect interaction between these three genes in lung in vivo. Our data indicate that genetic variation within the single functional ENG gene influences quantitative and/or qualitative differences in ENG expression that contribute to risk of pulmonary AVM in HHT1, and provide correlative support for PTPN14 involvement in endoglin/ALK1 lung biology in vivo. PTPN14 has been shown to be a negative regulator of Yap/Taz signaling, which is implicated in mechanotransduction, providing a possible molecular link between endoglin/ALK1 signaling and mechanical stress. EMILIN2, which showed suggestive genetic association with pulmonary AVM, is also reported to interact with Taz in angiogenesis. Elucidation of the molecular mechanisms regulating these interactions in endothelial cells may ultimately provide more rational choices for HHT therapy.

Activation of Nrf2 Attenuates Pulmonary Vascular Remodeling via Inhibiting Endothelial-to-Mesenchymal Transition: an Insight from a Plant Polyphenol

PubMed Central

Chen, Yucai; Yuan, Tianyi; Zhang, Huifang; Yan, Yu; Wang, Danshu; Fang, Lianhua; Lu, Yang; Du, Guanhua

2017-01-01

The endothelial-to-mesenchymal transition (EndMT) has been demonstrated to be involved in pulmonary vascular remodeling. It is partly attributed to oxidative and inflammatory stresses in endothelial cells. In current study, we conducted a series of experiments to clarify the effect of salvianolic acid A (SAA), a kind of polyphenol compound, in the process of EndMT in human pulmonary arterial endothelial cells and in vivo therapeutic efficacy on vascular remodeling in monocrotaline (MCT)-induced EndMT. EndMT was induced by TGFβ1 in human pulmonary arterial endothelial cells (HPAECs). SAA significantly attenuated EndMT, simultaneously inhibited cell migration and reactive oxygen species (ROS) formation. In MCT-induced pulmonary arterial hypertension (PAH) model, SAA improved vascular function, decreased TGFβ1 level and inhibited inflammation. Mechanistically, SAA stimulated Nrf2 translocation and subsequent heme oxygenase-1 (HO-1) up-regulation. The effect of SAA on EndMT in vitro was abolished by ZnPP, a HO-1 inhibitor. In conclusion, this study indicates a deleterious impact of oxidative stress on EndMT. Polyphenol antioxidant treatment may provide an adjunctive action to alleviate pulmonary vascular remodeling via inhibiting EndMT. PMID:28924387

Microhemorrhage is an Early Event in the Pulmonary Fibrotic Disease of PECAM-1 Deficient FVB/n Mice

PubMed Central

Young, Lena C.; Woods, Steven J.; Groshong, Steven D.; Basaraba, Randall J.; Gilchrist, John M.; Higgins, David M.; Gonzalez-Juarrero, Mercedes; Bass, Todd A.; Muller, William A.; Schenkel, Alan R.

2014-01-01

Platelet Endothelial Cell Adhesion Molecule 1 (PECAM-1) deficient mice in the FVB/n strain exhibit fatal chronic pulmonary fibrotic disease. The illness occurs in the absence of a detectable pro-inflammatory event. PECAM-1 is vital to the stability of vascular permeability, leukocyte extravasation, clotting of platelets, and clearance of apoptotic cells. We show here that the spontaneous development of fibrotic disease in PECAM-1 deficient FVB/n mice is characterized by early loss of vascular integrity in pulmonary capillaries, resulting in spontaneous microbleeds. Hemosiderin-positive macrophages were found in interstitial spaces and bronchoalveolar lavage (BAL) fluid in relatively healthy animals. We also observed a gradually increasing presence of hemosiderin-positive macrophages and fibrin deposition in the advanced stages of disease, corresponding to the accumulation of collagen, IL-10 expression, and myofibroblasts expressing alpha smooth muscle actin (SMA). Together with the growing evidence that pulmonary microbleeds and coagulation play an active part in human pulmonary fibrosis, this data further supports our hypothesis that PECAM-1 expression is necessary for vascular barrier function control and regulation of homeostasis specifically, in the pulmonary environment. PMID:24972347

Tuberculin-Specific T Cells Are Reduced in Active Pulmonary Tuberculosis Compared to LTBI or Status Post BCG Vaccination

PubMed Central

Streitz, Mathias; Fuhrmann, Stephan; Powell, Fiona; Quassem, Ali; Nomura, Laurel; Maecker, Holden; Martus, Peter; Volk, Hans-Dieter

2011-01-01

Functional characteristics of tuberculosis (TB)–specific CD4 T cells were studied in clinically active pulmonary TB (n = 21) and high TB exposure including LTBI (n = 17). Following tuberculin stimulation, activated CD4 T cells were identified by flow-cytometry (CD154 up-regulation, degranulation, interferon γ [IFN-γ], tumor necrosis factor α [TNF-α], and interleukin 2 [IL-2\\ production). Interestingly, CD154 up-regulation accounted for ∼80% of activated CD4 T cells in the active TB group but just 40% in the controls, whereas IFN-γ accounted for only ∼50% of activated cells in each group. The frequencies of CD4 T cells displaying at least 1 activation marker discriminated better between the groups than those displaying degranulation or IFN-γ production alone. PMID:21186260

Intrauterine growth restriction decreases nuclear factor-kappa B signaling in fetal pulmonary artery endothelial cells of fetal sheep.

PubMed

Dodson, R Blair; Powers, Kyle N; Gien, Jason; Rozance, Paul J; Seedorf, Gregory J; Astling, David; Jones, Kenneth Lloyd; Crombleholme, Timothy M; Abman, Steven H; Alvira, Cristina M

2018-05-03

Intrauterine growth restriction (IUGR) in premature newborns increases the risk for bronchopulmonary dysplasia (BPD), a chronic lung disease characterized by disrupted pulmonary angiogenesis and alveolarization. We previously showed that experimental IUGR impairs angiogenesis, however, mechanisms that impair pulmonary artery endothelial cell (PAEC) function are uncertain. The nuclear factor-kappa-B (NFκB) pathway promotes vascular growth in the developing mouse lung, and we hypothesized that IUGR disrupts NFκB-regulated pro-angiogenic targets in fetal PAEC. PAECs were isolated from lungs of control fetal sheep and sheep with experimental IUGR from an established model of chronic placental insufficiency. Microarray analysis identified suppression of NFκB signaling and significant alterations in extracellular matrix (ECM) pathways in IUGR PAEC, including decreases in collagen 4α1 and laminin α4, components of the basement membrane and putative NFκB targets. In comparison with controls: (i) immunostaining of active NFκB complexes; (ii) NFκB-DNA binding; (iii) baseline expression of NFκB subunits, p65 and p50; and (iv) LPS-mediated inducible activation of NFκB signaling were decreased in IUGR PAEC. Although pharmacologic NFκB inhibition did not affect angiogenic function in IUGR PAEC, angiogenic function of control PAEC was reduced to a similar degree as that observed in IUGR PAEC. These data identify reductions in endothelial NFκB signaling as central to the disrupted angiogenesis observed in IUGR, likely by impairing both intrinsic PAEC angiogenic function and NFκB-mediated regulation of ECM components necessary for vascular development. These data further suggest that strategies that preserve endothelial NFκB activation may be useful in lung diseases marked by disrupted angiogenesis such as IUGR.

Control of vascular smooth muscle function by Src-family kinases and reactive oxygen species in health and disease

PubMed Central

MacKay, Charles E; Knock, Greg A

2015-01-01

Abstract Reactive oxygen species (ROS) are now recognised as second messenger molecules that regulate cellular function by reversibly oxidising specific amino acid residues of key target proteins. Amongst these are the Src-family kinases (SrcFKs), a multi-functional group of non-receptor tyrosine kinases highly expressed in vascular smooth muscle (VSM). In this review we examine the evidence supporting a role for ROS-induced SrcFK activity in normal VSM contractile function and in vascular remodelling in cardiovascular disease. VSM contractile responses to G-protein-coupled receptor stimulation, as well as hypoxia in pulmonary artery, are shown to be dependent on both ROS and SrcFK activity. Specific phosphorylation targets are identified amongst those that alter intracellular Ca2+ concentration, including transient receptor potential channels, voltage-gated Ca2+ channels and various types of K+ channels, as well as amongst those that regulate actin cytoskeleton dynamics and myosin phosphatase activity, including focal adhesion kinase, protein tyrosine kinase-2, Janus kinase, other focal adhesion-associated proteins, and Rho guanine nucleotide exchange factors. We also examine a growing weight of evidence in favour of a key role for SrcFKs in multiple pro-proliferative and anti-apoptotic signalling pathways relating to oxidative stress and vascular remodelling, with a particular focus on pulmonary hypertension, including growth-factor receptor transactivation and downstream signalling, hypoxia-inducible factors, positive feedback between SrcFK and STAT3 signalling and positive feedback between SrcFK and NADPH oxidase dependent ROS production. We also discuss evidence for and against the potential therapeutic targeting of SrcFKs in the treatment of pulmonary hypertension. PMID:25384773

Aldosterone mediates metastatic spread of renal cancer via the G protein-coupled estrogen receptor (GPER).

PubMed

Feldman, Ross D; Ding, Qingming; Hussain, Yasin; Limbird, Lee E; Pickering, J Geoffrey; Gros, Robert

2016-06-01

Although aldosterone is a known regulator of renal and cardiovascular function, its role as a regulator of cancer growth and spread has not been widely considered. This study tested the hypothesis that aldosterone regulates cancer cell growth/spread via G protein-coupled estrogen receptor (GPER) activation. In vitro in murine renal cortical adenocarcinoma (RENCA) cells, a widely used murine in vitro model for the study of renal cell adenocarcinoma, aldosterone increased RENCA cell proliferation to a maximum of 125 ± 3% of control at a concentration of 10 nM, an effect blocked by the GPER antagonist G15 or by GPER knockdown using short interfering (sh) RNA techniques. Further, aldosterone increased RENCA cell migration to a maximum of 170 ± 20% of control at a concentration of 100 nM, an effect also blocked by G15 or by GPER down-regulation. In vivo, after orthotopic RENCA cell renal transplantation, pulmonary tumor spread was inhibited by pharmacologic blockade of aldosterone effects with spironolactone (percentage of lung occupied by metastasis: control = 68 ± 13, spironolactone = 26 ± 8, P < 0.05) or inhibition of aldosterone synthesis with a high dietary salt diet (percentage of lung: control = 44 ± 6, high salt = 12 ± 3, P < 0.05), without reducing primary tumor size. Additionally, adrenalectomy significantly reduced the extent of pulmonary tumor spread, whereas aldosterone infusion recovered pulmonary metastatic spread toward baseline levels. Finally, inhibition of GPER either with the GPER antagonist G15 or by GPER knockdown comparably inhibited RENCA cell pulmonary metastatic cancer spread. Taken together, these findings provide strong evidence for aldosterone serving a causal role in renal cell cancer regulation via its GPER receptor; thus, antagonism of GPER represents a potential new target for treatment to reduce metastatic spread.-Feldman, R. D., Ding, Q., Hussain, Y., Limbird, L. E., Pickering, J. G., Gros, R. Aldosterone mediates metastatic spread of renal cancer via the G protein-coupled estrogen receptor (GPER). © FASEB.

Maternal exposure to fine particulate air pollution induces epithelial-to-mesenchymal transition resulting in postnatal pulmonary dysfunction mediated by transforming growth factor-β/Smad3 signaling.

PubMed

Tang, Wenting; Du, Lili; Sun, Wen; Yu, Zhiqiang; He, Fang; Chen, Jingsi; Li, Xiaomei; Li, Xiuying; Yu, Lin; Chen, Dunjin

2017-02-05

Fine particles from air pollution, also called particulate matter, less than 2.5 micrometers in diameter (PM2.5), are a threat to child health. Epidemiological investigations have related maternal exposure to PM2.5 to postnatal respiratory symptoms, such as frequent wheezing, chronic cough, and lung function decrements. However, only few experimental animal studies have been performed to study the effects of PM2.5.The aim of this study was to investigate the effects of maternal exposure to PM2.5 on postnatal pulmonary dysfunction in a rat model and to examine the mechanism of PM2.5-induced morphological pulmonary changes.Timed pregnant Sprague-Dawley rats were treated with PM2.5 (0.1, 0.5, 2.5, or 7.5mg/kg) once every three days from day 0 to 18 of pregnancy. After delivery, pups were sacrificed on postnatal day (PND)1 and 28. The effects of transforming growth factor-beta (TGF-β) on epithelial-mesenchymal transition (EMT) were determined by immunohistochemistry, Western blotting, and quantitative RT-PCR. The offspring underwent pulmonary function measurements on PND28, lung tissues were histopathologically examined, and markers of oxidative stress were measured. Maternally PM2.5-exposed offspring pups displayed significant decreases in lung volume parameters, compliance, and airflow during expiration on PND28. The PM2.5-exposed group showed interstitial proliferation in lung histology, significant oxidative stress in lungs, and up-regulation of TGF-β-induced EMT via increased vimentin and α-smooth muscle actin and decreased E-cadherin levels on PND1 and PND28.These results suggest that EMT up-regulation mediated by the TGF-β/Smad3 pathway plays a role in postnatal pulmonary dysfunction associated with maternal exposure to PM2.5. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The influence of kyphosis correction surgery on pulmonary function and thoracic volume.

PubMed

Zeng, Yan; Chen, Zhongqiang; Ma, Desi; Guo, Zhaoqing; Qi, Qiang; Li, Weishi; Sun, Chuiguo; Liu, Ning; White, Andrew P

2014-10-01

A clinical study. To measure the changes in pulmonary function and thoracic volume associated with surgical correction of kyphotic deformities. No prior study has focused on the pulmonary function and thoracic cavity volume before and after corrective surgery for kyphosis. Thirty-four patients with kyphosis underwent posterior deformity correction with instrumented fusion. Preoperative and postoperative pulmonary function was measured, and pulmonary function grade was evaluated as mild, significant, or severe. The change in preoperative to postoperative pulmonary function was analyzed, using 6 comparative subgroupings of patients on the basis of age, severity of kyphosis, location of kyphosis apex, length of follow-up time after surgery, degree of kyphosis correction, and number of segments fused. A second group of 19 patients also underwent posterior surgical correction of kyphosis, which had thoracic volume measured preoperatively and postoperatively with computed tomographic scanning. All of the pulmonary impairments were found to be restrictive. After surgery, most of the patients had improvement of the pulmonary function. Before surgery, the pulmonary function differences were found to be significant based on both severity of preoperative kyphosis (<60° vs. >60°) and location of the kyphosis apex (above T10 vs. below T10). Younger patients (younger than 35 yr) were more likely to exhibit statistically significant improvements in pulmonary function after surgery. However, thoracic volume was not significantly related to pulmonary function parameters. After surgery, average thoracic volume had no significant change. The major pulmonary impairment caused by kyphosis was found to be restrictive. Patients with kyphosis angle of 60° or greater or with kyphosis apex above T10 had more severe pulmonary dysfunction. Patients' age was significantly related to change in pulmonary function after surgery. However, the average thoracic volume had no significant change after surgery. 3.

Milrinone attenuates thromboxane receptor-mediated hyperresponsiveness in hypoxic pulmonary arterial myocytes

PubMed Central

Santhosh, KT; Elkhateeb, O; Nolette, N; Outbih, O; Halayko, AJ; Dakshinamurti, S

2011-01-01

BACKGROUND AND PURPOSE Neonatal pulmonary hypertension (PPHN) is characterized by pulmonary vasoconstriction, due in part to dysregulation of the thromboxane prostanoid (TP) receptor. Hypoxia induces TP receptor–mediated hyperresponsiveness, whereas serine phosphorylation mediates desensitization of TP receptors. We hypothesized that prostacyclin (IP) receptor activity induces TP receptor phosphorylation and decreases ligand affinity; that TP receptor sensitization in hypoxic myocytes is due to IP receptor inactivation; and that this would be reversible by the cAMP-specific phosphodiesterase inhibitor milrinone. EXPERIMENTAL APPROACH We examined functional regulation of TP receptors by serine phosphorylation and effects of IP receptor stimulation and protein kinase A (PKA) activity on TP receptor sensitivity in myocytes from neonatal porcine resistance pulmonary arteries after 72 h hypoxia in vitro. Ca2+ response curves to U46619 (TP receptor agonist) were determined in hypoxic and normoxic myocytes incubated with or without iloprost (IP receptor agonist), forskolin (adenylyl cyclase activator), H8 (PKA inhibitor) or milrinone. TP and IP receptor saturation binding kinetics were measured in presence of iloprost or 8-bromo-cAMP. KEY RESULTS Ligand affinity for TP receptors was normalized in vitro by IP receptor signalling intermediates. However, IP receptor affinity was compromised in hypoxic myocytes, decreasing cAMP production. Milrinone normalized TP receptor sensitivity in hypoxic myocytes by restoring PKA-mediated regulatory TP receptor phosphorylation. CONCLUSIONS AND IMPLICATIONS TP receptor sensitivity and EC50 for TP receptor agonists was regulated by PKA, as TP receptor serine phosphorylation by PKA down-regulated Ca2+ mobilization. Hypoxia decreased IP receptor activity and cAMP generation, inducing TP receptor hyperresponsiveness, which was reversed by milrinone. PMID:21385177

Losartan attenuates chronic cigarette smoke exposure-induced pulmonary arterial hypertension in rats: possible involvement of angiotensin-converting enzyme-2.

PubMed

Han, Su-Xia; He, Guang-Ming; Wang, Tao; Chen, Lei; Ning, Yun-Ye; Luo, Feng; An, Jin; Yang, Ting; Dong, Jia-Jia; Liao, Zeng-Lin; Xu, Dan; Wen, Fu-Qiang

2010-05-15

Chronic cigarette smoking induces pulmonary arterial hypertension (PAH) by largely unknown mechanisms. Renin-angiotensin system (RAS) is known to function in the development of PAH. Losartan, a specific angiotensin II receptor antagonist, is a well-known antihypertensive drug with a potential role in regulating angiotensin-converting enzyme-2 (ACE2), a recently found regulator of RAS. To determine the effect of losartan on smoke-induced PAH and its possible mechanism, rats were daily exposed to cigarette smoke for 6months in the absence and in the presence of losartan. Elevated right ventricular systolic pressure (RVSP), thickened wall of pulmonary arteries with apparent medial hypertrophy along with increased angiotensin II (Ang II) and decreased ACE2 levels were observed in smoke-exposed-only rats. Losartan administration ameliorated pulmonary vascular remodeling, inhibited the smoke-induced RVSP and Ang II elevation and partially reversed the ACE2 decrease in rat lungs. In cultured primary pulmonary artery smooth muscle cells (PASMCs) from 3- and 6-month smoke-exposed rats, ACE2 levels were significantly lower than in those from the control rats. Moreover, PASMCs from 6-month exposed rats proliferated more rapidly than those from 3-month exposed or control rats, and cells grew even more rapidly in the presence of DX600, an ACE2 inhibitor. Consistent with the in vivo study, in vitro losartan pretreatment also inhibited cigarette smoke extract (CSE)-induced cell proliferation and ACE2 reduction in rat PASMCs. The results suggest that losartan may be therapeutically useful in the chronic smoking-induced pulmonary vascular remodeling and PAH and ACE2 may be involved as part of its mechanism. Our study might provide insight into the development of new therapeutic interventions for PAH smokers.

Losartan attenuates chronic cigarette smoke exposure-induced pulmonary arterial hypertension in rats: Possible involvement of angiotensin-converting enzyme-2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Han Suxia; He Guangming; Wang Tao

Chronic cigarette smoking induces pulmonary arterial hypertension (PAH) by largely unknown mechanisms. Renin-angiotensin system (RAS) is known to function in the development of PAH. Losartan, a specific angiotensin II receptor antagonist, is a well-known antihypertensive drug with a potential role in regulating angiotensin-converting enzyme-2 (ACE2), a recently found regulator of RAS. To determine the effect of losartan on smoke-induced PAH and its possible mechanism, rats were daily exposed to cigarette smoke for 6 months in the absence and in the presence of losartan. Elevated right ventricular systolic pressure (RVSP), thickened wall of pulmonary arteries with apparent medial hypertrophy along withmore » increased angiotensin II (Ang II) and decreased ACE2 levels were observed in smoke-exposed-only rats. Losartan administration ameliorated pulmonary vascular remodeling, inhibited the smoke-induced RVSP and Ang II elevation and partially reversed the ACE2 decrease in rat lungs. In cultured primary pulmonary artery smooth muscle cells (PASMCs) from 3- and 6-month smoke-exposed rats, ACE2 levels were significantly lower than in those from the control rats. Moreover, PASMCs from 6-month exposed rats proliferated more rapidly than those from 3-month exposed or control rats, and cells grew even more rapidly in the presence of DX600, an ACE2 inhibitor. Consistent with the in vivo study, in vitro losartan pretreatment also inhibited cigarette smoke extract (CSE)-induced cell proliferation and ACE2 reduction in rat PASMCs. The results suggest that losartan may be therapeutically useful in the chronic smoking-induced pulmonary vascular remodeling and PAH and ACE2 may be involved as part of its mechanism. Our study might provide insight into the development of new therapeutic interventions for PAH smokers.« less

PPAR-γ in innate and adaptive lung immunity.

PubMed

Nobs, Samuel Philip; Kopf, Manfred

2018-05-16

The transcription factor PPAR-γ (peroxisome proliferator-activated receptor-γ) is a key regulator of lung immunity exhibiting multiple cell type specific roles in controlling development and function of the lung immune system. It is strictly required for the generation of alveolar macrophages by controlling differentiation of fetal lung monocyte precursors. Furthermore, it plays an important role in lung allergic inflammation by licensing lung dendritic cell t helper 2 (Th2) priming capacity as well as acting as a master transcription factor for pathogenic Th2 cells. Due to this plethora of functions and its involvement in multiple pulmonary diseases including asthma and pulmonary alveolar proteinosis, understanding the role of PPAR-γ in lung immunity is an important subject of ongoing research. ©2018 Society for Leukocyte Biology.

Deregulated angiogenesis in chronic lung diseases: a possible role for lung mesenchymal progenitor cells (2017 Grover Conference Series)

PubMed Central

Kropski, Jonathan A.; Richmond, Bradley W.; Gaskill, Christa F.; Foronjy, Robert F.

2017-01-01

Chronic lung disease (CLD), including pulmonary fibrosis (PF) and chronic obstructive pulmonary disease (COPD), is the fourth leading cause of mortality worldwide. Both are debilitating pathologies that impede overall tissue function. A common co-morbidity in CLD is vasculopathy, characterized by deregulated angiogenesis, remodeling, and loss of microvessels. This substantially worsens prognosis and limits survival, with most current therapeutic strategies being largely palliative. The relevance of angiogenesis, both capillary and lymph, to the pathophysiology of CLD has not been resolved as conflicting evidence depicts angiogenesis as both reparative or pathologic. Therefore, we must begin to understand and model the underlying pathobiology of pulmonary vascular deregulation, alone and in response to injury induced disease, to define cell interactions necessary to maintain normal function and promote repair. Capillary and lymphangiogenesis are deregulated in both PF and COPD, although the mechanisms by which they co-regulate and underlie early pathogenesis of disease are unknown. The cell-specific mechanisms that regulate lung vascular homeostasis, repair, and remodeling represent a significant gap in knowledge, which presents an opportunity to develop targeted therapies. We have shown that that ABCG2pos multipotent adult mesenchymal stem or progenitor cells (MPC) influence the function of the capillary microvasculature as well as lymphangiogenesis. A balance of both is required for normal tissue homeostasis and repair. Our current models suggest that when lymph and capillary angiogenesis are out of balance, the non-equivalence appears to support the progression of disease and tissue remodeling. The angiogenic regulatory mechanisms underlying CLD likely impact other interstitial lung diseases, tuberous sclerosis, and lymphangioleiomyomatosis. PMID:29040010

The role of nitric oxide in the cardiopulmonary response to hypoxia in highland and lowland newborn llamas.

PubMed

Reyes, Roberto V; Díaz, Marcela; Ebensperger, Germán; Herrera, Emilio A; Quezada, Sebastián A; Hernandez, Ismael; Sanhueza, Emilia M; Parer, Julian T; Giussani, Dino A; Llanos, Aníbal J

2018-01-25

Perinatal hypoxia causes pulmonary hypertension in neonates, including humans. However, in species adapted to hypoxia, such as the llama, there is protection against pulmonary hypertension. Nitric oxide (NO) is a vasodilatator with an established role in the cardiopulmonary system of many species, but its function in the hypoxic pulmonary vasoconstrictor response in the newborn llama is unknown. Therefore, we studied the role of NO in the cardiopulmonary responses to acute hypoxia in high- and lowland newborn llamas. We show that high- compared to lowland newborn llamas have a reduced pulmonary vasoconstrictor response to acute hypoxia. Protection against excessive pulmonary vasoconstriction in the highland llama is mediated via enhancement of NO pathways, including increased MYPT1 and reduced ROCK expression as well as Ca 2+ desensitization. Blunting of pulmonary hypertensive responses to hypoxia through enhanced NO pathways may be an adaptive mechanism to withstand life at high altitude in the newborn llama. Llamas are born in the Alto Andino with protection against pulmonary hypertension. The physiology underlying protection against pulmonary vasoconstrictor responses to acute hypoxia in highland species is unknown. We determined the role of nitric oxide (NO) in the cardiopulmonary responses to acute hypoxia in high- and lowland newborn llamas. The cardiopulmonary function of newborn llamas born at low (580 m) or high altitude (3600 m) was studied under acute hypoxia, with and without NO blockade. In pulmonary arteries, we measured the reactivity to potassium and sodium nitroprusside (SNP), and in lung we determined the content of cGMP and the expression of the NO-related proteins: BKCa, PDE5, PSer92-PDE5, PKG-1, ROCK1 and 2, MYPT1, PSer695-MYPT1, PThr696-MYPT1, MLC20 and PSer19-MLC20. Pulmonary vascular remodelling was evaluated by morphometry and based on α-actin expression. High- compared to lowland newborn llamas showed lower in vivo pulmonary arterial pressor responses to acute hypoxia. This protection involved enhanced NO function, as NO blockade reverted the effect and the pulmonary arterial dilatator response to SNP was significantly enhanced in highland neonates. The pulmonary expression of ROCK2 and the phosphorylation of MLC20 were lower in high-altitude llamas. Conversely, MYPT1 was up-regulated whilst PSer695-MYPT1 and PThr695-MYPT1 did not change. Enhanced NO-dependent mechanisms were insufficient to prevent pulmonary arterial remodelling. Combined, the data strongly support that in the highland newborn llama reduced ROCK, increased MYPT1 expression and Ca 2+ desensitization in pulmonary tissue allow an enhanced NO biology to limit hypoxic pulmonary constrictor responses. Blunting of hypoxic pulmonary hypertensive responses may be an adaptive mechanism to life at high altitude. © 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.

Mycobacterium tuberculosis strains exhibit differential and strain-specific molecular signatures in pulmonary epithelial cells.

PubMed

Mvubu, Nontobeko Eunice; Pillay, Balakrishna; Gamieldien, Junaid; Bishai, William; Pillay, Manormoney

2016-12-01

Although pulmonary epithelial cells are integral to innate and adaptive immune responses during Mycobacterium tuberculosis infection, global transcriptomic changes in these cells remain largely unknown. Changes in gene expression induced in pulmonary epithelial cells infected with M. tuberculosis F15/LAM4/KZN, F11, F28, Beijing and Unique genotypes were investigated by RNA sequencing (RNA-Seq). The Illumina HiSeq 2000 platform generated 50 bp reads that were mapped to the human genome (Hg19) using Tophat (2.0.10). Differential gene expression induced by the different strains in infected relative to the uninfected cells was quantified and compared using Cufflinks (2.1.0) and MeV (4.0.9), respectively. Gene expression varied among the strains with the total number of genes as follows: F15/LAM4/KZN (1187), Beijing (1252), F11 (1639), F28 (870), Unique (886) and H37Rv (1179). A subset of 292 genes was commonly induced by all strains, where 52 genes were down-regulated while 240 genes were up-regulated. Differentially expressed genes were compared among the strains and the number of induced strain-specific gene signatures were as follows: F15/LAM4/KZN (138), Beijing (52), F11 (255), F28 (55), Unique (186) and H37Rv (125). Strain-specific molecular gene signatures associated with functional pathways were observed only for the Unique and H37Rv strains while certain biological functions may be associated with other strain signatures. This study demonstrated that strains of M. tuberculosis induce differential gene expression and strain-specific molecular signatures in pulmonary epithelial cells. Specific signatures induced by clinical strains of M. tuberculosis can be further explored for novel host-associated biomarkers and adjunctive immunotherapies. Copyright © 2016 Elsevier Ltd. All rights reserved.

Obstructive lung disease as a complication in post pulmonary TB

NASA Astrophysics Data System (ADS)

Tarigan, A. P.; Pandia, P.; Eyanoer, P.; Tina, D.; Pratama, R.; Fresia, A.; Tamara; Silvanna

2018-03-01

The case of post TB is a problem that arises in the community. Pulmonary tuberculosis (TB) can affect lung function. Therefore, we evaluated impaired pulmonary function in subjects with diagnosed prior pulmonary TB. A Case Series study, pulmonary function test was performed in subjects with a history of pulmonary tuberculosis; aged ≥18 years were included. Exclusion criteria was a subject who had asthma, obesity, abnormal thorax and smoking history. We measured FEV1 and FVC to evaluate pulmonary function. Airflow obstruction was FEV1/FVC%<75 and restriction was FVC<80% according to Indonesia’s pneumomobile project. This study was obtained from 23 patients with post pulmonary TB, 5 subjects (23%) had airflow obstruction with FEV1/FVC% value <75%, 15 subjects (71.4%) had abnormalities restriction with FVC value <80% and 3 subjects (5.6%) had normal lung function. Obstructive lung disease is one of the complications of impaired lung function in post pulmonary TB.

Cyclic Nucleotide Phosphodiesterases: important signaling modulators and therapeutic targets

PubMed Central

Ahmad, Faiyaz; Murata, Taku; Simizu, Kasumi; Degerman, Eva; Maurice, Donald; Manganiello, Vincent

2014-01-01

By catalyzing hydrolysis of cAMP and cGMP, cyclic nucleotide phosphodiesterases are critical regulators of their intracellular concentrations and their biological effects. Since these intracellular second messengers control many cellular homeostatic processes, dysregulation of their signals and signaling pathways initiate or modulate pathophysiological pathways related to various disease states, including erectile dysfunction, pulmonary hypertension, acute refractory cardiac failure, intermittent claudication, chronic obstructive pulmonary disease, and psoriasis. Alterations in expression of PDEs and PDE-gene mutations (especially mutations in PDE6, PDE8B, PDE11A and PDE4) have been implicated in various diseases and cancer pathologies. PDEs also play important role in formation and function of multi-molecular signaling/regulatory complexes called signalosomes. At specific intracellular locations, individual PDEs, together with pathway-specific signaling molecules, regulators, and effectors, are incorporated into specific signalosomes, where they facilitate and regulate compartmentalization of cyclic nucleotide signaling pathways and specific cellular functions. Currently, only a limited number of PDE inhibitors (PDE3, PDE4, PDE5 inhibitors) are used in clinical practice. Future paths to novel drug discovery include the crystal structure-based design approach, which has resulted in generation of more effective family-selective inhibitors, as well as burgeoning development of strategies to alter compartmentalized cyclic nucleotide signaling pathways by selectively targeting individual PDEs and their signalosome partners. PMID:25056711

Cystic Fibrosis Transmembrane Conductance Regulator Potentiation as a Therapeutic Strategy for Pulmonary Edema: A Proof-of-Concept Study in Pigs.

PubMed

Li, Xiaopeng; Vargas Buonfiglio, Luis G; Adam, Ryan J; Stoltz, David A; Zabner, Joseph; Comellas, Alejandro P

2017-12-01

To determine the feasibility of using a cystic fibrosis transmembrane conductance regulator potentiator, ivacaftor (VX-770/Kalydeco, Vertex Pharmaceuticals, Boston, MA), as a therapeutic strategy for treating pulmonary edema. Prospective laboratory animal investigation. Animal research laboratory. Newborn and 3 days to 1 week old pigs. Hydrostatic pulmonary edema was induced in pigs by acute volume overload. Ivacaftor was nebulized into the lung immediately after volume overload. Grams of water per grams of dry lung tissue were determined in the lungs harvested 1 hour after volume overload. Ivacaftor significantly improved alveolar liquid clearance in isolated pig lung lobes ex vivo and reduced edema in a volume overload in vivo pig model of hydrostatic pulmonary edema. To model hydrostatic pressure-induced edema in vitro, we developed a method of applied pressure to the basolateral surface of alveolar epithelia. Elevated hydrostatic pressure resulted in decreased cystic fibrosis transmembrane conductance regulator activity and liquid absorption, an effect which was partially reversed by cystic fibrosis transmembrane conductance regulator potentiation with ivacaftor. Cystic fibrosis transmembrane conductance regulator potentiation by ivacaftor is a novel therapeutic approach for pulmonary edema.

Heterozygous RTEL1 mutations are associated with familial pulmonary fibrosis.

PubMed

Kannengiesser, Caroline; Borie, Raphael; Ménard, Christelle; Réocreux, Marion; Nitschké, Patrick; Gazal, Steven; Mal, Hervé; Taillé, Camille; Cadranel, Jacques; Nunes, Hilario; Valeyre, Dominique; Cordier, Jean François; Callebaut, Isabelle; Boileau, Catherine; Cottin, Vincent; Grandchamp, Bernard; Revy, Patrick; Crestani, Bruno

2015-08-01

Pulmonary fibrosis is a fatal disease with progressive loss of respiratory function. Defective telomere maintenance leading to telomere shortening is a cause of pulmonary fibrosis, as mutations in the telomerase component genes TERT (reverse transcriptase) and TERC (RNA component) are found in 15% of familial pulmonary fibrosis (FPF) cases. However, so far, about 85% of FPF remain genetically uncharacterised.Here, in order to identify new genetic causes of FPF, we performed whole-exome sequencing, with a candidate-gene approach, of 47 affected subjects from 35 families with FPF without TERT and TERC mutations.We identified heterozygous mutations in regulator of telomere elongation helicase 1 (RTEL1) in four families. RTEL1 is a DNA helicase with roles in DNA replication, genome stability, DNA repair and telomere maintenance. The heterozygous RTEL1 mutations segregated as an autosomal dominant trait in FPF, and were predicted by structural analyses to severely affect the function and/or stability of RTEL1. In agreement with this, RTEL1-mutated patients exhibited short telomeres in comparison with age-matched controls.Our results provide evidence that heterozygous RTEL1 mutations are responsible for FPF and, thereby, extend the clinical spectrum of RTEL1 deficiency. Thus, RTEL1 enlarges the number of telomere-associated genes implicated in FPF. Copyright ©ERS 2015.

CFTR and lung homeostasis

PubMed Central

Matalon, Sadis

2014-01-01

CFTR is a cAMP-activated chloride and bicarbonate channel that is critical for lung homeostasis. Decreases in CFTR expression have dire consequences in cystic fibrosis (CF) and have been suggested to be a component of the lung pathology in chronic obstructive pulmonary disease. Decreases or loss of channel function often lead to mucus stasis, chronic bacterial infections, and the accompanying chronic inflammatory responses that promote progressive lung destruction, and, eventually in CF, lung failure. Here we discuss CFTR's functional role airway surface liquid hydration and pH, in regulation of other channels such as the epithelial sodium channel, and in regulating inflammatory responses in the lung. PMID:25381027

Is insufficient pulmonary air support the cause of dysphonia in chronic obstructive pulmonary disease?

PubMed

Hassan, Megahed M; Hussein, Mona T; Emam, Ahmed Mamdouh; Rashad, Usama M; Rezk, Ibrahim; Awad, Al Hussein

2018-08-01

Optimal pulmonary air support is essential pre-requisite for efficient phonation. The objective is to correlate pulmonary and vocal functions in chronic obstructive pulmonary disease (COPD) to find out whether the reduced pulmonary function per se could induce dysphonia. In this prospective case-control study, sixty subjects with stable COPD underwent evaluation of pulmonary and vocal functions. The pulmonary functions measured include {Forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), FEV1/FVC ratio, peak expiratory flow (PEF), maximum mid-expiratory flow (MMEF)}. The vocal functions were {jitter, shimmer, noise-to-harmonic ratio, pitch perturbation quotient, amplitude perturbation quotient, maximum phonation time (MPT), sound pressure level, phonatory efficiency, resistance and power. A control group (n=35) underwent the same measurements. These functions were compared between subjects and controls. Also, correlation of the vocal and pulmonary functions was conducted. Thirty five (58.3%) of COPD subjects have dysphonia. The pulmonary functions were lower in all COPD group than in the control group (P<0.001 for all parameters). Also, the FVC, FEV1, PEF and MMEF % of predicted values were significantly lower in subjects with dysphonia (n=35) than those without dysphonia (n=25) with P values 0.0018, <0.001, 0.0011 and 0.0026 respectively. In addition, the MPT in all subjects showed positive correlations to the 5 pulmonary functions (P=0.004 for FEV1/FVC ratio and P<0.001 for the rest). Also, the phonatory efficiency showed significant positive correlations with the pulmonary functions FVC, FEV1, PEF and MMEF (P=0.001, 0.001, 0.002 and 0.001 respectively). Unlike efficiency, the phonatory resistance revealed significant negative correlations with these pulmonary functions in the same order (P=0.001, 0.003, 0.002, 0.001 respectively). Dysphonia is a common comorbidity with COPD which attributed to multifactorial etiologies. The lower the pulmonary function in COPD patients is the more likely to have dysphonia. Decreased pulmonary function was associated with reduced MPT and phonatory efficiency but with increased phonatory resistance. The reduced pulmonary functions in COPD can be the underlying cause of the altered vocal function and dysphonia. Great part of this dysphonia is functional, and hence, can be corrected by voice therapy in compensated subjects. Further researches are needed to evaluate the efficacy of voice therapy in these patients. Copyright © 2017 Elsevier B.V. All rights reserved.

Uncoupling protein 2 deficiency mimics the effects of hypoxia and endoplasmic reticulum stress on mitochondria and triggers pseudohypoxic pulmonary vascular remodeling and pulmonary hypertension.

PubMed

Dromparis, Peter; Paulin, Roxane; Sutendra, Gopinath; Qi, Andrew C; Bonnet, Sébastien; Michelakis, Evangelos D

2013-07-05

Mitochondrial signaling regulates both the acute and the chronic response of the pulmonary circulation to hypoxia, and suppressed mitochondrial glucose oxidation contributes to the apoptosis-resistance and proliferative diathesis in the vascular remodeling in pulmonary hypertension. Hypoxia directly inhibits glucose oxidation, whereas endoplasmic reticulum (ER)-stress can indirectly inhibit glucose oxidation by decreasing mitochondrial calcium (Ca²⁺m levels). Both hypoxia and ER stress promote proliferative pulmonary vascular remodeling. Uncoupling protein 2 (UCP2) has been shown to conduct calcium from the ER to mitochondria and suppress mitochondrial function. We hypothesized that UCP2 deficiency reduces Ca²⁺m in pulmonary artery smooth muscle cells (PASMCs), mimicking the effects of hypoxia and ER stress on mitochondria in vitro and in vivo, promoting normoxic hypoxia inducible factor-1α activation and pulmonary hypertension. Ucp2 knockout (KO)-PASMCs had lower mitochondrial calcium than Ucp2 wildtype (WT)-PASMCs at baseline and during histamine-stimulated ER-Ca²⁺ release. Normoxic Ucp2KO-PASMCs had mitochondrial hyperpolarization, lower Ca²⁺-sensitive mitochondrial enzyme activity, reduced levels of mitochondrial reactive oxygen species and Krebs' cycle intermediates, and increased resistance to apoptosis, mimicking the hypoxia-induced changes in Ucp2WT-PASMC. Ucp2KO mice spontaneously developed pulmonary vascular remodeling and pulmonary hypertension and exhibited a pseudohypoxic state with pulmonary vascular and systemic hypoxia inducible factor-1α activation (increased hematocrit), not exacerbated further by chronic hypoxia. This first description of the role of UCP2 in oxygen sensing and in pulmonary hypertension vascular remodeling may open a new window in biomarker and therapeutic strategies.

The Effects of Aging on Pulmonary Oxidative Damage, Protein Nitration and Extracellular Superoxide Dismutase Down-Regulation During Systemic Inflammation

PubMed Central

Starr, Marlene E; Ueda, Junji; Yamamoto, Shoji; Evers, B. Mark; Saito, Hiroshi

2011-01-01

Systemic inflammatory response syndrome (SIRS), a serious clinical condition characterized by whole body inflammation, is particularly threatening for elderly patients who suffer much higher mortality rates than the young. A major pathological consequence of SIRS is acute lung injury caused by neutrophil-mediated oxidative damage. Previously, we reported an increase in protein tyrosine nitration (a marker of oxidative/nitrosative damage), and a decrease in antioxidant enzyme, extra-cellular superoxide dismutase (EC-SOD), in the lungs of young mice during endotoxemia-induced SIRS. Here we demonstrate that during endotoxemia, down-regulation of EC-SOD is significantly more profound and prolonged, while up-regulation of iNOS is augmented in aged compared to young mice. Aged mice also showed 2.5-fold higher protein nitration levels, compared to young mice, with particularly strong nitration in the pulmonary vascular endothelium during SIRS. Additionally, by 2-dimensional gel electrophoresis, Western blotting and mass spectrometry, we identified proteins which show increased tyrosine nitration in age- and SIRS-dependent manners; these proteins (profilin-1, transgelin-2, LASP 1, tropomyosin and myosin) include components of the actin cytoskeleton responsible for maintaining pulmonary vascular permeability. Reduced EC-SOD in combination with increased oxidative/nitrosative damage and altered cytoskeletal protein function due to tyrosine nitration may contribute to augmented lung injury in the aged with SIRS. PMID:21092756

21 CFR 868.1890 - Predictive pulmonary-function value calculator.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Predictive pulmonary-function value calculator. 868.1890 Section 868.1890 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... pulmonary-function value calculator. (a) Identification. A predictive pulmonary-function value calculator is...

21 CFR 868.1890 - Predictive pulmonary-function value calculator.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Predictive pulmonary-function value calculator. 868.1890 Section 868.1890 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... pulmonary-function value calculator. (a) Identification. A predictive pulmonary-function value calculator is...

Autophagy in lung disease pathogenesis and therapeutics

PubMed Central

Ryter, Stefan W.; Choi, Augustine M.K.

2015-01-01

Autophagy, a cellular pathway for the degradation of damaged organelles and proteins, has gained increasing importance in human pulmonary diseases, both as a modulator of pathogenesis and as a potential therapeutic target. In this pathway, cytosolic cargos are sequestered into autophagosomes, which are delivered to the lysosomes where they are enzymatically degraded and then recycled as metabolic precursors. Autophagy exerts an important effector function in the regulation of inflammation, and immune system functions. Selective pathways for autophagic degradation of cargoes may have variable significance in disease pathogenesis. Among these, the autophagic clearance of bacteria (xenophagy) may represent a crucial host defense mechanism in the pathogenesis of sepsis and inflammatory diseases. Our recent studies indicate that the autophagic clearance of mitochondria, a potentially protective program, may aggravate the pathogenesis of chronic obstructive pulmonary disease by activating cell death programs. We report similar findings with respect to the autophagic clearance of cilia components, which can contribute to airways dysfunction in chronic lung disease. In certain diseases such as pulmonary hypertension, autophagy may confer protection by modulating proliferation and cell death. In other disorders, such as idiopathic pulmonary fibrosis and cystic fibrosis, impaired autophagy may contribute to pathogenesis. In lung cancer, autophagy has multiple consequences by limiting carcinogenesis, modulating therapeutic effectiveness, and promoting tumor cell survival. In this review we highlight the multiple functions of autophagy and its selective autophagy subtypes that may be of significance to the pathogenesis of human disease, with an emphasis on lung disease and therapeutics. PMID:25617802

The Role of Transient Receptor Potential Channel 6 Channels in the Pulmonary Vasculature

PubMed Central

Malczyk, Monika; Erb, Alexandra; Veith, Christine; Ghofrani, Hossein Ardeschir; Schermuly, Ralph T.; Gudermann, Thomas; Dietrich, Alexander; Weissmann, Norbert; Sydykov, Akylbek

2017-01-01

Canonical or classical transient receptor potential channel 6 (TRPC6) is a Ca2+-permeable non-selective cation channel that is widely expressed in the heart, lung, and vascular tissues. The use of TRPC6-deficient (“knockout”) mice has provided important insights into the role of TRPC6 in normal physiology and disease states of the pulmonary vasculature. Evidence indicates that TRPC6 is a key regulator of acute hypoxic pulmonary vasoconstriction. Moreover, several studies implicated TRPC6 in the pathogenesis of pulmonary hypertension. Furthermore, a unique genetic variation in the TRPC6 gene promoter has been identified, which might link the inflammatory response to the upregulation of TRPC6 expression and ultimate development of pulmonary vascular abnormalities in idiopathic pulmonary arterial hypertension. Additionally, TRPC6 is critically involved in the regulation of pulmonary vascular permeability and lung edema formation during endotoxin or ischemia/reperfusion-induced acute lung injury. In this review, we will summarize latest findings on the role of TRPC6 in the pulmonary vasculature. PMID:28670316

Up-regulation of the mammalian target of rapamycin complex 1 subunit Raptor by aldosterone induces abnormal pulmonary artery smooth muscle cell survival patterns to promote pulmonary arterial hypertension

PubMed Central

Aghamohammadzadeh, Reza; Zhang, Ying-Yi; Stephens, Thomas E.; Arons, Elena; Zaman, Paula; Polach, Kevin J.; Matar, Majed; Yung, Lai-Ming; Yu, Paul B.; Bowman, Frederick P.; Opotowsky, Alexander R.; Waxman, Aaron B.; Loscalzo, Joseph; Leopold, Jane A.; Maron, Bradley A.

2016-01-01

Activation of the mammalian target of rapamycin complex 1 (mTORC1) subunit Raptor induces cell growth and is a downstream target of Akt. Elevated levels of aldosterone activate Akt, and, in pulmonary arterial hypertension (PAH), correlate with pulmonary arteriole thickening, which suggests that mTORC1 regulation by aldosterone may mediate adverse pulmonary vascular remodeling. We hypothesized that aldosterone-Raptor signaling induces abnormal pulmonary artery smooth muscle cell (PASMC) survival patterns to promote PAH. Remodeled pulmonary arterioles from SU-5416/hypoxia-PAH rats and monocrotaline-PAH rats with hyperaldosteronism expressed increased levels of the Raptor target, p70S6K, which provided a basis for investigating aldosterone-Raptor signaling in human PASMCs. Aldosterone (10−9 to 10−7 M) increased Akt/mTOR/Raptor to activate p70S6K and increase proliferation, viability, and apoptosis resistance in PASMCs. In PASMCs transfected with Raptor–small interfering RNA or treated with spironolactone/eplerenone, aldosterone or pulmonary arterial plasma from patients with PAH failed to increase p70S6K activation or to induce cell survival in vitro. Optimal inhibition of pulmonary arteriole Raptor was achieved by treatment with Staramine-monomethoxy polyethylene glycol that was formulated with Raptor-small interfering RNA plus spironolactone in vivo, which decreased arteriole muscularization and pulmonary hypertension in 2 experimental animal models of PAH in vivo. Up-regulation of mTORC1 by aldosterone is a critical pathobiologic mechanism that controls PASMC survival to promote hypertrophic vascular remodeling and PAH.—Aghamohammadzadeh, R., Zhang, Y.-Y., Stephens, T. E., Arons, E., Zaman, P., Polach, K. J., Matar, M., Yung, L.-M., Yu, P. B., Bowman, F. P., Opotowsky, A. R., Waxman, A. B., Loscalzo, J., Leopold, J. A., Maron, B. A. Up-regulation of the mammalian target of rapamycin complex 1 subunit Raptor by aldosterone induces abnormal pulmonary artery smooth muscle cell survival patterns to promote pulmonary arterial hypertension. PMID:27006450

Up-regulation of the mammalian target of rapamycin complex 1 subunit Raptor by aldosterone induces abnormal pulmonary artery smooth muscle cell survival patterns to promote pulmonary arterial hypertension.

PubMed

Aghamohammadzadeh, Reza; Zhang, Ying-Yi; Stephens, Thomas E; Arons, Elena; Zaman, Paula; Polach, Kevin J; Matar, Majed; Yung, Lai-Ming; Yu, Paul B; Bowman, Frederick P; Opotowsky, Alexander R; Waxman, Aaron B; Loscalzo, Joseph; Leopold, Jane A; Maron, Bradley A

2016-07-01

Activation of the mammalian target of rapamycin complex 1 (mTORC1) subunit Raptor induces cell growth and is a downstream target of Akt. Elevated levels of aldosterone activate Akt, and, in pulmonary arterial hypertension (PAH), correlate with pulmonary arteriole thickening, which suggests that mTORC1 regulation by aldosterone may mediate adverse pulmonary vascular remodeling. We hypothesized that aldosterone-Raptor signaling induces abnormal pulmonary artery smooth muscle cell (PASMC) survival patterns to promote PAH. Remodeled pulmonary arterioles from SU-5416/hypoxia-PAH rats and monocrotaline-PAH rats with hyperaldosteronism expressed increased levels of the Raptor target, p70S6K, which provided a basis for investigating aldosterone-Raptor signaling in human PASMCs. Aldosterone (10(-9) to 10(-7) M) increased Akt/mTOR/Raptor to activate p70S6K and increase proliferation, viability, and apoptosis resistance in PASMCs. In PASMCs transfected with Raptor-small interfering RNA or treated with spironolactone/eplerenone, aldosterone or pulmonary arterial plasma from patients with PAH failed to increase p70S6K activation or to induce cell survival in vitro Optimal inhibition of pulmonary arteriole Raptor was achieved by treatment with Staramine-monomethoxy polyethylene glycol that was formulated with Raptor-small interfering RNA plus spironolactone in vivo, which decreased arteriole muscularization and pulmonary hypertension in 2 experimental animal models of PAH in vivo Up-regulation of mTORC1 by aldosterone is a critical pathobiologic mechanism that controls PASMC survival to promote hypertrophic vascular remodeling and PAH.-Aghamohammadzadeh, R., Zhang, Y.-Y., Stephens, T. E., Arons, E., Zaman, P., Polach, K. J., Matar, M., Yung, L.-M., Yu, P. B., Bowman, F. P., Opotowsky, A. R., Waxman, A. B., Loscalzo, J., Leopold, J. A., Maron, B. A. Up-regulation of the mammalian target of rapamycin complex 1 subunit Raptor by aldosterone induces abnormal pulmonary artery smooth muscle cell survival patterns to promote pulmonary arterial hypertension. © FASEB.

Milrinone attenuates thromboxane receptor-mediated hyperresponsiveness in hypoxic pulmonary arterial myocytes.

PubMed

Santhosh, K T; Elkhateeb, O; Nolette, N; Outbih, O; Halayko, A J; Dakshinamurti, S

2011-07-01

Neonatal pulmonary hypertension (PPHN) is characterized by pulmonary vasoconstriction, due in part to dysregulation of the thromboxane prostanoid (TP) receptor. Hypoxia induces TP receptor-mediated hyperresponsiveness, whereas serine phosphorylation mediates desensitization of TP receptors. We hypothesized that prostacyclin (IP) receptor activity induces TP receptor phosphorylation and decreases ligand affinity; that TP receptor sensitization in hypoxic myocytes is due to IP receptor inactivation; and that this would be reversible by the cAMP-specific phosphodiesterase inhibitor milrinone. We examined functional regulation of TP receptors by serine phosphorylation and effects of IP receptor stimulation and protein kinase A (PKA) activity on TP receptor sensitivity in myocytes from neonatal porcine resistance pulmonary arteries after 72 h hypoxia in vitro. Ca(2+) response curves to U46619 (TP receptor agonist) were determined in hypoxic and normoxic myocytes incubated with or without iloprost (IP receptor agonist), forskolin (adenylyl cyclase activator), H8 (PKA inhibitor) or milrinone. TP and IP receptor saturation binding kinetics were measured in presence of iloprost or 8-bromo-cAMP. Ligand affinity for TP receptors was normalized in vitro by IP receptor signalling intermediates. However, IP receptor affinity was compromised in hypoxic myocytes, decreasing cAMP production. Milrinone normalized TP receptor sensitivity in hypoxic myocytes by restoring PKA-mediated regulatory TP receptor phosphorylation. TP receptor sensitivity and EC(50) for TP receptor agonists was regulated by PKA, as TP receptor serine phosphorylation by PKA down-regulated Ca(2+) mobilization. Hypoxia decreased IP receptor activity and cAMP generation, inducing TP receptor hyperresponsiveness, which was reversed by milrinone. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Lung extracellular matrix and redox regulation

PubMed Central

Watson, Walter H.; Ritzenthaler, Jeffrey D.; Roman, Jesse

2016-01-01

Pulmonary fibrosis affects millions worldwide and, even though there has been a significant investment in understanding the processes involved in wound healing and maladaptive repair, a complete understanding of the mechanisms responsible for lung fibrogenesis eludes us, and interventions capable of reversing or halting disease progression are not available. Pulmonary fibrosis is characterized by the excessive expression and uncontrolled deposition of extracellular matrix (ECM) proteins resulting in erosion of the tissue structure. Initially considered an ‘end-stage’ process elicited after injury, these events are now considered pathogenic and are believed to contribute to the course of the disease. By interacting with integrins capable of signal transduction and by influencing tissue mechanics, ECM proteins modulate processes ranging from cell adhesion and migration to differentiation and growth factor expression. In doing so, ECM proteins help orchestrate complex developmental processes and maintain tissue homeostasis. However, poorly controlled deposition of ECM proteins promotes inflammation, fibroproliferation, and aberrant differentiation of cells, and has been implicated in the pathogenesis of pulmonary fibrosis, atherosclerosis and cancer. Considering their vital functions, ECM proteins are the target of investigation, and oxidation–reduction (redox) reactions have emerged as important regulators of the ECM. Oxidative stress invariably accompanies lung disease and promotes ECM expression directly or through the overproduction of pro-fibrotic growth factors, while affecting integrin binding and activation. In vitro and in vivo investigations point to redox reactions as targets for intervention in pulmonary fibrosis and related disorders, but studies in humans have been disappointing probably due to the narrow impact of the interventions tested, and our poor understanding of the factors that regulate these complex reactions. This review is not meant to provide a comprehensive review of this field, but rather to highlight what has been learned and to raise interest in this area in need of much attention. PMID:26938939

[CF Lung Disease - a German S3 Guideline: Module 2: Diagnostics and Treatment in Chronic Infection with Pseudomonas aeruginosa].

PubMed

Schwarz, C; Schulte-Hubbert, B; Bend, J; Abele-Horn, M; Baumann, I; Bremer, W; Brunsmann, F; Dieninghoff, D; Eickmeier, O; Ellemunter, H; Fischer, R; Grosse-Onnebrink, J; Hammermann, J; Hebestreit, H; Hogardt, M; Hügel, C; Hug, M; Illing, S; Jung, A; Kahl, B; Koitschev, A; Mahlberg, R; Mainz, J G; Mattner, F; Mehl, A; Möller, A; Muche-Borowski, C; Nüßlein, T; Puderbach, M; Renner, S; Rietschel, E; Ringshausen, F C; Schmidt, S; Sedlacek, L; Sitter, H; Smaczny, C; Tümmler, B; Vonberg, R; Wielpütz, M O; Wilkens, H; Wollschläger, B; Zerlik, J; Düesberg, U; van Koningsbruggen-Rietschel, S

2018-05-01

Cystic Fibrosis (CF) is the most common autosomal-recessive genetic disease affecting approximately 8000 people in Germany. The disease is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene leading to dysfunction of CFTR, a transmembrane chloride channel. This defect causes insufficient hydration of the epithelial lining fluid which leads to chronic inflammation of the airways. Recurrent infections of the airways as well as pulmonary exacerbations aggravate chronic inflammation, lead to pulmonary fibrosis and tissue destruction up to global respiratory insufficiency, which is responsible for the mortality in over 90 % of patients. The main aim of pulmonary treatment in CF is to reduce pulmonary inflammation and chronic infection. Pseudomonas aeruginosa ( Pa ) is the most relevant pathogen in the course of CF lung disease. Colonization and chronic infection are leading to additional loss of pulmonary function. There are many possibilities to treat Pa -infection. This is a S3-clinical guideline which implements a definition for chronic Pa -infection and demonstrates evidence-based diagnostic methods and medical treatment for Pa -infection in order to give guidance for individual treatment options. © Georg Thieme Verlag KG Stuttgart · New York.

Endothelin B receptor blockade attenuates pulmonary vasodilation in oxygen-ventilated fetal lambs.

PubMed

Ivy, D Dunbar; Lee, Dong-Seok; Rairigh, Robyn L; Parker, Thomas A; Abman, Steven H

2004-01-01

Endothelin-1 (ET-1) contributes to the regulation of pulmonary vascular tone in the normal ovine fetus and in models of perinatal pulmonary hypertension. In the fetal lamb lung, the effects of ET-1 depend on the balance of at least two endothelin receptor subtypes: ETA and ETB. ETA receptors are located on smooth muscle cells and mediate vasoconstriction and smooth muscle proliferation. Stimulation of endothelial ETB receptors causes vasodilation through release of nitric oxide and also functions to remove ET-1 from the circulation. However, whether activation of ETB receptors contributes to the fall in pulmonary vascular tone at birth is unknown. To determine the role of acute ETB receptor blockade in pulmonary vasodilation in response to birth-related stimuli, we studied the hemodynamic effects of selective ETB receptor blockade with BQ-788 during mechanical ventilation with low (<10%) and high FiO2 (100%) in near-term fetal sheep. Intrapulmonary infusion of BQ-788 did not change left pulmonary artery (LPA) blood flow and pulmonary vascular resistance (PVR) at baseline. In comparison with controls, BQ-788 treatment attenuated the rise in LPA flow with low and high FiO2 ventilation (p <0.001 vs. control for each FiO2 concentration). PVR progressively decreased during mechanical ventilation with low and high FiO2 in both groups, but PVR remained higher after BQ-788 treatment throughout the study period (p <0.001). We conclude that selective ETB receptor blockade attenuates pulmonary vasodilation at birth. We speculate that ETB receptor stimulation contributes to pulmonary vasodilation at birth in the ovine fetus.

Naja naja atra venom ameliorates pulmonary fibrosis by inhibiting inflammatory response and oxidative stress.

PubMed

Cui, Kui; Kou, Jian-Qun; Gu, Jin-Hua; Han, Rong; Wang, Guanghui; Zhen, Xuechu; Qin, Zheng-Hong

2014-12-02

Naja naja atra venom (NNAV) displays diverse pharmacological actions including analgesia, anti-inflammation and immune regulation.In this study, we investigated the effects of NNAV on pulmonary fibrosis and its mechanisms of action. To determine if Naja naja atra venom (NNAV) can produce beneficial effects on pulmonary fibrosis, two marine models of pulmonary fibrosis were produced with bleomycin (BLM) and lipopolysaccharide (LPS). NNAV (30, 90, 270 μg/kg) was orally administered once a day started five days before BLM and LPS until to the end of experiment. The effects of NNAV treatment on pulmonary injury were evaluated with arterial blood gas analysis, hydroxyproline (HYP) content assessment and HE/Masson staining. The effects of NNAV treatment on inflammatory related cytokines, fibrosis related TGF-β/Smad signaling pathway and oxidative stress were examined. The results showed that NNAV improved the lung gas-exchange function and attenuated the fibrotic lesions in lung. NNAV decreased IL-1β and TNF-α levels in serum in both pulmonary fibrosis models. NNAV inhibited the activation of NF-κB in LPS-induced and TGF-β/Smad pathway in BLM-induced pulmonary fibrosis. Additionally, NNAV also increased the levels of SOD and GSH and reduced the levels of MDA in BLM-induced pulmonary fibrosis model. The present study indicates that NNAV attenuates LPS- and BLM-induced lung fibrosis. Its mechanisms of action are associated with inhibiting inflammatory response and oxidative stress. The study suggests that NNAV might be a potential therapeutic drug for treatment of pulmonary fibrosis.

Airway smooth muscle in airway reactivity and remodeling: what have we learned?

PubMed Central

2013-01-01

It is now established that airway smooth muscle (ASM) has roles in determining airway structure and function, well beyond that as the major contractile element. Indeed, changes in ASM function are central to the manifestation of allergic, inflammatory, and fibrotic airway diseases in both children and adults, as well as to airway responses to local and environmental exposures. Emerging evidence points to novel signaling mechanisms within ASM cells of different species that serve to control diverse features, including 1) [Ca2+]i contractility and relaxation, 2) cell proliferation and apoptosis, 3) production and modulation of extracellular components, and 4) release of pro- vs. anti-inflammatory mediators and factors that regulate immunity as well as the function of other airway cell types, such as epithelium, fibroblasts, and nerves. These diverse effects of ASM “activity” result in modulation of bronchoconstriction vs. bronchodilation relevant to airway hyperresponsiveness, airway thickening, and fibrosis that influence compliance. This perspective highlights recent discoveries that reveal the central role of ASM in this regard and helps set the stage for future research toward understanding the pathways regulating ASM and, in turn, the influence of ASM on airway structure and function. Such exploration is key to development of novel therapeutic strategies that influence the pathophysiology of diseases such as asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis. PMID:24142517

Adiponectin attenuates lung fibroblasts activation and pulmonary fibrosis induced by paraquat.

PubMed

Yao, Rong; Cao, Yu; He, Ya-rong; Lau, Wayne Bond; Zeng, Zhi; Liang, Zong-an

2015-01-01

Pulmonary fibrosis is one of the most common complications of paraquat (PQ) poisoning, which demands for more effective therapies. Accumulating evidence suggests adiponectin (APN) may be a promising therapy against fibrotic diseases. In the current study, we determine whether the exogenous globular APN isoform protects against pulmonary fibrosis in PQ-treated mice and human lung fibroblasts, and dissect the responsible underlying mechanisms. BALB/C mice were divided into control group, PQ group, PQ + low-dose APN group, and PQ + high-dose APN group. Mice were sacrificed 3, 7, 14, and 21 days after PQ treatment. We compared pulmonary histopathological changes among different groups on the basis of fibrosis scores, TGF-β1, CTGF and α-SMA pulmonary content via Western blot and real-time quantitative fluorescence-PCR (RT-PCR). Blood levels of MMP-9 and TIMP-1 were determined by ELISA. Human lung fibroblasts WI-38 were divided into control group, PQ group, APN group, and APN receptor (AdipoR) 1 small-interfering RNA (siRNA) group. Fibroblasts were collected 24, 48, and 72 hours after PQ exposure for assay. Cell viability and apoptosis were determined via Kit-8 (CCK-8) and fluorescein Annexin V-FITC/PI double labeling. The protein and mRNA expression level of collagen type III, AdipoR1, and AdipoR2 were measured by Western blot and RT-PCR. APN treatment significantly decreased the lung fibrosis scores, protein and mRNA expression of pulmonary TGF-β1, CTGF and α-SMA content, and blood MMP-9 and TIMP-1 in a dose-dependent manner (p<0.05). Pretreatment with APN significantly attenuated the reduced cell viability and up-regulated collagen type III expression induced by PQ in lung fibroblasts, (p<0.05). APN pretreatment up-regulated AdipoR1, but not AdipoR2, expression in WI-38 fibroblasts. AdipoR1 siRNA abrogated APN-mediated protective effects in PQ-exposed fibroblasts. Taken together, our data suggests APN protects against PQ-induced pulmonary fibrosis in a dose-dependent manner, via suppression of lung fibroblast activation. Functional AdipoR1 are expressed by human WI-38 lung fibroblasts, suggesting potential future clinical applicability of APN against pulmonary fibrosis.

Targeting the mevalonate cascade as a new therapeutic approach in heart disease, cancer and pulmonary disease.

PubMed

Yeganeh, Behzad; Wiechec, Emilia; Ande, Sudharsana R; Sharma, Pawan; Moghadam, Adel Rezaei; Post, Martin; Freed, Darren H; Hashemi, Mohammad; Shojaei, Shahla; Zeki, Amir A; Ghavami, Saeid

2014-07-01

The cholesterol biosynthesis pathway, also known as the mevalonate (MVA) pathway, is an essential cellular pathway that is involved in diverse cell functions. The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR) is the rate-limiting step in cholesterol biosynthesis and catalyzes the conversion of HMG-CoA to MVA. Given its role in cholesterol and isoprenoid biosynthesis, the regulation of HMGCR has been intensely investigated. Because all cells require a steady supply of MVA, both the sterol (i.e. cholesterol) and non-sterol (i.e. isoprenoid) products of MVA metabolism exert coordinated feedback regulation on HMGCR through different mechanisms. The proper functioning of HMGCR as the proximal enzyme in the MVA pathway is essential under both normal physiologic conditions and in many diseases given its role in cell cycle pathways and cell proliferation, cholesterol biosynthesis and metabolism, cell cytoskeletal dynamics and stability, cell membrane structure and fluidity, mitochondrial function, proliferation, and cell fate. The blockbuster statin drugs ('statins') directly bind to and inhibit HMGCR, and their use for the past thirty years has revolutionized the treatment of hypercholesterolemia and cardiovascular diseases, in particular coronary heart disease. Initially thought to exert their effects through cholesterol reduction, recent evidence indicates that statins also have pleiotropic immunomodulatory properties independent of cholesterol lowering. In this review we will focus on the therapeutic applications and mechanisms involved in the MVA cascade including Rho GTPase and Rho kinase (ROCK) signaling, statin inhibition of HMGCR, geranylgeranyltransferase (GGTase) inhibition, and farnesyltransferase (FTase) inhibition in cardiovascular disease, pulmonary diseases (e.g. asthma and chronic obstructive pulmonary disease (COPD)), and cancer. Copyright © 2014 Elsevier Inc. All rights reserved.

ASK1 Inhibition Halts Disease Progression in Preclinical Models of Pulmonary Arterial Hypertension.

PubMed

Budas, Grant R; Boehm, Mario; Kojonazarov, Baktybek; Viswanathan, Gayathri; Tian, Xia; Veeroju, Swathi; Novoyatleva, Tatyana; Grimminger, Friedrich; Hinojosa-Kirschenbaum, Ford; Ghofrani, Hossein A; Weissmann, Norbert; Seeger, Werner; Liles, John T; Schermuly, Ralph T

2018-02-01

Progression of pulmonary arterial hypertension (PAH) is associated with pathological remodeling of the pulmonary vasculature and the right ventricle (RV). Oxidative stress drives the remodeling process through activation of MAPKs (mitogen-activated protein kinases), which stimulate apoptosis, inflammation, and fibrosis. We investigated whether pharmacological inhibition of the redox-sensitive apical MAPK, ASK1 (apoptosis signal-regulating kinase 1), can halt the progression of pulmonary vascular and RV remodeling. A selective, orally available ASK1 inhibitor, GS-444217, was administered to two preclinical rat models of PAH (monocrotaline and Sugen/hypoxia), a murine model of RV pressure overload induced by pulmonary artery banding, and cellular models. Oral administration of GS-444217 dose dependently reduced pulmonary arterial pressure and reduced RV hypertrophy in PAH models. The therapeutic efficacy of GS-444217 was associated with reduced ASK1 phosphorylation, reduced muscularization of the pulmonary arteries, and reduced fibrotic gene expression in the RV. Importantly, efficacy was observed when GS-444217 was administered to animals with established disease and also directly reduced cardiac fibrosis and improved cardiac function in a model of isolated RV pressure overload. In cellular models, GS-444217 reduced phosphorylation of p38 and JNK (c-Jun N-terminal kinase) induced by adenoviral overexpression of ASK1 in rat cardiomyocytes and reduced activation/migration of primary mouse cardiac fibroblasts and human pulmonary adventitial fibroblasts derived from patients with PAH. ASK1 inhibition reduced pathological remodeling of the pulmonary vasculature and the right ventricle and halted progression of pulmonary hypertension in rodent models. These preclinical data inform the first description of a causal role of ASK1 in PAH disease pathogenesis.

Surfactant proteins, SP-A and SP-D, in respiratory fungal infections: their role in the inflammatory response.

PubMed

Carreto-Binaghi, Laura Elena; Aliouat, El Moukhtar; Taylor, Maria Lucia

2016-06-01

Pulmonary surfactant is a complex fluid that comprises phospholipids and four proteins (SP-A, SP-B, SP-C, and SP-D) with different biological functions. SP-B, SP-C, and SP-D are essential for the lungs' surface tension function and for the organization, stability and metabolism of lung parenchyma. SP-A and SP-D, which are also known as pulmonary collectins, have an important function in the host's lung immune response; they act as opsonins for different pathogens via a C-terminal carbohydrate recognition domain and enhance the attachment to phagocytic cells or show their own microbicidal activity by increasing the cellular membrane permeability. Interactions between the pulmonary collectins and bacteria or viruses have been extensively studied, but this is not the same for fungal pathogens. SP-A and SP-D bind glucan and mannose residues from fungal cell wall, but there is still a lack of information on their binding to other fungal carbohydrate residues. In addition, both their relation with immune cells for the clearance of these pathogens and the role of surfactant proteins' regulation during respiratory fungal infections remain unknown. Here we highlight the relevant findings associated with SP-A and SP-D in those respiratory mycoses where the fungal infective propagules reach the lungs by the airways.

Pulmonary Cerium Dioxide Nanoparticles Exposure Differentially Impairs Coronary and Mesenteric Arteriolar Reactivity

PubMed Central

Minarchick, Valerie C; Stapleton, Phoebe A; Porter, Dale W; Wolfarth, Michael G; Çiftyürek, Engin; Barger, Mark; Sabolsky, Edward M.; Nurkiewicz, Timothy R

2013-01-01

Cerium dioxide nanoparticles (CeO2 NPs) are an engineered nanomaterial that possesses unique catalytic, oxidative and reductive properties. Currently, CeO2 NPs are being used as a fuel catalyst but these properties are also utilized in the development of potential drug treatments for radiation and stroke protection. These uses of CeO2 NPs present a risk for human exposure; however, to date no studies have investigated the effects of CeO2 NPs on the microcirculation following pulmonary exposure. Previous studies in our laboratory with other nanomaterials have shown impairments in normal microvascular function after pulmonary exposures. Therefore, we predicted that CeO2 NP exposure would cause microvascular dysfunction that is dependent on the tissue bed and dose. Twenty-four hour post exposure to CeO2 NPs (0–400 μg), mesenteric and coronary arterioles were isolated and microvascular function was assessed. Our results provided evidence that pulmonary CeO2 NP exposure impairs endothelium-dependent and -independent arteriolar dilation in a dose-dependent manner. The CeO2 NP exposure dose which causes a 50% impairment in arteriolar function (EC50) was calculated and ranged from 15 – 100 μg depending on the chemical agonist and microvascular bed. Microvascular assessments with acetylcholine revealed a 33–75% reduction in function following exposure. Additionally, there was a greater sensitivity to CeO2 NP exposure in the mesenteric microvasculature due to the 40% decrease in the calculated EC50 compared to the coronary microvasculature EC50. CeO2 NP exposure increased mean arterial pressure in some groups. Taken together these observed microvascular changes may likely have detrimental effects on local blood flow regulation and contribute to cardiovascular dysfunction associated with particle exposure. PMID:23645470

Loss-of-function thrombospondin-1 mutations in familial pulmonary hypertension

PubMed Central

Stearman, Robert S.; Bull, Todd M.; Calabrese, David W.; Tripp-Addison, Megan L.; Wick, Marilee J.; Broeckel, Ulrich; Robbins, Ivan M.; Wheeler, Lisa A.; Cogan, Joy D.; Loyd, James E.

2012-01-01

Most patients with familial pulmonary arterial hypertension (FPAH) carry mutations in the bone morphogenic protein receptor 2 gene (BMPR2). Yet carriers have only a 20% risk of disease, suggesting that other factors influence penetrance. Thrombospondin-1 (TSP1) regulates activation of TGF-β and inhibits endothelial and smooth muscle cell proliferation, pathways coincidentally altered in pulmonary arterial hypertension (PAH). To determine whether a subset of FPAH patients also have mutations in the TSP1 gene (THBS1) we resequenced the type I repeats of THBS1 encoding the TGF-β regulation and cell growth inhibition domains in 60 FPAH probands, 70 nonfamilial PAH subjects, and in large control groups. We identified THBS1 mutations in three families: a novel missense mutation in two (Asp362Asn), and an intronic mutation in a third (IVS8+255 G/A). Neither mutation was detected in population controls. Mutant 362Asn TSP1 had less than half of the ability of wild-type TSP1 to activate TGF-β. Mutant 362Asn TSP1 also lost the ability to inhibit growth of pulmonary arterial smooth muscle cells and was over threefold less effective at inhibiting endothelial cell growth. The IVS8+255 G/A mutation decreased and/or eliminated local binding of the transcription factors SP1 and MAZ but did not affect RNA splicing. These novel mutations implicate THBS1 as a modifier gene in FPAH. These THBS1 mutations have implications in the genetic evaluation of FPAH patients. However, since FPAH is rare, these data are most relevant as evidence for the importance of TSP1 in pulmonary vascular homeostasis. Further examination of THBS1 in the pathogenesis of PAH is warranted. PMID:22198906

Impact of pulmonary rehabilitation on postoperative complications in patients with lung cancer and chronic obstructive pulmonary disease.

PubMed

Saito, Hajime; Hatakeyama, Kazutoshi; Konno, Hayato; Matsunaga, Toshiki; Shimada, Yoichi; Minamiya, Yoshihiro

2017-09-01

Given the extent of the surgical indications for pulmonary lobectomy in breathless patients, preoperative care and evaluation of pulmonary function are increasingly necessary. The aim of this study was to assess the contribution of preoperative pulmonary rehabilitation (PR) for reducing the incidence of postoperative pulmonary complications in non-small cell lung cancer (NSCLC) patients with chronic obstructive pulmonary disease (COPD). The records of 116 patients with COPD, including 51 patients who received PR, were retrospectively analyzed. Pulmonary function testing, including slow vital capacity (VC) and forced expiratory volume in one second (FEV 1 ), was obtained preoperatively, after PR, and at one and six months postoperatively. The recovery rate of postoperative pulmonary function was standardized for functional loss associated with the different resected lung volumes. Propensity score analysis generated matched pairs of 31 patients divided into PR and non-PR groups. The PR period was 18.7 ± 12.7 days in COPD patients. Preoperative pulmonary function was significantly improved after PR (VC 5.3%, FEV 1 5.5%; P < 0.05). The FEV 1 recovery rate one month after surgery was significantly better in the PR (101.6%; P < 0.001) than in the non-PR group (93.9%). In logistic regression analysis, predicted postoperative FEV 1 , predicted postoperative %FEV 1 , and PR were independent factors related to postoperative pulmonary complications after pulmonary lobectomy (odds ratio 18.9, 16.1, and 13.9, respectively; P < 0.05). PR improved the recovery rate of pulmonary function after lobectomy in the early period, and may decrease postoperative pulmonary complications. © 2017 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

Activation of GPER ameliorates experimental pulmonary hypertension in male rats.

PubMed

Alencar, Allan K; Montes, Guilherme C; Montagnoli, Tadeu; Silva, Ananssa M; Martinez, Sabrina T; Fraga, Aline G; Wang, Hao; Groban, Leanne; Sudo, Roberto T; Zapata-Sudo, Gisele

2017-01-15

Pulmonary hypertension (PH) is characterized by pulmonary vascular remodeling that leads to pulmonary congestion, uncompensated right-ventricle (RV) failure, and premature death. Preclinical studies have demonstrated that the G protein-coupled estrogen receptor (GPER) is cardioprotective in male rats and that its activation elicits vascular relaxation in rats of either sex. To study the effects of GPER on the cardiopulmonary system by the administration of its selective agonist G1 in male rats with monocrotaline (MCT)-induced PH. Rats received a single intraperitoneal injection of MCT (60mg/kg) for PH induction. Experimental groups were as follows: control, MCT+vehicle, and MCT+G1 (400μg/kg/daysubcutaneous). Animals (n=5pergroup) were treated with vehicle or G1 for 14days after disease onset. Activation of GPER attenuated exercise intolerance and reduced RV overload in PH rats. Rats with PH exhibited echocardiographic alterations, such as reduced pulmonary flow, RV hypertrophy, and left-ventricle dysfunction, by the end of protocol. G1 treatment reversed these PH-related abnormalities of cardiopulmonary function and structure, in part by promoting pulmonary endothelial nitric oxide synthesis, Ca 2+ handling regulation and reduction of inflammation in cardiomyocytes, and a decrease of collagen deposition by acting in pulmonary and cardiac fibroblasts. G1 was effective to reverse PH-induced RV dysfunction and exercise intolerance in male rats, a finding that have important implications for ongoing clinical evaluation of new cardioprotective and vasodilator drugs for the treatment of the disease. Copyright © 2016 Elsevier B.V. All rights reserved.

Vagal Afferent Innervation of the Airways in Health and Disease

PubMed Central

Mazzone, Stuart B.

2016-01-01

Vagal sensory neurons constitute the major afferent supply to the airways and lungs. Subsets of afferents are defined by their embryological origin, molecular profile, neurochemistry, functionality, and anatomical organization, and collectively these nerves are essential for the regulation of respiratory physiology and pulmonary defense through local responses and centrally mediated neural pathways. Mechanical and chemical activation of airway afferents depends on a myriad of ionic and receptor-mediated signaling, much of which has yet to be fully explored. Alterations in the sensitivity and neurochemical phenotype of vagal afferent nerves and/or the neural pathways that they innervate occur in a wide variety of pulmonary diseases, and as such, understanding the mechanisms of vagal sensory function and dysfunction may reveal novel therapeutic targets. In this comprehensive review we discuss historical and state-of-the-art concepts in airway sensory neurobiology and explore mechanisms underlying how vagal sensory pathways become dysfunctional in pathological conditions. PMID:27279650

Bone Marrow CD11c+ Cell-Derived Amphiregulin Promotes Pulmonary Fibrosis

PubMed Central

Ding, Lin; Liu, Tianju; Wu, Zhe; Hu, Biao; Nakashima, Taku; Ullenbruch, Matthew; De Los Santos, Francina Gonzalez; Phan, Sem H.

2016-01-01

Amphiregulin (AREG), an epidermal growth factor receptor ligand, is implicated in tissue repair and fibrosis but its cellular source and role in regeneration vs. fibrosis remain unclear. In this study we hypothesize that AREG induced in bone marrow derived CD11c+ cells is essential for pulmonary fibrosis. Thus the objectives were to evaluate the importance and role of AREG in pulmonary fibrosis, identify the cellular source of AREG induction and analyze its regulation of fibroblast function and activation. The results showed that lung AREG expression was significantly induced in bleomycin-induced pulmonary fibrosis. AREG deficiency in knockout (KO) mice significantly diminished pulmonary fibrosis. Analysis of AREG expression in major lung cell types revealed induction in fibrotic lungs predominantly occurred in CD11c+ cells. Moreover depletion of bone marrow derived CD11c+ cells suppressed both induction of lung AREG expression and pulmonary fibrosis. Conversely, adoptive transfer of bone marrow-derived CD11c+ cells from BLM-treated donor mice exacerbated pulmonary fibrosis but not if the donor cells were made AREG-deficient prior to transfer. CD11c+ cell conditioned media or co-culture stimulated fibroblast proliferation, activation and myofibroblast differentiation in an AREG dependent manner. Furthermore recombinant AREG induced telomerase reverse transcriptase (TERT) which appeared to be essential for the proliferative effect. Finally AREG significantly enhanced fibroblast motility, which was associated with increased expression of α6 integrin. These findings suggested that induced AREG specifically in recruited bone marrow-derived CD11c+ cells promoted bleomycin induced pulmonary fibrosis by activation of fibroblast TERT dependent proliferation, motility and indirectly, myofibroblast differentiation. PMID:27206766

Novel critical role of Toll-like receptor 4 in lung ischemia-reperfusion injury and edema

PubMed Central

Zanotti, Giorgio; Casiraghi, Monica; Abano, John B.; Tatreau, Jason R.; Sevala, Mayura; Berlin, Hilary; Smyth, Susan; Funkhouser, William K.; Burridge, Keith; Randell, Scott H.; Egan, Thomas M.

2009-01-01

Toll-like receptors (TLRs) of the innate immune system contribute to noninfectious inflammatory processes. We employed a murine model of hilar clamping (1 h) with reperfusion times between 15 min and 3 h in TLR4-sufficient (C3H/OuJ) and TLR4-deficient (C3H/HeJ) anesthetized mice with additional studies in chimeric and myeloid differentiation factor 88 (MyD88)- and TLR4-deficient mice to determine the role of TLR4 in lung ischemia-reperfusion injury. Human pulmonary microvascular endothelial monolayers were subjected to simulated warm ischemia and reperfusion with and without CRX-526, a competitive TLR4 inhibitor. Functional TLR4 solely on pulmonary parenchymal cells, not bone marrow-derived cells, mediates early lung edema following ischemia-reperfusion independent of MyD88. Activation of MAPKs and NF-κB was significantly blunted and/or delayed in lungs of TLR4-deficient mice as a consequence of ischemia-reperfusion injury, but edema development appeared to be independent of activation of these signaling pathways. Pretreatment with a competitive TLR4 inhibitor prevented edema in vivo and reduced actin cytoskeletal rearrangement and gap formation in pulmonary microvascular endothelial monolayers subjected to simulated warm ischemia and reperfusion. In addition to its well-accepted role to alter gene transcription, functioning TLR4 on pulmonary parenchymal cells plays a key role in very early and profound pulmonary edema in murine lung ischemia-reperfusion injury. This may be due to a novel mechanism: regulation of endothelial cell cytoskeleton affecting microvascular endothelial cell permeability. PMID:19376887

Micro-RNAs in regenerating lungs: an integrative systems biology analysis of murine influenza pneumonia.

PubMed

Tan, Kai Sen; Choi, Hyungwon; Jiang, Xiaoou; Yin, Lu; Seet, Ju Ee; Patzel, Volker; Engelward, Bevin P; Chow, Vincent T

2014-07-11

Tissue regeneration in the lungs is gaining increasing interest as a potential influenza management strategy. In this study, we explored the role of microRNAs, short non-coding RNAs involved in post-transcriptional regulation, during pulmonary regeneration after influenza infection. We profiled miRNA and mRNA expression levels following lung injury and tissue regeneration using a murine influenza pneumonia model. BALB/c mice were infected with a sub-lethal dose of influenza A/PR/8(H1N1) virus, and their lungs were harvested at 7 and 15 days post-infection to evaluate the expression of ~300 miRNAs along with ~36,000 genes using microarrays. A global network was constructed between differentially expressed miRNAs and their potential target genes with particular focus on the pulmonary repair and regeneration processes to elucidate the regulatory role of miRNAs in the lung repair pathways. The miRNA arrays revealed a global down-regulation of miRNAs. TargetScan analyses also revealed specific miRNAs highly involved in targeting relevant gene functions in repair such as miR-290 and miR-505 at 7 dpi; and let-7, miR-21 and miR-30 at 15 dpi. The significantly differentially regulated miRNAs are implicated in the activation or suppression of cellular proliferation and stem cell maintenance, which are required during the repair of the damaged lungs. These findings provide opportunities in the development of novel repair strategies in influenza-induced pulmonary injury.

Dual Functions of ASCIZ in the DNA Base Damage Response and Pulmonary Organogenesis

PubMed Central

Tenis, Nora; Hammet, Andrew; Hewitt, Kimberly; Ng, Jane-Lee; McNees, Carolyn J.; Kozlov, Sergei V.; Oka, Hayato; Kobayashi, Masahiko; Conlan, Lindus A.; Cole, Timothy J.; Yamamoto, Ken-ichi; Taniguchi, Yoshihito; Takeda, Shunichi; Lavin, Martin F.; Heierhorst, Jörg

2010-01-01

Zn2+-finger proteins comprise one of the largest protein superfamilies with diverse biological functions. The ATM substrate Chk2-interacting Zn2+-finger protein (ASCIZ; also known as ATMIN and ZNF822) was originally linked to functions in the DNA base damage response and has also been proposed to be an essential cofactor of the ATM kinase. Here we show that absence of ASCIZ leads to p53-independent late-embryonic lethality in mice. Asciz-deficient primary fibroblasts exhibit increased sensitivity to DNA base damaging agents MMS and H2O2, but Asciz deletion or knock-down does not affect ATM levels and activation in mouse, chicken, or human cells. Unexpectedly, Asciz-deficient embryos also exhibit severe respiratory tract defects with complete pulmonary agenesis and severe tracheal atresia. Nkx2.1-expressing respiratory precursors are still specified in the absence of ASCIZ, but fail to segregate properly within the ventral foregut, and as a consequence lung buds never form and separation of the trachea from the oesophagus stalls early. Comparison of phenotypes suggests that ASCIZ functions between Wnt2-2b/ß-catenin and FGF10/FGF-receptor 2b signaling pathways in the mesodermal/endodermal crosstalk regulating early respiratory development. We also find that ASCIZ can activate expression of reporter genes via its SQ/TQ-cluster domain in vitro, suggesting that it may exert its developmental functions as a transcription factor. Altogether, the data indicate that, in addition to its role in the DNA base damage response, ASCIZ has separate developmental functions as an essential regulator of respiratory organogenesis. PMID:20975950

Differentially Expressed Plasma MicroRNAs and the Potential Regulatory Function of Let-7b in Chronic Thromboembolic Pulmonary Hypertension

PubMed Central

Guo, Lijuan; Yang, Yuanhua; Liu, Jie; Wang, Lei; Li, Jifeng; Wang, Ying; Liu, Yan; Gu, Song; Gan, Huili; Cai, Jun; Yuan, Jason X.-J.; Wang, Jun; Wang, Chen

2014-01-01

Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive disease characterized by misguided thrombolysis and remodeling of pulmonary arteries. MicroRNAs are small non-coding RNAs involved in multiple cell processes and functions. During CTEPH, circulating microRNA profile endued with characteristics of diseased cells could be identified as a biomarker, and might help in recognition of pathogenesis. Thus, in this study, we compared the differentially expressed microRNAs in plasma of CTEPH patients and healthy controls and investigated their potential functions. Microarray was used to identify microRNA expression profile and qRT-PCR for validation. The targets of differentially expressed microRNAs were identified in silico, and the Gene Ontology database and Kyoto Encyclopedia of Genes and Genomes pathway database were used for functional investigation of target gene profile. Targets of let-7b were validated by fluorescence reporter assay. Protein expression of target genes was determined by ELISA or western blotting. Cell migration was evaluated by wound healing assay. The results showed that 1) thirty five microRNAs were differentially expressed in CTEPH patients, among which, a signature of 17 microRNAs, which was shown to be related to the disease pathogenesis by in silico analysis, gave diagnostic efficacy of both sensitivity and specificity >0.9. 2) Let-7b, one of the down-regulated anti-oncogenic microRNAs in the signature, was validated to decrease to about 0.25 fold in CTEPH patients. 3) ET-1 and TGFBR1 were direct targets of let-7b. Altering let-7b level influenced ET-1 and TGFBR1 expression in pulmonary arterial endothelial cells (PAECs) as well as the migration of PAECs and pulmonary arterial smooth muscle cells (PASMCs). These results suggested that CTEPH patients had aberrant microRNA signature which might provide some clue for pathogenesis study and biomarker screening. Reduced let-7b might be involved in the pathogenesis of CTEPH by affecting ET-1 expression and the function of PAECs and PASMCs. PMID:24978044

Heterogeneous distribution of type I nitric oxide synthase in pulmonary vasculature of ovine fetus.

PubMed

Tzao, C; Nickerson, P A; Russell, J A; Noble, B K; Steinhorn, R H

2000-11-01

The nitric oxide/guanosine 3',5'-cyclic monophosphate pathway plays an essential role in mediating pulmonary vasodilation at birth. Small resistance arteries in the fetal lung are vessels of major significance in the regulation of pulmonary vascular tone. The present study is to determine that type I nitric oxide synthase (NOS-I) is present in ovine fetal pulmonary vasculature and that NOS-I is distributed heterogeneously in ovine fetal pulmonary circulation. We used reduced nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) histochemistry and NOS-I immunohistochemistry to localize NOS-I in fetal sheep lungs and showed a colocalization for NADPH-d activity with NOS-I immunoreactivity. Strong NOS-I immunoreactivity was observed exclusively in the endothelium of the terminal bronchiole and respiratory bronchiole-associated arteries. As a comparison, adult sheep lung did not show positive immunoreactivity in the pulmonary endothelium. NOS-I was absent in the umbilical or systemic arteries from the ovine fetus, whereas abundant NOS-III immunoreactivity was present in these arteries. We conclude that NOS-I is present uniquely in the ovine fetal pulmonary circulation as opposed to the adult pulmonary or the fetal systemic circulation. NOS-I is distributed heterogeneously in the ovine pulmonary vasculature. We speculate that NOS-I plays an active role in the regulation of perinatal pulmonary circulation.

Sphingolipids as targets for inhalation treatment of cystic fibrosis.

PubMed

Becker, Katrin Anne; Riethmüller, Joachim; Seitz, Aaron P; Gardner, Aaron; Boudreau, Ryan; Kamler, Markus; Kleuser, Burkhard; Schuchman, Edward; Caldwell, Charles C; Edwards, Michael J; Grassmé, Heike; Brodlie, Malcolm; Gulbins, Erich

2018-04-24

Studies over the past several years have demonstrated the important role of sphingolipids in cystic fibrosis (CF), chronic obstructive pulmonary disease and acute lung injury. Ceramide is increased in airway epithelial cells and alveolar macrophages of CF mice and humans, while sphingosine is dramatically decreased. This increase in ceramide results in chronic inflammation, increased death of epithelial cells, release of DNA into the bronchial lumen and thereby an impairment of mucociliary clearance; while the lack of sphingosine in airway epithelial cells causes high infection susceptibility in CF mice and possibly patients. The increase in ceramide mediates an ectopic expression of β1-integrins in the luminal membrane of CF epithelial cells, which results, via an unknown mechanism, in a down-regulation of acid ceramidase. It is predominantly this down-regulation of acid ceramidase that results in the imbalance of ceramide and sphingosine in CF cells. Correction of ceramide and sphingosine levels can be achieved by inhalation of functional acid sphingomyelinase inhibitors, recombinant acid ceramidase or by normalization of β1-integrin expression and subsequent re-expression of endogenous acid ceramidase. These treatments correct pulmonary inflammation and prevent or treat, respectively, acute and chronic pulmonary infections in CF mice with Staphylococcus aureus and mucoid or non-mucoid Pseudomonas aeruginosa. Inhalation of sphingosine corrects sphingosine levels only and seems to mainly act against the infection. Many antidepressants are functional inhibitors of the acid sphingomyelinase and were designed for systemic treatment of major depression. These drugs could be repurposed to treat CF by inhalation. Copyright © 2018. Published by Elsevier B.V.

Pulmonary functions in tannery workers--a cross sectional study.

PubMed

Chandrasekaran, Vasanthi; Dilara, K; Padmavathi, R

2014-01-01

Tannery workers are at potential exposure to detrimental agents rendering them vulnerable to respiratory and dermal problems. Thus by performing pulmonary functions among leather tannery workers, we can decipher the effect of chromium and leather dust on lung functions and also the decline of respiratory functions with increasing years of exposure to leather dust. Pulmonary functions were assessed for 130 tannery workers and compared with the 130 unexposed office workers. Pulmonary function measurements namely FVC, FEV1, FEF25-75% and PEFR were measured using portable data logging Spirometer (KOKO Spirometer). The observed pulmonary functions of Tannery-workers in this study showed a reduction in FEV1, FVC, FEV1/FVC ratio, FEF25-75 and PEFR in relation to their predicted values and also compared to the unexposed. Smokers showed a decline in pulmonary functions compared to the non smokers because smoking acts as an additional risk factor in the development of respiratory illnesses. It is worthy to mention that the pulmonary function values correlate negatively with the duration of exposure to leather dust. So this study could provide base line information based upon which legal implementation of preventive measures could be undertaken.

Leptin promotes pulmonary fibrosis development by inhibiting autophagy via PI3K/Akt/mTOR pathway.

PubMed

Gui, Xianhua; Chen, Hongwei; Cai, Hourong; Sun, Lingyun; Gu, Luo

2018-04-06

Leptin, a protein-related product of the obesity gene, plays an important role in the pathogenesis of fibrotic diseases including pulmonary fibrosis. As a highly conservative process, autophagy regulates various biological functions. Otherwise, insufficient autophagy has been described in alveolar epithelial cells (AEC) to cope with the progression of pulmonary fibrosis. Hence, this study is to investigate the effects of leptin on fibrosis in TGF-β1 induced epithelial mesenchymal transition (EMT) and the potential roles of autophagy in this processes. Our results showed that the elevated leptin level in serum correlated with the severity of lung fibrosis and leptin significantly promoted the EMT in A549 cells as evidenced by promoting collagen I and α-SMA production. Additionally, treatment with leptin decreased autophagosome formation, inhibited the lipidation of LC3I to LC3II, and up-regulated the expression of p62 via activating PI3K/Akt/mTOR pathway, which is indicative of inhibition of autophagy by leptin. Finally, rapmycin pretreatment reversed the pro-fibrogenic effects of leptin. Taken together, our study suggested that leptin accelerated the EMT of A549 cells through inhibiting autophagy via PI3K/Akt/mTOR pathway. Copyright © 2018 Elsevier Inc. All rights reserved.

Pulmonary function tests correlated with thoracic volumes in adolescent idiopathic scoliosis.

PubMed

Ledonio, Charles Gerald T; Rosenstein, Benjamin E; Johnston, Charles E; Regelmann, Warren E; Nuckley, David J; Polly, David W

2017-01-01

Scoliosis deformity has been linked with deleterious changes in the thoracic cavity that affect pulmonary function. The causal relationship between spinal deformity and pulmonary function has yet to be fully defined. It has been hypothesized that deformity correction improves pulmonary function by restoring both respiratory muscle efficiency and increasing the space available to the lungs. This research aims to correlate pulmonary function and thoracic volume before and after scoliosis correction. Retrospective correlational analysis between thoracic volume modeling from plain x-rays and pulmonary function tests was conducted. Adolescent idiopathic scoliosis patients enrolled in a multicenter database were sorted by pre-operative Total Lung Capacities (TLC) % predicted values from their Pulmonary Function Tests (PFT). Ten patients with the best and ten patients with the worst TLC values were included. Modeled thoracic volume and TLC values were compared before and 2 years after surgery. Scoliosis correction resulted in an increase in the thoracic volume for patients with the worst initial TLCs (11.7%) and those with the best initial TLCs (12.5%). The adolescents with the most severe pulmonary restriction prior to surgery strongly correlated with post-operative change in total lung capacity and thoracic volume (r 2  = 0.839; p < 0.001). The mean increase in thoracic volume in this group was 373.1 cm 3 (11.7%) which correlated with a 21.2% improvement in TLC. Scoliosis correction in adolescents was found to increase thoracic volume and is strongly correlated with improved TLC in cases with severe restrictive pulmonary function, but no correlation was found in cases with normal pulmonary function. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:175-182, 2017. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Emerging hemodynamic signatures of the right heart (Third International Right Heart Failure Summit, part 2).

PubMed

Maron, Bradley A

2014-12-01

Despite the importance of preserved right ventricular structure and function with respect to outcome across the spectrum of lung, cardiac, and pulmonary vascular diseases, only recently have organized efforts developed to consider the pulmonary vascular-right ventricular apparatus as a specific unit within the larger context of cardiopulmonary pathophysiology. The Third International Right Heart Failure Summit (Boston, MA) was a multidisciplinary event dedicated to promoting a dialogue about the scientific and clinical basis of right heart disease. The current review provides a synopsis of key discussions presented during the section of the summit titled "Emerging Hemodynamic Signatures of the Right Heart." Specifically, topics emphasized in this element of the symposium included (1) the effects of pulmonary vascular dysfunction at rest or provoked by exercise on the right ventricular pressure-volume relationship, (2) the role of pressure-volume loop analysis as a method to characterize right ventricular inefficiency and predict right heart failure, and (3) the importance of a systems biology approach to identifying novel factors that contribute to pathophenotypes associated with pulmonary arterial hypertension and/or right ventricular dysfunction. Collectively, these concepts frame a forward-thinking paradigm shift in the approach to right heart disease by emphasizing factors that regulate the transition from adaptive to maladaptive right ventricular-pulmonary vascular (patho)physiology.

Microarray-based analysis of the lung recovery process after stainless-steel welding fume exposure in Sprague-Dawley rats.

PubMed

Oh, Jung-Hwa; Yang, Mi-jin; Yang, Young-Su; Park, Han-Jin; Heo, Sun Hee; Lee, Eun-Hee; Song, Chang-Woo; Yoon, Seokjoo

2009-02-01

Repeated exposure to welding fumes promotes a reversible increase in pulmonary disease risk, but the molecular mechanisms by which welding fumes induce lung injury and how the lung recovers from such insults are unclear. In the present study, pulmonary function and gene-expression profiles in the lung were analyzed by Affymetrix GeneChip microarray after 30 days of consecutive exposure to manual metal arc welding combined with stainless-steel (MMA-SS) welding fumes, and again after 30 days of recovery from MMA-SS fume exposure. In total, 577 genes were identified as being either up-regulated or down-regulated (over twofold changes, p < 0.05) in the lungs of low-dose or high-dose groups. Differentially expressed genes were classified based on a k-means clustering algorithm and biological functions and molecular networks were further analyzed using Ingenuity Pathways Analysis. Among the genes affected by exposure to or recovery from MMA-SS fumes, the transcriptional changes of 13 genes that were highly altered by treatment were confirmed by quantitative real-time PCR. Notably, Mmp12, Cd5l, Ccl7, Cxcl5, and Spp1 related to the immune response were up-regulated only in the exposure group, whereas Trem2, IgG-2a, Igh-1a, and Igh were persistently up-regulated in both the exposure and recovery groups. In addition, several genes that might play a role in the repair process of the lung were up-regulated exclusively in the recovery group. Collectively, these data may help elucidate the molecular mechanism of the recovery process of the lung after welding fume exposure.

Structural basis for pulmonary functional imaging.

PubMed

Itoh, H; Nakatsu, M; Yoxtheimer, L M; Uematsu, H; Ohno, Y; Hatabu, H

2001-03-01

An understanding of fine normal lung morphology is important for effective pulmonary functional imaging. The lung specimens must be inflated. These include (a) unfixed, inflated lung specimen, (b) formaldehyde fixed lung specimen, (c) fixed, inflated dry lung specimen, and (d) histology specimen. Photography, magnified view, radiograph, computed tomography, and histology of these specimens are demonstrated. From a standpoint of diagnostic imaging, the main normal lung structures consist of airways (bronchi and bronchioles), alveoli, pulmonary vessels, secondary pulmonary lobules, and subpleural pulmonary lymphatic channels. This review summarizes fine radiologic normal lung morphology as an aid to effective pulmonary functional imaging.

Regulation of Membrane-Type 4 Matrix Metalloproteinase by SLUG Contributes to Hypoxia-Mediated Metastasis12

PubMed Central

Huang, Chi-Hung; Yang, Wen-Hao; Chang, Shyue-Yih; Tai, Shyh-Kuan; Tzeng, Cheng-Hwei; Kao, Jung-Yie; Wu, Kou-Juey; Yang, Muh-Hwa

2009-01-01

The hypoxic tumor environment has been shown to be critical to cancer metastasis through the promotion of angiogenesis, induction of epithelial-mesenchymal transition (EMT), and acquisition of invasive potential. However, the impact of hypoxia on the expression profile of the proteolytic enzymes involved in invasiveness is relatively unknown. Membrane-type 4 matrix metalloproteinase (MT4-MMP) is a glycosyl-phosphatidyl inositol-anchored protease that has been shown to be overexpressed in human cancers. However, detailed mechanisms regarding the regulation and function of MT4-MMP expression in tumor cells remain unknown. Here, we demonstrate that hypoxia or overexpression of hypoxia-inducible factor-1α (HIF-1α) induced MT4-MMP expression in human cancer cells. Activation of SLUG, a transcriptional factor regulating the EMT process of human cancers, by HIF-1α was critical for the induction of MT4-MMP under hypoxia. SLUG regulated the transcription of MT4-MMP through direct binding to the E-box located in its proximal promoter. Short-interference RNA-mediated knockdown of MT4-MMP attenuated in vitro invasiveness and in vivo pulmonary colonization of tumor cells without affecting cell migratory ability. MT4-MMP promoted invasiveness and pulmonary colonization through modulation of the expression profile of MMPs and angiogenic factors. Finally, coexpression of HIF-1α and MT4-MMP in human head and neck cancer was predictive of a worse clinical outcome. These findings establish a novel signaling pathway for hypoxia-mediated metastasis and elucidate the underlying regulatory mechanism and functional significance of MT4-MMP in cancer metastasis. PMID:20019845

21 CFR 868.1880 - Pulmonary-function data calculator.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Pulmonary-function data calculator. 868.1880 Section 868.1880 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES...-function values based on actual physical data obtained during pulmonary-function testing. (b...

21 CFR 868.1880 - Pulmonary-function data calculator.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Pulmonary-function data calculator. 868.1880 Section 868.1880 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES...-function values based on actual physical data obtained during pulmonary-function testing. (b...

Opposing actions of TRPV4 channel activation in the lung vasculature.

PubMed

Ke, Sun-Kui; Chen, Lan; Duan, Hong-Bing; Tu, Yuan-Rong

2015-12-01

Transient receptor potential vanilloid 4 (TRPV4) calcium channels are known to promote endothelium-dependent relaxation of mouse mesenteric arteries but TRPV4's role in the pulmonary vasculature is uncertain. Thus, we characterized TRPV4 channel vascular tone regulation in mouse main pulmonary artery rings and in the isolated perfused pulmonary circulation and studied possible mechanisms behind these characterizations. Using myography and a TRPV4 specific agonist GSK1016790A in a C57BL/6 WT mouse model of isolated constant-flow lung perfusion, we studied vascular tone regulation in arterial rings from the main left and right pulmonary arteries and vascular resistance of the intra-pulmonary circulation beyond the second branches of the pulmonary arteries. Removal of the endothelium confirmed endothelial dependence. GSK1016790A relaxed the main pulmonary artery (EC50 4 × 10(-8)mol/L), which was inhibited by removal of the endothelium from main pulmonary artery rings. GSK1016790A significantly increased vascular resistance of the pulmonary circulation in isolated perfused lungs, but these effects were inhibited by a TRPV4 antagonist AB159908. A nitric oxide inhibitor NG-nitro-L-arginine methyl ester (L-NAME) and K(+) channel blockers apamin plus charybdotoxin (ChTx) significantly inhibited GSK1016790A in the main pulmonary artery and in an isolated perfused lung in vitro. Activated TRPV4 channels increase pulmonary vascular resistance and vasodilate the main pulmonary artery. Copyright © 2015 Elsevier B.V. All rights reserved.

Endothelial follistatin-like-1 regulates the postnatal development of the pulmonary vasculature by modulating BMP/Smad signaling

PubMed Central

Tania, Navessa P.; Maarsingh, Harm; T. Bos, I. Sophie; Mattiotti, Andrea; Prakash, Stuti; Timens, Wim; Gunst, Quinn D.; Jimenez-Borreguero, Luis J.; Schmidt, Martina; van den Hoff, Maurice J.B.; Gosens, Reinoud

2017-01-01

Bone morphogenetic protein (BMP) signaling regulates vascular smooth muscle maturation, endothelial cell proliferation, and tube formation. The endogenous BMP antagonist Follistatin-like 1 (Fstl1) is highly expressed in pulmonary vascular endothelium of the developing mouse lung, suggesting a role in pulmonary vascular formation and vascular homeostasis. The aim of this study was to investigate the role of Fstl1 in the pulmonary vascular endothelium. To this aim, Fstl1 was conditionally deleted from endothelial and endothelial-derived cells using Tie2-cre driven Fstl1-KO mice (Fstl1-eKO mice). Endothelial-specific Fstl1 deletion was postnatally lethal, as ∼70% of Fstl1-eKO mice died at three weeks after birth. Deletion of Fstl1 from endothelium resulted in a reduction of right ventricular output at three weeks after birth compared with controls. This was associated with pulmonary vascular remodeling, as the percentage of actin-positive small pulmonary vessels was increased at three weeks in Fstl1-eKO mice compared with controls. Endothelial deletion of Fstl1 resulted in activation of Smad1/5/8 signaling and increased BMP/Smad-regulated gene expression of Jagged1, Endoglin, and Gata2 at one week after birth compared with controls. In addition, potent vasoconstrictor Endothelin-1, the expression of which is driven by Gata2, was increased in expression, both on the mRNA and protein levels, at one week after birth compared with controls. At three weeks, Jagged1 was reduced in the Fstl1-eKO mice whereas Endoglin and Endothelin-1 were unchanged. In conclusion, loss of endothelial Fstl1 in the lung is associated with elevated BMP-regulated genes, impaired small pulmonary vascular remodeling, and decreased right ventricular output. PMID:28680581

Endothelial follistatin-like-1 regulates the postnatal development of the pulmonary vasculature by modulating BMP/Smad signaling.

PubMed

Tania, Navessa P; Maarsingh, Harm; T Bos, I Sophie; Mattiotti, Andrea; Prakash, Stuti; Timens, Wim; Gunst, Quinn D; Jimenez-Borreguero, Luis J; Schmidt, Martina; van den Hoff, Maurice J B; Gosens, Reinoud

2017-03-01

Bone morphogenetic protein (BMP) signaling regulates vascular smooth muscle maturation, endothelial cell proliferation, and tube formation. The endogenous BMP antagonist Follistatin-like 1 (Fstl1) is highly expressed in pulmonary vascular endothelium of the developing mouse lung, suggesting a role in pulmonary vascular formation and vascular homeostasis. The aim of this study was to investigate the role of Fstl1 in the pulmonary vascular endothelium. To this aim, Fstl1 was conditionally deleted from endothelial and endothelial-derived cells using Tie2-cre driven Fstl1 -KO mice ( Fstl1 -eKO mice). Endothelial-specific Fstl1 deletion was postnatally lethal, as ∼70% of Fstl1 -eKO mice died at three weeks after birth. Deletion of Fstl1 from endothelium resulted in a reduction of right ventricular output at three weeks after birth compared with controls. This was associated with pulmonary vascular remodeling, as the percentage of actin-positive small pulmonary vessels was increased at three weeks in Fstl1 -eKO mice compared with controls. Endothelial deletion of Fstl1 resulted in activation of Smad1/5/8 signaling and increased BMP/Smad-regulated gene expression of Jagged1, Endoglin, and Gata2 at one week after birth compared with controls. In addition, potent vasoconstrictor Endothelin-1, the expression of which is driven by Gata2, was increased in expression, both on the mRNA and protein levels, at one week after birth compared with controls. At three weeks, Jagged1 was reduced in the Fstl1 -eKO mice whereas Endoglin and Endothelin-1 were unchanged. In conclusion, loss of endothelial Fstl1 in the lung is associated with elevated BMP-regulated genes, impaired small pulmonary vascular remodeling, and decreased right ventricular output.

The Hypoxic Response Contributes to Altered Gene Expression and Pre-Capillary Pulmonary Hypertension in Patients with Sickle Cell Disease

PubMed Central

Zhang, Xu; Zhang, Wei; Ma, Shwu-Fan; Desai, Ankit A.; Saraf, Santosh; Miasniakova, Galina; Sergueeva, Adelina; Ammosova, Tatiana; Xu, Min; Nekhai, Sergei; Abbasi, Taimur; Casanova, Nancy G.; Steinberg, Martin H.; Baldwin, Clinton T.; Sebastiani, Paola; Prchal, Josef T.; Kittles, Rick; Garcia, Joe G. N.; Machado, Roberto F.; Gordeuk, Victor R.

2014-01-01

Background We postulated that the hypoxic response in sickle cell disease (SCD) contributes to altered gene expression and pulmonary hypertension, a complication associated with early mortality. Methods and Results To identify genes regulated by the hypoxic response and not other effects of chronic anemia, we compared expression variation in peripheral blood mononuclear cells from 13 SCD subjects with hemoglobin SS genotype and 15 Chuvash polycythemia subjects (VHLR200W homozygotes with constitutive up-regulation of hypoxia inducible factors in the absence of anemia or hypoxia). At 5% false discovery rate, 1040 genes exhibited >1.15 fold change in both conditions; 297 were up-regulated and 743 down-regulated including MAPK8 encoding a mitogen-activated protein kinase important for apoptosis, T-cell differentiation and inflammatory responses. Association mapping with a focus on local regulatory polymorphisms in 61 SCD patients identified expression quantitative trait loci (eQTL) for 103 of these hypoxia response genes. In a University of Illinois SCD cohort the A allele of a MAPK8 eQTL, rs10857560, was associated with pre-capillary pulmonary hypertension defined as mean pulmonary artery pressure ≥25 and pulmonary capillary wedge pressure ≤15 mm Hg at right heart catheterization (allele frequency=0.66; OR=13.8, P=0.00036, n=238). This association was confirmed in an independent Walk-PHaSST cohort (allele frequency=0.65; OR=11.3, P=0.0025, n=519). The homozygous AA genotype of rs10857560 was associated with decreased MAPK8 expression and present in all 14 identified pre-capillary pulmonary hypertension cases among the combined 757 patients. Conclusions Our study demonstrates a prominent hypoxic transcription component in SCD and a MAPK8 eQTL associated with pre-capillary pulmonary hypertension. PMID:24515990

NFE2L2 pathway polymorphisms and lung function decline in chronic obstructive pulmonary disease

PubMed Central

Malhotra, Deepti; Boezen, H. Marike; Siedlinski, Mateusz; Postma, Dirkje S.; Wong, Vivien; Akhabir, Loubna; He, Jian-Qing; Connett, John E.; Anthonisen, Nicholas R.; Paré, Peter D.; Biswal, Shyam

2012-01-01

An oxidant-antioxidant imbalance in the lung contributes to the development of chronic obstructive pulmonary disease (COPD) that is caused by a complex interaction of genetic and environmental risk factors. Nuclear erythroid 2-related factor 2 (NFE2L2 or NRF2) is a critical molecule in the lung's defense mechanism against oxidants. We investigated whether polymorphisms in the NFE2L2 pathway affected the rate of decline of lung function in smokers from the Lung Health Study (LHS)(n = 547) and in a replication set, the Vlagtwedde-Vlaardingen cohort (n = 533). We selected polymorphisms in NFE2L2 in genes that positively or negatively regulate NFE2L2 transcriptional activity and in genes that are regulated by NFE2L2. Polymorphisms in 11 genes were significantly associated with rate of lung function decline in the LHS. One of these polymorphisms, rs11085735 in the KEAP1 gene, was previously shown to be associated with the level of lung function in the Vlagtwedde-Vlaardingen cohort but not with decline of lung function. Of the 23 associated polymorphisms in the LHS, only rs634534 in the FOSL1 gene showed a significant association in the Vlagtwedde-Vlaardingen cohort with rate of lung function decline, but the direction of the association was not consistent with that in the LHS. In summary, despite finding several nominally significant polymorphisms in the LHS, none of these associations were replicated in the Vlagtwedde-Vlaardingen cohort, indicating lack of effect of polymorphisms in the NFE2L2 pathway on the rate of decline of lung function. PMID:22693272

NFE2L2 pathway polymorphisms and lung function decline in chronic obstructive pulmonary disease.

PubMed

Sandford, Andrew J; Malhotra, Deepti; Boezen, H Marike; Siedlinski, Mateusz; Postma, Dirkje S; Wong, Vivien; Akhabir, Loubna; He, Jian-Qing; Connett, John E; Anthonisen, Nicholas R; Paré, Peter D; Biswal, Shyam

2012-08-01

An oxidant-antioxidant imbalance in the lung contributes to the development of chronic obstructive pulmonary disease (COPD) that is caused by a complex interaction of genetic and environmental risk factors. Nuclear erythroid 2-related factor 2 (NFE2L2 or NRF2) is a critical molecule in the lung's defense mechanism against oxidants. We investigated whether polymorphisms in the NFE2L2 pathway affected the rate of decline of lung function in smokers from the Lung Health Study (LHS)(n = 547) and in a replication set, the Vlagtwedde-Vlaardingen cohort (n = 533). We selected polymorphisms in NFE2L2 in genes that positively or negatively regulate NFE2L2 transcriptional activity and in genes that are regulated by NFE2L2. Polymorphisms in 11 genes were significantly associated with rate of lung function decline in the LHS. One of these polymorphisms, rs11085735 in the KEAP1 gene, was previously shown to be associated with the level of lung function in the Vlagtwedde-Vlaardingen cohort but not with decline of lung function. Of the 23 associated polymorphisms in the LHS, only rs634534 in the FOSL1 gene showed a significant association in the Vlagtwedde-Vlaardingen cohort with rate of lung function decline, but the direction of the association was not consistent with that in the LHS. In summary, despite finding several nominally significant polymorphisms in the LHS, none of these associations were replicated in the Vlagtwedde-Vlaardingen cohort, indicating lack of effect of polymorphisms in the NFE2L2 pathway on the rate of decline of lung function.

Three-dimensional computed tomographic volumetry precisely predicts the postoperative pulmonary function.

PubMed

Kobayashi, Keisuke; Saeki, Yusuke; Kitazawa, Shinsuke; Kobayashi, Naohiro; Kikuchi, Shinji; Goto, Yukinobu; Sakai, Mitsuaki; Sato, Yukio

2017-11-01

It is important to accurately predict the patient's postoperative pulmonary function. The aim of this study was to compare the accuracy of predictions of the postoperative residual pulmonary function obtained with three-dimensional computed tomographic (3D-CT) volumetry with that of predictions obtained with the conventional segment-counting method. Fifty-three patients scheduled to undergo lung cancer resection, pulmonary function tests, and computed tomography were enrolled in this study. The postoperative residual pulmonary function was predicted based on the segment-counting and 3D-CT volumetry methods. The predicted postoperative values were compared with the results of postoperative pulmonary function tests. Regarding the linear correlation coefficients between the predicted postoperative values and the measured values, those obtained using the 3D-CT volumetry method tended to be higher than those acquired using the segment-counting method. In addition, the variations between the predicted and measured values were smaller with the 3D-CT volumetry method than with the segment-counting method. These results were more obvious in COPD patients than in non-COPD patients. Our findings suggested that the 3D-CT volumetry was able to predict the residual pulmonary function more accurately than the segment-counting method, especially in patients with COPD. This method might lead to the selection of appropriate candidates for surgery among patients with a marginal pulmonary function.

Role of Autonomic Reflex Arcs in Cardiovascular Responses to Air Pollution Exposure

PubMed Central

Hazari, Mehdi S.; Farraj, Aimen K.

2016-01-01

The body responds to environmental stressors by triggering autonomic reflexes in the pulmonary receptors, baroreceptors, and chemoreceptors to maintain homeostasis. Numerous studies have shown that exposure to various gases and airborne particles can alter the functional outcome of these reflexes, particularly with respect to the cardiovascular system. Modulation of autonomic neural input to the heart and vasculature following direct activation of sensory nerves in the respiratory system, elicitation of oxidative stress and inflammation, or through other mechanisms is one of the primary ways that exposure to air pollution affects normal cardiovascular function. Any homeostatic process that utilizes the autonomic nervous system to regulate organ function might be affected. Thus, air pollution and other inhaled environmental irritants have the potential to alter both local airway function and baro-and chemoreflex responses, which modulate autonomic control of blood pressure and detect concentrations of key gases in the body. While each of these reflex pathways causes distinct responses, the systems are heavily integrated and communicate through overlapping regions of the brainstem to cause global effects. This short review summarizes the function of major pulmonary sensory receptors, baroreceptors, and carotid body chemoreceptors and discusses the impacts of air pollution exposure on these systems. PMID:25123706

Effects of Bisphenol A Metabolite 4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene on Lung Function and Type 2 Pulmonary Alveolar Epithelial Cell Growth

PubMed Central

Liu, Shing-Hwa; Su, Chin-Chuan; Lee, Kuan-I; Chen, Ya-Wen

2016-01-01

Bisphenol A (BPA) is recognized as a major pollutant worldwide. 4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP) is a major active metabolite of BPA. The epidemiological and animal studies have reported that BPA is harmful to lung function. The role of MBP in lung dysfunction after BPA exposure still remains unclear. This study investigated whether MBP would induce lung alveolar cell damage and evaluated the role of MBP in the BPA exposure-induced lung dysfunction. An in vitro type 2 alveolar epithelial cell (L2) model and an ex vivo isolated reperfused rat lung model were used to determine the effects of BPA or MBP on cell growth and lung function. MBP, but not BPA, dose-dependently increased the mean artery pressure (Pa), pulmonary capillary pressure (Pc), pulmonary capillary filtration coefficient (Kfc), and wet/dry weight ratio in isolated reperfused rat lungs. MBP significantly reduced cell viability and induced caspases-3/7 cleavage and apoptosis and increased AMP-activated protein kinas (AMPK) phosphorylation and endoplasmic reticulum (ER) stress-related molecules expression in L2 cells, which could be reversed by AMPK-siRNA transfection. These findings demonstrated for the first time that MBP exposure induced type 2 alveolar cell apoptosis and lung dysfunction through an AMPK-regulated ER stress signaling pathway. PMID:27982077

Effects of Bisphenol A Metabolite 4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene on Lung Function and Type 2 Pulmonary Alveolar Epithelial Cell Growth.

PubMed

Liu, Shing-Hwa; Su, Chin-Chuan; Lee, Kuan-I; Chen, Ya-Wen

2016-12-16

Bisphenol A (BPA) is recognized as a major pollutant worldwide. 4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP) is a major active metabolite of BPA. The epidemiological and animal studies have reported that BPA is harmful to lung function. The role of MBP in lung dysfunction after BPA exposure still remains unclear. This study investigated whether MBP would induce lung alveolar cell damage and evaluated the role of MBP in the BPA exposure-induced lung dysfunction. An in vitro type 2 alveolar epithelial cell (L2) model and an ex vivo isolated reperfused rat lung model were used to determine the effects of BPA or MBP on cell growth and lung function. MBP, but not BPA, dose-dependently increased the mean artery pressure (Pa), pulmonary capillary pressure (Pc), pulmonary capillary filtration coefficient (K fc ), and wet/dry weight ratio in isolated reperfused rat lungs. MBP significantly reduced cell viability and induced caspases-3/7 cleavage and apoptosis and increased AMP-activated protein kinas (AMPK) phosphorylation and endoplasmic reticulum (ER) stress-related molecules expression in L2 cells, which could be reversed by AMPK-siRNA transfection. These findings demonstrated for the first time that MBP exposure induced type 2 alveolar cell apoptosis and lung dysfunction through an AMPK-regulated ER stress signaling pathway.

Adiponectin Attenuates Lung Fibroblasts Activation and Pulmonary Fibrosis Induced by Paraquat

PubMed Central

He, Ya-rong; Lau, Wayne Bond; Zeng, Zhi; Liang, Zong-an

2015-01-01

Pulmonary fibrosis is one of the most common complications of paraquat (PQ) poisoning, which demands for more effective therapies. Accumulating evidence suggests adiponectin (APN) may be a promising therapy against fibrotic diseases. In the current study, we determine whether the exogenous globular APN isoform protects against pulmonary fibrosis in PQ-treated mice and human lung fibroblasts, and dissect the responsible underlying mechanisms. BALB/C mice were divided into control group, PQ group, PQ + low-dose APN group, and PQ + high-dose APN group. Mice were sacrificed 3, 7, 14, and 21 days after PQ treatment. We compared pulmonary histopathological changes among different groups on the basis of fibrosis scores, TGF-β1, CTGF and α-SMA pulmonary content via Western blot and real-time quantitative fluorescence-PCR (RT-PCR). Blood levels of MMP-9 and TIMP-1 were determined by ELISA. Human lung fibroblasts WI-38 were divided into control group, PQ group, APN group, and APN receptor (AdipoR) 1 small-interfering RNA (siRNA) group. Fibroblasts were collected 24, 48, and 72 hours after PQ exposure for assay. Cell viability and apoptosis were determined via Kit-8 (CCK-8) and fluorescein Annexin V-FITC/PI double labeling. The protein and mRNA expression level of collagen type III, AdipoR1, and AdipoR2 were measured by Western blot and RT-PCR. APN treatment significantly decreased the lung fibrosis scores, protein and mRNA expression of pulmonary TGF-β1, CTGF and α-SMA content, and blood MMP-9 and TIMP-1 in a dose-dependent manner (p<0.05). Pretreatment with APN significantly attenuated the reduced cell viability and up-regulated collagen type III expression induced by PQ in lung fibroblasts, (p<0.05). APN pretreatment up-regulated AdipoR1, but not AdipoR2, expression in WI-38 fibroblasts. AdipoR1 siRNA abrogated APN-mediated protective effects in PQ-exposed fibroblasts. Taken together, our data suggests APN protects against PQ-induced pulmonary fibrosis in a dose-dependent manner, via suppression of lung fibroblast activation. Functional AdipoR1 are expressed by human WI-38 lung fibroblasts, suggesting potential future clinical applicability of APN against pulmonary fibrosis. PMID:25945502

Pulmonary edema in meningococcal septicemia associated with reduced epithelial chloride transport.

PubMed

Eisenhut, Michael; Wallace, Helen; Barton, Paul; Gaillard, Erol; Newland, Paul; Diver, Michael; Southern, Kevin W

2006-03-01

To test the hypothesis that meningococcal septicemia-related pulmonary edema is associated with a systemic abnormality of epithelial sodium and chloride transport and to investigate an association with hormones regulating Na transport. Prospective observational study. The 24-bed pediatric intensive care unit and pediatric wards of Royal Liverpool Children's Hospital. Consecutive children admitted to the pediatric intensive care unit and pediatric wards with a diagnosis of meningococcal septicemia and children (controls) with noninfectious critical illness receiving ventilatory support in the pediatric intensive care unit. We measured sweat and saliva electrolytes, renal electrolyte excretion, nasal potential difference, and aldosterone, thyroxine, and cortisol levels. Pulmonary edema was diagnosed by chest radiography and its severity quantified by calculation of ventilation index at admission and duration of mechanical ventilation. We recruited 17 patients with severe meningococcal septicemia (nine patients with pulmonary edema), 14 patients with mild meningococcal septicemia, and 20 controls. Sweat and saliva Na and Cl concentrations and renal Na excretion were significantly (p < .05) higher in patients with pulmonary edema compared with controls. Nasal potential difference and amiloride response in patients with pulmonary edema were not significantly different to controls, but response to a low Cl solution was reduced in the nasal airway of patients with pulmonary edema (p < .05). Sweat and saliva chloride concentrations correlated significantly and better with ventilation index and duration of ventilation than sodium concentrations. Aldosterone, thyroxine, and cortisol levels were not significantly different between groups. We have confirmed that meningococcal septicemia-related pulmonary edema is associated with reduced systemic sodium and chloride transport. Features of reduced Cl transport were most closely associated with markers of respiratory compromise, and this was supported by the reduced chloride channel function detected on nasal potential difference measurement.

Bone Marrow CD11c+ Cell-Derived Amphiregulin Promotes Pulmonary Fibrosis.

PubMed

Ding, Lin; Liu, Tianju; Wu, Zhe; Hu, Biao; Nakashima, Taku; Ullenbruch, Matthew; Gonzalez De Los Santos, Francina; Phan, Sem H

2016-07-01

Amphiregulin (AREG), an epidermal growth factor receptor ligand, is implicated in tissue repair and fibrosis, but its cellular source and role in regeneration versus fibrosis remain unclear. In this study, we hypothesize that AREG induced in bone marrow-derived CD11c(+) cells is essential for pulmonary fibrosis. Thus, the objectives were to evaluate the importance and role of AREG in pulmonary fibrosis, identify the cellular source of AREG induction, and analyze its regulation of fibroblast function and activation. The results showed that lung AREG expression was significantly induced in bleomycin-induced pulmonary fibrosis. AREG deficiency in knockout mice significantly diminished pulmonary fibrosis. Analysis of AREG expression in major lung cell types revealed induction in fibrotic lungs predominantly occurred in CD11c(+) cells. Moreover, depletion of bone marrow-derived CD11c(+) cells suppressed both induction of lung AREG expression and pulmonary fibrosis. Conversely, adoptive transfer of bone marrow-derived CD11c(+) cells from bleomycin-treated donor mice exacerbated pulmonary fibrosis, but not if the donor cells were made AREG deficient prior to transfer. CD11c(+) cell-conditioned media or coculture stimulated fibroblast proliferation, activation, and myofibroblast differentiation in an AREG-dependent manner. Furthermore, recombinant AREG induced telomerase reverse transcriptase, which appeared to be essential for the proliferative effect. Finally, AREG significantly enhanced fibroblast motility, which was associated with increased expression of α6 integrin. These findings suggested that induced AREG specifically in recruited bone marrow-derived CD11c(+) cells promoted bleomycin-induced pulmonary fibrosis by activation of fibroblast telomerase reverse transcriptase-dependent proliferation, motility, and indirectly, myofibroblast differentiation. Copyright © 2016 by The American Association of Immunologists, Inc.

Longitudinal analysis of pulmonary dysfunction in the initial years of employment in the grain industry.

PubMed

Olfert, S M; Pahwa, P; Dosman, J A

2005-11-01

The negative health effects of exposure to grain dust have previously been examined, but few studies have observed the effects on newly hired employees. Young grain workers are of interest because changes in pulmonary function may occur after a short duration of employment, and because older grain workers may represent a survivor population. The New Grain Workers Study (NGWS), a longitudinal study of 299 newly hired male grain industry workers, was conducted between 1980 and 1985. The objectives were to determine the effects of employment in the grain industry on pulmonary function. Pre-employment physical examinations and pulmonary function tests were conducted on subjects at the Division of Respiratory Medicine, Department of Medicine, Royal University Hospital, University of Saskatchewan. The Grain Dust Medical Surveillance Program (GDMSP) was a Labour Canada program that began in 1978. All subjects were grain workers employed in the grain industry in Saskatchewan. All subjects completed a respiratory symptoms questionnaire and underwent pulmonary function testing. Baseline observations were recorded every three years between 1978 and 1993. Data were available on 2184 grain workers. Generalized estimating equations were used to fit marginal and transitional multivariable regression models to determine the effects of grain dust exposure on pulmonary function. Marginal and transitional models were then compared. Height, exposure weeks, and previous FVC were predictive of FVC in the NGWS, while exposure weeks and previous FEV1 were predictive of FEV1. These models, as well as a transitional regression model built using the GDMSP data, were used to compute predicted mean annual decline inpulmonary function. Non-smoking grain workers in the NGWS had the highest pulmonary function test values, but also had the greatest predicted annual decline in pulmonary function. Ever-smoking grain workers in the GDMSP had the lowest pulmonary function test values. Non-smoking grain workers in the GDMSP had the least predicted annual decline in pulmonary function.

The role of nitric oxide in regulation of the cardiovascular system in reptiles.

PubMed

Skovgaard, Nini; Galli, Gina; Abe, Augusto; Taylor, Edwin W; Wang, Tobias

2005-10-01

The roles that nitric oxide (NO) plays in the cardiovascular system of reptiles are reviewed, with particular emphasis on its effects on central vascular blood flows in the systemic and pulmonary circulations. New data is presented that describes the effects on hemodynamic variables in varanid lizards of exogenously administered NO via the nitric oxide donor sodium nitroprusside (SNP) and inhibition of nitric oxide synthase (NOS) by l-nitroarginine methyl ester (l-NAME). Furthermore, preliminary data on the effects of SNP on hemodynamic variables in the tegu lizard are presented. The findings are compared with previously published data from our laboratory on three other species of reptiles: pythons (), rattlesnakes () and turtles (). These five species of reptiles possess different combinations of division of the heart and structural complexity of the lungs. Comparison of their responses to NO donors and NOS inhibitors may reveal whether the potential contribution of NO to vascular tone correlates with pulmonary complexity and/or with blood pressure. All existing studies on reptiles have clearly established a potential role for NO in regulating vascular tone in the systemic circulation and NO may be important for maintaining basal systemic vascular tone in varanid lizards, pythons and turtles, through a continuous release of NO. In contrast, the pulmonary circulation is less responsive to NO donors or NOS inhibitors, and it was only in pythons and varanid lizards that the lungs responded to SNP. Both species have a functionally separated heart, so it is possible that NO may exert a larger role in species with low pulmonary blood pressures, irrespective of lung complexity.

Aspergillus fumigatus Preexposure Worsens Pathology and Improves Control of Mycobacterium abscessus Pulmonary Infection in Mice.

PubMed

Monin, Leticia; Mehta, Shail; Elsegeiny, Waleed; Gopal, Radha; McAleer, Jeremy P; Oury, Tim D; Kolls, Jay; Khader, Shabaana A

2018-03-01

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Mutations in this chloride channel lead to mucus accumulation, subsequent recurrent pulmonary infections, and inflammation, which, in turn, cause chronic lung disease and respiratory failure. Recently, rates of nontuberculous mycobacterial (NTM) infections in CF patients have been increasing. Of particular relevance is infection with Mycobacterium abscessus , which causes a serious, life-threatening disease and constitutes one of the most antibiotic-resistant NTM species. Interestingly, an increased prevalence of NTM infections is associated with worsening lung function in CF patients who are also coinfected with Aspergillus fumigatus We established a new mouse model to investigate the relationship between A. fumigatus and M. abscessus pulmonary infections. In this model, animals exposed to A. fumigatus and coinfected with M. abscessus exhibited increased lung inflammation and decreased mycobacterial burden compared with those of mice infected with M. abscessus alone. This increased control of M. abscessus infection in coinfected mice was mucus independent but dependent on both transcription factors T-box 21 (Tbx21) and retinoic acid receptor (RAR)-related orphan receptor gamma t (RORγ-t), master regulators of type 1 and type 17 immune responses, respectively. These results implicate a role for both type 1 and type 17 responses in M. abscessus control in A. fumigatus -coinfected lungs. Our results demonstrate that A. fumigatus , an organism found commonly in CF patients with NTM infection, can worsen pulmonary inflammation and impact M. abscessus control in a mouse model. Copyright © 2018 American Society for Microbiology.

Quantitative computed tomography for the prediction of pulmonary function after lung cancer surgery: a simple method using simulation software.

PubMed

Ueda, Kazuhiro; Tanaka, Toshiki; Li, Tao-Sheng; Tanaka, Nobuyuki; Hamano, Kimikazu

2009-03-01

The prediction of pulmonary functional reserve is mandatory in therapeutic decision-making for patients with resectable lung cancer, especially those with underlying lung disease. Volumetric analysis in combination with densitometric analysis of the affected lung lobe or segment with quantitative computed tomography (CT) helps to identify residual pulmonary function, although the utility of this modality needs investigation. The subjects of this prospective study were 30 patients with resectable lung cancer. A three-dimensional CT lung model was created with voxels representing normal lung attenuation (-600 to -910 Hounsfield units). Residual pulmonary function was predicted by drawing a boundary line between the lung to be preserved and that to be resected, directly on the lung model. The predicted values were correlated with the postoperative measured values. The predicted and measured values corresponded well (r=0.89, p<0.001). Although the predicted values corresponded with values predicted by simple calculation using a segment-counting method (r=0.98), there were two outliers whose pulmonary functional reserves were predicted more accurately by CT than by segment counting. The measured pulmonary functional reserves were significantly higher than the predicted values in patients with extensive emphysematous areas (<-910 Hounsfield units), but not in patients with chronic obstructive pulmonary disease. Quantitative CT yielded accurate prediction of functional reserve after lung cancer surgery and helped to identify patients whose functional reserves are likely to be underestimated. Hence, this modality should be utilized for patients with marginal pulmonary function.

Differential roles of endothelin-1 ETA and ETB receptors and vasoactive intestinal polypeptide in regulation of the airways and the pulmonary vasculature in isolated rat lung.

PubMed

Janosi, Tibor; Peták, Ferenc; Fontao, Fabienne; Morel, Denis R; Beghetti, Maurice; Habre, Walid

2008-11-01

The available treatment strategies against pulmonary hypertension include the administration of endothelin-1 (ET-1) receptor subtype blockers (ET(A) and ET(B) antagonists); vasoactive intestinal polypeptide (VIP) has recently been suggested as a potential new therapeutic agent. We set out to investigate the ability of these agents to protect against the vasoconstriction and impairment of lung function commonly observed in patients with pulmonary hypertension. An ET(A) blocker (BQ123), ET(B) blocker (BQ788), a combination of these selective blockers (ET(A) + ET(B) blockers) or VIP (V6130) was administered into the pulmonary circulation in four groups of perfused normal rat lungs. Pulmonary vascular resistance (PVR) and forced oscillatory lung input impedance (Z(L)) were measured in all groups under baseline conditions and at 1 min intervals following ET-1 administrations. The airway resistance, inertance, tissue damping and elastance were extracted from the Z(L) spectra. While VIP, ET(A) blocker and combined ET(A) and ET(B) blockers significantly prevented the pulmonary vasoconstriction induced by ET-1, ET(B) blockade enhanced the ET-1-induced increases in PVR. In contrast, the ET(A) and ET(B) blockers markedly elevated the ET-1-induced increases in airway resistance, while VIP blunted this constrictor response. Our results suggest that VIP potently acts against the airway and pulmonary vascular constriction mediated by endothelin-1, while the ET(A) and ET(B) blockers exert a differential effect between airway resistance and PVR.

Effects of whole body vibration on pulmonary function, functional exercise capacity and quality of life in people with chronic obstructive pulmonary disease: a systematic review.

PubMed

Yang, Xiaotian; Zhou, Yujing; Wang, Pu; He, Chengqi; He, Hongchen

2016-05-01

To examine the effect of whole-body vibration in enhancing pulmonary function, functional exercise capacity and quality of life in people with chronic obstructive pulmonary disease and examine its safety. Randomized controlled trials examining the effects of whole body vibration among people with chronic obstructive pulmonary disease were identified by two independent researchers. Articles were excluded if they were studies on people with other primary diagnosis, abstracts published in the conferences or books. PEDro scale was used to assess the methodological quality of the selected studies. We evaluated the level of evidence by using the GRADE approach. The results were extracted by two researchers and confirmed by the third researcher if disagreement existed. Sources included Cochrane Central Register of Controlled Trials, PubMed, CINAHL, EMBASE, PEDro, AMED, PsycINFO, ClinicalTrials.gov, Current Controlled Trials and reference lists of all relevant articles. Four studies involving 206 participants were included in this systematic review. Methodological quality was rated as good for two studies. No great benefits on pulmonary function were found in whole body vibration treatment group. Two studies showed that quality of life was improved in people with chronic obstructive pulmonary disease. Whole body vibration led to significant improvements in functional exercise capacity measured with six minutes walking test. Nearly no adverse events were observed. Whole body vibration may improve functional exercise capacity and quality of life in people with chronic obstructive pulmonary disease. There was insufficient evidence to prove the effects of whole body vibration on pulmonary function. © The Author(s) 2015.

The immediate effect of individual manipulation techniques on pulmonary function measures in persons with chronic obstructive pulmonary disease

PubMed Central

Noll, Donald R; Johnson, Jane C; Baer, Robert W; Snider, Eric J

2009-01-01

Background The use of manipulation has long been advocated in the treatment of chronic obstructive pulmonary disease (COPD), but few randomized controlled clinical trials have measured the effect of manipulation on pulmonary function. In addition, the effects of individual manipulative techniques on the pulmonary system are poorly understood. Therefore, the purpose of this study was to determine the immediate effects of four osteopathic techniques on pulmonary function measures in persons with COPD relative to a minimal-touch control protocol. Methods Persons with COPD aged 50 and over were recruited for the study. Subjects received five, single-technique treatment sessions: minimal-touch control, thoracic lymphatic pump (TLP) with activation, TLP without activation, rib raising, and myofascial release. There was a 4-week washout period between sessions. Protocols were given in random order until all five techniques had been administered. Pulmonary function measures were obtained at baseline and 30-minutes posttreatment. For the actual pulmonary function measures and percent predicted values, Wilcoxon signed rank tests were used to test within-technique changes from baseline. For the percent change from baseline, Friedman tests were used to test for between-technique differences. Results Twenty-five subjects were enrolled in the study. All four tested osteopathic techniques were associated with adverse posttreatment changes in pulmonary function measures; however, different techniques changed different measures. TLP with activation increased posttreatment residual volume compared to baseline, while TLP without activation did not. Side effects were mild, mostly posttreatment chest wall soreness. Surprisingly, the majority of subjects believed they could breathe better after receiving osteopathic manipulation. Conclusion In persons with COPD, TLP with activation, TLP without activation, rib raising, and myofascial release mildly worsened pulmonary function measures immediately posttreatment relative to baseline measurements. The activation component of the TLP technique appears to increase posttreatment residual volume. Despite adverse changes in pulmonary function measures, persons with COPD subjectively reported they benefited from osteopathic manipulation. PMID:19814829

The immediate effect of individual manipulation techniques on pulmonary function measures in persons with chronic obstructive pulmonary disease.

PubMed

Noll, Donald R; Johnson, Jane C; Baer, Robert W; Snider, Eric J

2009-10-08

The use of manipulation has long been advocated in the treatment of chronic obstructive pulmonary disease (COPD), but few randomized controlled clinical trials have measured the effect of manipulation on pulmonary function. In addition, the effects of individual manipulative techniques on the pulmonary system are poorly understood. Therefore, the purpose of this study was to determine the immediate effects of four osteopathic techniques on pulmonary function measures in persons with COPD relative to a minimal-touch control protocol. Persons with COPD aged 50 and over were recruited for the study. Subjects received five, single-technique treatment sessions: minimal-touch control, thoracic lymphatic pump (TLP) with activation, TLP without activation, rib raising, and myofascial release. There was a 4-week washout period between sessions. Protocols were given in random order until all five techniques had been administered. Pulmonary function measures were obtained at baseline and 30-minutes posttreatment. For the actual pulmonary function measures and percent predicted values, Wilcoxon signed rank tests were used to test within-technique changes from baseline. For the percent change from baseline, Friedman tests were used to test for between-technique differences. Twenty-five subjects were enrolled in the study. All four tested osteopathic techniques were associated with adverse posttreatment changes in pulmonary function measures; however, different techniques changed different measures. TLP with activation increased posttreatment residual volume compared to baseline, while TLP without activation did not. Side effects were mild, mostly posttreatment chest wall soreness. Surprisingly, the majority of subjects believed they could breathe better after receiving osteopathic manipulation. In persons with COPD, TLP with activation, TLP without activation, rib raising, and myofascial release mildly worsened pulmonary function measures immediately posttreatment relative to baseline measurements. The activation component of the TLP technique appears to increase posttreatment residual volume. Despite adverse changes in pulmonary function measures, persons with COPD subjectively reported they benefited from osteopathic manipulation.

21 CFR 868.1900 - Diagnostic pulmonary-function interpretation calculator.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Diagnostic pulmonary-function interpretation calculator. 868.1900 Section 868.1900 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND... pulmonary-function values. (b) Classification. Class II (performance standards). ...

21 CFR 868.1900 - Diagnostic pulmonary-function interpretation calculator.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Diagnostic pulmonary-function interpretation calculator. 868.1900 Section 868.1900 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND... pulmonary-function values. (b) Classification. Class II (performance standards). ...

Supplementation of iron in pulmonary hypertension: Rationale and design of a phase II clinical trial in idiopathic pulmonary arterial hypertension

PubMed Central

Howard, Luke S.G.E.; Watson, Geoffrey M.J.; Wharton, John; Rhodes, Christopher J.; Chan, Kakit; Khengar, Rajeshree; Robbins, Peter A.; Kiely, David G.; Condliffe, Robin; Elliott, Charlie A.; Pepke-Zaba, Joanna; Sheares, Karen; Morrell, Nicholas W.; Davies, Rachel; Ashby, Deborah; Gibbs, J. Simon R.; Wilkins, Martin R.

2013-01-01

Our aim is to assess the safety and potential clinical benefit of intravenous iron (Ferinject) infusion in iron deficient patients with idiopathic pulmonary arterial hypertension (IPAH). Iron deficiency in the absence of anemia (1) is common in patients with IPAH; (2) is associated with inappropriately raised levels of hepcidin, the key regulator of iron homeostasis; and (3) correlates with disease severity and worse clinical outcomes. Oral iron absorption may be impeded by reduced absorption due to elevated hepcidin levels. The safety and benefits of parenteral iron replacement in IPAH are unknown. Supplementation of Iron in Pulmonary Hypertension (SIPHON) is a Phase II, multicenter, double-blind, randomized, placebo-controlled, crossover clinical trial of iron in IPAH. At least 60 patients will be randomized to intravenous ferric carboxymaltose (Ferinject) or saline placebo with a crossover point after 12 weeks of treatment. The primary outcome will be the change in resting pulmonary vascular resistance from baseline at 12 weeks, measured by cardiac catheterization. Secondary measures include resting and exercise hemodynamics and exercise performance from serial bicycle incremental and endurance cardiopulmonary exercise tests. Other secondary measurements include serum iron indices, 6-Minute Walk Distance, WHO functional class, quality of life score, N-terminal pro-brain natriuretic peptide (NT-proBNP), and cardiac anatomy and function from cardiac magnetic resonance. We propose that intravenous iron replacement will improve hemodynamics and clinical outcomes in IPAH. If the data supports a potentially useful therapeutic effect and suggest this drug is safe, the study will be used to power a Phase III study to address efficacy. PMID:23662181

Differential Expression of VEGF-Axxx Isoforms Is Critical for Development of Pulmonary Fibrosis.

PubMed

Barratt, Shaney L; Blythe, Thomas; Jarrett, Caroline; Ourradi, Khadija; Shelley-Fraser, Golda; Day, Michael J; Qiu, Yan; Harper, Steve; Maher, Toby M; Oltean, Sebastian; Hames, Thomas J; Scotton, Chris J; Welsh, Gavin I; Bates, David O; Millar, Ann B

2017-08-15

Fibrosis after lung injury is related to poor outcome, and idiopathic pulmonary fibrosis (IPF) can be regarded as an exemplar. Vascular endothelial growth factor (VEGF)-A has been implicated in this context, but there are conflicting reports as to whether it is a contributory or protective factor. Differential splicing of the VEGF-A gene produces multiple functional isoforms including VEGF-A 165 a and VEGF-A 165 b, a member of the inhibitory family. To date there is no clear information on the role of VEGF-A in IPF. To establish VEGF-A isoform expression and functional effects in IPF. We used tissue sections, plasma, and lung fibroblasts from patients with IPF and control subjects. In a bleomycin-induced lung fibrosis model we used wild-type MMTV mice and a triple transgenic mouse SPC-rtTA +/- TetoCre +/- LoxP-VEGF-A +/+ to conditionally induce VEGF-A isoform deletion specifically in the alveolar type II (ATII) cells of adult mice. IPF and normal lung fibroblasts differentially expressed and responded to VEGF-A 165 a and VEGF-A 165 b in terms of proliferation and matrix expression. Increased VEGF-A 165 b was detected in plasma of progressing patients with IPF. In a mouse model of pulmonary fibrosis, ATII-specific deficiency of VEGF-A or constitutive overexpression of VEGF-A 165 b inhibited the development of pulmonary fibrosis, as did treatment with intraperitoneal delivery of VEGF-A 165 b to wild-type mice. These results indicate that changes in the bioavailability of VEGF-A sourced from ATII cells, namely the ratio of VEGF-A xxx a to VEGF-A xxx b, are critical in development of pulmonary fibrosis and may be a paradigm for the regulation of tissue repair.

Stenotrophomonas maltophilia Virulence and Specific Variations in Trace Elements during Acute Lung Infection: Implications in Cystic Fibrosis

PubMed Central

Crocetta, Valentina; Consalvo, Ada; Zappacosta, Roberta; Di Ilio, Carmine; Di Bonaventura, Giovanni

2014-01-01

Metal ions are necessary for the proper functioning of the immune system, and, therefore, they might have a significant influence on the interaction between bacteria and host. Ionic dyshomeostasis has been recently observed also in cystic fibrosis (CF) patients, whose respiratory tract is frequently colonized by Stenotrophomonas maltophilia. For the first time, here we used an inductively mass spectrometry method to perform a spatial and temporal analysis of the pattern of changes in a broad range of major trace elements in response to pulmonary infection by S. maltophilia. To this, DBA/2 mouse lungs were comparatively infected by a CF strain and by an environmental one. Our results showed that pulmonary ionomic profile was significantly affected during infection. Infected mice showed increased lung levels of Mg, P, S, K, Zn, Se, and Rb. To the contrary, Mn, Fe, Co, and Cu levels resulted significantly decreased. Changes of element concentrations were correlated with pulmonary bacterial load and markers of inflammation, and occurred mostly on day 3 post-exposure, when severity of infection culminated. Interestingly, CF strain – significantly more virulent than the environmental one in our murine model - provoked a more significant impact in perturbing pulmonary metal homeostasis. Particularly, exposure to CF strain exclusively increased P and K levels, while decreased Fe and Mn ones. Overall, our data clearly indicate that S. maltophilia modulates pulmonary metal balance in a concerted and virulence-dependent manner highlighting the potential role of the element dyshomeostasis during the progression of S. maltophilia infection, probably exacerbating the harmful effects of the loss of CF transmembrane conductance regulator function. Further investigations are required to understand the biological significance of these alterations and to confirm they are specifically caused by S. maltophilia. PMID:24586389

Pulmonary functions in patients with subclinical hypothyroidism.

PubMed

Cakmak, Gulfidan; Saler, Tayyibe; Saglam, Zuhal Aydan; Yenigun, Mustafa; Ataoglu, Esra; Demir, Tuncalp; Temiz, Levent Umit

2011-10-01

To determine whether alterations in pulmonary function takes place in subclinical hypothyroidism by examining the diffusion lung capacity and muscle strength of such patients. This is a descriptive study conducted in 2009 at Haseki Training and Research Hospital, Istanbul, Turkey. Hundred and twenty-six patients with subclinical hypothyroidism and 58 age and sex matched individuals were recruited. Simple spirometry tests were performed, and pulmonary diffusion capacity (DLco) and muscle strength were measured. ScH patients showed a significant reduciton of the following pulmonary function tests (% predicted value) as compared with control subjects: FVC, FEV1, FEV1%, FEF25-75, FEF25-75%, DLco, DLco/VA, Pimax, Pimax% and Pemax%. These data indicate that pulmonary functions are effected in subclinical hypothyrodism. Therefore patients with or who are at high risk of having subclinical hypothyroidism, should be subjected to evaluation of pulmonary functions with simple spirometry.

Pulmonary function and the risk of functional limitation in chronic obstructive pulmonary disease.

PubMed

Eisner, Mark D; Iribarren, Carlos; Yelin, Edward H; Sidney, Stephen; Katz, Patricia P; Ackerson, Lynn; Lathon, Phenius; Tolstykh, Irina; Omachi, Theodore; Byl, Nancy; Blanc, Paul D

2008-05-01

The authors' objective was to analyze the impact of respiratory impairment on the risk of physical functional limitations among adults with chronic obstructive pulmonary disease (COPD). They hypothesized that greater pulmonary function decrement would result in a broad array of physical functional limitations involving organ systems remote from the lung, a key step in the pathway leading to overall disability. The authors used baseline data from the Function, Living, Outcomes, and Work (FLOW) study, a prospective cohort study of adults with COPD recruited from northern California in 2005-2007. They studied the impact of pulmonary function impairment on the risk of functional limitations using validated measures: lower extremity function (Short Physical Performance Battery), submaximal exercise performance (6-Minute Walk Test), standing balance (Functional Reach Test), skeletal muscle strength (manual muscle testing with dynamometry), and self-reported functional limitation (standardized item battery). Multiple variable analysis was used to control for confounding by age, sex, race, height, educational attainment, and cigarette smoking. Greater pulmonary function impairment, as evidenced by lower forced expiratory volume in 1 second (FEV(1)), was associated with poorer Short Physical Performance Battery scores and less distance walked during the 6-Minute Walk Test. Lower forced expiratory volume in 1 second was also associated with weaker muscle strength and with a greater risk of self-reported functional limitation (p < 0.05). In conclusion, pulmonary function impairment is associated with multiple manifestations of physical functional limitation among COPD patients. Longitudinal follow-up can delineate the impact of these functional limitations on the prospective risk of disability, guiding preventive strategies that could attenuate the disablement process.

Rapamycin protects against paraquat-induced pulmonary fibrosis: Activation of Nrf2 signaling pathway.

PubMed

Xu, Yiheng; Tai, Wenlin; Qu, Xiaoyuan; Wu, Wenjuan; Li, ZhenKun; Deng, Shuhao; Vongphouttha, Chanthasone; Dong, Zhaoxing

2017-08-19

Paraquat (PQ) is a widely used herbicide indeveloping countries worldwide, and pulmonary fibrosis is one of the most typical features of PQ poisoning. The molecular mechanism of PQ toxicity especially how to treat PQ-induced pulmonary fibrosis is still largely unknown. In animal model of pulmonary fibrosis, we used HE staining, western blotting assay and Real-time PCR assay to analyze the effects of rapamycin on the PQ-induced epithelial mesenchymal transition (EMT). We found that PQ induced the pulmonary fibrosis using HE staining and Masson's staining, and up-regulated the activity of HYP and the mRNA expressions of Collagen I and III (COL-1and COL-3) in pulmonary tissues. We also found that rapamycin down-regulated the mesenchymal cell marker Vimentin and up-regulated the epithelial cell marker E-cadherin both in mRNA and protein levels compared with PQ group. And the EMT associated transcription factor Snail was decreased by rapamycin treatment compared with PQ group. And PQ decreased the Nrf2 expression both in mRNA and protein levels, and rapamycin inhibited these effects of PQ. SFN, a activator of Nrf2, could inhibit the EMT and the expression of Snail. And knockdowon of Nrf2 could abolish the inhibitory effects of rapamycin of PQ-induced EMT. In conclusion, rapamycin protects against paraquat-induced pulmonary fibrosis by activation of Nrf2 signaling pathway. Copyright © 2017 Elsevier Inc. All rights reserved.

Characterization of the Potent, Selective Nrf2 Activator, 3-(Pyridin-3-Ylsulfonyl)-5-(Trifluoromethyl)-2H-Chromen-2-One, in Cellular and In Vivo Models of Pulmonary Oxidative Stress.

PubMed

Yonchuk, John G; Foley, Joseph P; Bolognese, Brian J; Logan, Gregory; Wixted, William E; Kou, Jen-Pyng; Chalupowicz, Diana G; Feldser, Heidi G; Sanchez, Yolanda; Nie, Hong; Callahan, James F; Kerns, Jeffrey K; Podolin, Patricia L

2017-10-01

Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a key regulator of oxidative stress and cellular repair and can be activated through inhibition of its cytoplasmic repressor, Kelch-like ECH-associated protein 1 (Keap1). Several small molecule disrupters of the Nrf2-Keap1 complex have recently been tested and/or approved for human therapeutic use but lack either potency or selectivity. The main goal of our work was to develop a potent, selective activator of NRF2 as protection against oxidative stress. In human bronchial epithelial cells, our Nrf2 activator, 3-(pyridin-3-ylsulfonyl)-5-(trifluoromethyl)-2 H -chromen-2-one (PSTC), induced Nrf2 nuclear translocation, Nrf2-regulated gene expression, and downstream signaling events, including induction of NAD(P)H:quinone oxidoreductase 1 (NQO1) enzyme activity and heme oxygenase-1 protein expression, in an Nrf2-dependent manner. As a marker of subsequent functional activity, PSTC restored oxidant ( tert -butyl hydroperoxide)-induced glutathione depletion. The compound's engagement of the Nrf2 signaling pathway translated to an in vivo setting, with induction of Nrf2-regulated gene expression and NQO1 enzyme activity, as well as restoration of oxidant (ozone)-induced glutathione depletion, occurring in the lungs of PSTC-treated rodents. Under disease conditions, PSTC engaged its target, inducing the expression of Nrf2-regulated genes in human bronchial epithelial cells derived from patients with chronic obstructive pulmonary disease, as well as in the lungs of cigarette smoke-exposed mice. Subsequent to the latter, a dose-dependent inhibition of cigarette smoke-induced pulmonary inflammation was observed. Finally, in contrast with bardoxolone methyl and sulforaphane, PSTC did not inhibit interleukin-1 β -induced nuclear factor- κ B translocation or insulin-induced S6 phosphorylation in human cells, emphasizing the on-target activity of this compound. In summary, we characterize a potent, selective Nrf2 activator that offers protection against pulmonary oxidative stress in several cellular and in vivo models. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

The effects of balneotherapy on disease activity, functional status, pulmonary function and quality of life in patients with ankylosing spondylitis.

PubMed

Aydemir, Koray; Tok, Fatih; Peker, Fatma; Safaz, Ismail; Taskaynatan, Mehmet Ali; Ozgul, Ahmet

2010-01-01

This study aimed to determine the effects of balneotherapy on disease activity, functional status, metrology index, pulmonary function and quality of life in patients with ankylosing spondylitis (AS). The study included 28 patients (27 male and 1 female) diagnosed with AS according to modified New York criteria. The patients were treated with balneotherapy for 3 weeks (30 min/day, 5 days/week). The patients were evaluated using the global index, Bath ankylosing spondylitis disease activity index (BASDAI), disease functional index (BASFI), metrology index (BASMI), chest expansion measures, pulmonary function testing, and the medical outcomes study-short form-36 Health Survey (SF-36) (measure of quality of life) before balneotherapy and 1 month after treatment. Post balneotherapy BASDAI and global index decreased, BASMI parameters improved, chest expansion increased, and some SF-36 parameters improved; however, none of these changes were statistically significant (P > 0.05), except for the decrease in BASMI total score (P < 0.05). Before balneotherapy 6 patients had restrictive pulmonary disorder, according to pulmonary function test results. Pulmonary function test results in 3 (50%) patients were normalized following balneotherapy; however, as for the other index, balneotherapy did not significantly affect pulmonary function test results. The AS patients' symptoms, clinical findings, pulmonary function test results, and quality of life showed a trend to improve following balneotherapy, although without reaching significant differences. Comprehensive randomized controlled spa intervention studies with longer follow-up periods may be helpful in further delineating the therapeutic efficacy of balneotherapy in AS patients.

Human Immunodeficiency Virus nef signature sequences are associated with pulmonary hypertension.

PubMed

Almodovar, Sharilyn; Knight, Rob; Allshouse, Amanda A; Roemer, Sarah; Lozupone, Catherine; McDonald, Daniel; Widmann, Jeremy; Voelkel, Norbert F; Shelton, Robert J; Suarez, Edu B; Hammer, Kenneth W; Goujard, Cecile; Petrosillo, Nicola; Simonneau, Gerald; Hsue, Priscilla Y; Humbert, Marc; Flores, Sonia C

2012-06-01

Severe pulmonary hypertension (PH) associated with vascular remodeling is a long-term complication of HIV infection (HIV-PH) affecting 1/200 infected individuals vs. 1/200,000 frequency in the uninfected population. Factors accounting for increased PH susceptibility in HIV-infected individuals are unknown. Rhesus macaques infected with chimeric SHIVnef virions but not with SIV display PH-like pulmonary vascular remodeling suggesting that HIV-Nef is associated with PH; these monkeys showed changes in nef sequences that correlated with pathogenesis after passage in vivo. We further examined whether HIV-nef alleles in HIV-PH subjects have signature sequences associated with the disease phenotype. We evaluated specimens from participants with and without HIV-PH from European Registries and validated results with samples collected as part of the Lung-HIV Studies in San Francisco. We found that 10 polymorphisms in nef were overrepresented in blood cells or lung tissue specimens from European HIV-PH individuals but significantly less frequent in HIV-infected individuals without PH. These polymorphisms mapped to known functional domains in Nef. In the validation cohort, 7/10 polymorphisms in the HIV-nef gene were confirmed; these polymorphisms arose independently from viral load, CD4(+) T cell counts, length of infection, and antiretroviral therapy status. Two out of 10 polymorphisms were previously reported in macaques with PH-like pulmonary vascular remodeling. Cloned recombinant Nef proteins from clinical samples down-regulated CD4, suggesting that these primary isolates are functional. This study offers new insights into the association between Nef polymorphisms in functional domains and the HIV-PH phenotype. The utility of these polymorphisms as predictors of PH should be examined in a larger population.

Lung extracellular matrix and redox regulation.

PubMed

Watson, Walter H; Ritzenthaler, Jeffrey D; Roman, Jesse

2016-08-01

Pulmonary fibrosis affects millions worldwide and, even though there has been a significant investment in understanding the processes involved in wound healing and maladaptive repair, a complete understanding of the mechanisms responsible for lung fibrogenesis eludes us, and interventions capable of reversing or halting disease progression are not available. Pulmonary fibrosis is characterized by the excessive expression and uncontrolled deposition of extracellular matrix (ECM) proteins resulting in erosion of the tissue structure. Initially considered an 'end-stage' process elicited after injury, these events are now considered pathogenic and are believed to contribute to the course of the disease. By interacting with integrins capable of signal transduction and by influencing tissue mechanics, ECM proteins modulate processes ranging from cell adhesion and migration to differentiation and growth factor expression. In doing so, ECM proteins help orchestrate complex developmental processes and maintain tissue homeostasis. However, poorly controlled deposition of ECM proteins promotes inflammation, fibroproliferation, and aberrant differentiation of cells, and has been implicated in the pathogenesis of pulmonary fibrosis, atherosclerosis and cancer. Considering their vital functions, ECM proteins are the target of investigation, and oxidation-reduction (redox) reactions have emerged as important regulators of the ECM. Oxidative stress invariably accompanies lung disease and promotes ECM expression directly or through the overproduction of pro-fibrotic growth factors, while affecting integrin binding and activation. In vitro and in vivo investigations point to redox reactions as targets for intervention in pulmonary fibrosis and related disorders, but studies in humans have been disappointing probably due to the narrow impact of the interventions tested, and our poor understanding of the factors that regulate these complex reactions. This review is not meant to provide a comprehensive review of this field, but rather to highlight what has been learned and to raise interest in this area in need of much attention. Copyright © 2016. Published by Elsevier B.V.

Cardiopulmonary Laboratory AFSC 904X0

DTIC Science & Technology

1990-10-01

SET UP POSITIVE END EXPIRATORY PRESSURE (PEEP) DEVICES 100 J321 SET UP CONTINUOUS POSITIVE AIRWAY PRESSURE ( CPAP ) DEVICES 100 J298 ASSIST PHYSICIAN IN...PRESSURE VENTILATORS 61 COMPUTERIZED PULMONARY FUNCTION ANALYZERS 61 TREADMILLS 59 HOLTER MONITOR EQUIPMENT 57 CPAP EQUIPMENT 54 PRESSURE REGULATORS 48...SUCTIONING PROCEDURES 95 J321 SET UP CONTINUOUS POSITIVE AIRWAY PRESSURE ( CPAP ) DEVICES 95 J332 SET UP VOLUME VENTILATORS 93 F148 PERFORM ARTERIAL PUNCTURES 93

Mechanisms of pertussis toxin-induced barrier dysfunction in bovine pulmonary artery endothelial cell monolayers.

PubMed

Patterson, C E; Stasek, J E; Schaphorst, K L; Davis, H W; Garcia, J G

1995-06-01

We have previously characterized several G proteins in endothelial cells (EC) as substrates for the ADP-ribosyltransferase activity of both pertussis (PT) and cholera toxin and described the modulation of key EC physiological responses, including gap formation and barrier function, by these toxins. In this study, we investigated the mechanisms involved in PT-mediated regulation of bovine pulmonary artery endothelial cells barrier function. PT caused a dose-dependent increase in albumin transfer, dependent upon action of the holotoxin, since neither the heat-inactivated PT, the isolated oligomer, nor the protomer induced EC permeability. PT-induced gap formation and barrier dysfunction were additive to either thrombin- or thrombin receptor-activating peptide-induced permeability, suggesting that thrombin and PT utilize distinct mechanisms. PT did not result in Ca2+ mobilization or alter either basal or thrombin-induced myosin light chain phosphorylation. However, PT stimulated protein kinase C (PKC) activation, and both PKC downregulation and PKC inhibition attenuated PT-induced permeability, indicating that PKC activity is involved in PT-induced barrier dysfunction. Like thrombin-induced permeability, the PT effect was blocked by prior increases in adenosine 3',5'-cyclic monophosphate. Thus PT-catalyzed ADP-ribosylation of a G protein (possibly other than Gi) may regulate cytoskeletal protein interactions, leading to EC barrier dysfunction.

Pulmonary function and fuel use: a population survey.

PubMed

Saha, Asim; Rao, N Mohan; Kulkarni, P K; Majumdar, P K; Saiyed, H N

2005-10-31

In the backdrop of conflicting reports (some studies reported adverse outcomes of biomass fuel use whereas few studies reported absence of any association between adverse health effect and fuel use, may be due to presence of large number of confounding variables) on the respiratory health effects of biomass fuel use, this cross sectional survey was undertaken to understand the role of fuel use on pulmonary function. This study was conducted in a village of western India involving 369 randomly selected adult subjects (165 male and 204 female). All the subjects were interviewed and were subjected to pulmonary function test. Analysis of covariance was performed to compare the levels of different pulmonary function test parameters in relation to different fuel use taking care of the role of possible confounding factors. This study showed that biomass fuel use (especially wood) is an important factor for deterioration of pulmonary function (particularly in female). FEV1 (p < .05), FEV1% (p < .01), PEFR (p < .05) and FEF(25-75) (p < .01) values were significantly lower in biomass fuel using females than nonusers. Comparison of only biomass fuel use vs. only LPG (Liquefied Petroleum Gas) use and only wood vs. only LPG use has showed that LPG is a safer fuel so far as deterioration of pulmonary function is concerned. This study observes some deterioration of pulmonary function in the male subjects also, who came from biomass fuel using families. This study concluded that traditional biomass fuels like wood have adverse effects on pulmonary function.

Methods for measuring right ventricular function and hemodynamic coupling with the pulmonary vasculature.

PubMed

Bellofiore, Alessandro; Chesler, Naomi C

2013-07-01

The right ventricle (RV) is a pulsatile pump, the efficiency of which depends on proper hemodynamic coupling with the compliant pulmonary circulation. The RV and pulmonary circulation exhibit structural and functional differences with the more extensively investigated left ventricle (LV) and systemic circulation. In light of these differences, metrics of LV function and efficiency of coupling to the systemic circulation cannot be used without modification to characterize RV function and efficiency of coupling to the pulmonary circulation. In this article, we review RV physiology and mechanics, established and novel methods for measuring RV function and hemodynamic coupling, and findings from application of these methods to RV function and coupling changes with pulmonary hypertension. We especially focus on non-invasive measurements, as these may represent the future for clinical monitoring of disease progression and the effect of drug therapies.

Cytoplasmic YY1 Is Associated with Increased Smooth Muscle-Specific Gene Expression

PubMed Central

Favot, Laure; Hall, Susan M.; Haworth, Sheila G.; Kemp, Paul R.

2005-01-01

Immediately after birth the adluminal vascular SMCs of the pulmonary elastic arteries undergo transient actin cytoskeletal remodeling as well as cellular de-differentiation and proliferation. Vascular smooth muscle phenotype is regulated by serum response factor, which is itself regulated in part by the negative regulator YY1. We therefore studied the subcellular localization of YY1 in arteries of normal newborn piglets and piglets affected by neonatal pulmonary hypertension. We found that YY1 localization changed during development and that expression of γ-smooth muscle actin correlated with expression of cytoplasmic rather than nuclear YY1. Analysis of the regulation of YY1 localization in vitro demonstrated that polymerized γ-actin sequestered EGFP-YY1 in the cytoplasm and that YY1 activation of c-myc promoter activity was inhibited by LIM kinase, which increases actin polymerization. Consistent with these data siRNA-mediated down-regulation of YY1 in C2C12 cells increased SM22-α expression and inhibited cell proliferation. Thus, actin polymerization controls subcellular YY1 localization, which contributes to vascular SMC proliferation and differentiation in normal pulmonary artery development. In the absence of actin depolymerization, YY1 does not relocate to the nucleus, and this lack of relocation may contribute to the pathobiology of pulmonary hypertension. PMID:16314465

Redox Signaling in the Right Ventricle.

PubMed

Suzuki, Yuichiro J; Shults, Nataliia V

2017-01-01

Pulmonary hypertension is a devastating disease without cure. The major cause of death among patients with pulmonary hypertension is right heart failure; however, biology of the right heart is not well understood. This lack of knowledge interferes with developing effective therapeutic strategies to treat these patients. In this chapter, we summarize studies performed in our laboratory that investigated the role of redox signaling in the regulation of the right ventricle (RV), using rat models of experimental pulmonary hypertension and right heart failure. Specifically, this chapter covers the topics of (a) redox regulation of serotonin signaling in the RV, (b) the carbonylation-degradation pathway of signal transduction in RV hypertrophy and (c) oxidative modifications in the RV of the SU5416/ovalbumin model of pulmonary arterial hypertension. These studies revealed that redox regulation in the RV is complex and simply giving lots of antioxidants to patients will unlikely benefit them. Deeper understanding of specific and selective redox mechanisms should shed light on how we can develop therapeutic strategies by modulating redox reactions.

Idiopathic Pulmonary Fibrosis: Gender-Age-Physiology Index Stage for Predicting Future Lung Function Decline.

PubMed

Salisbury, Margaret L; Xia, Meng; Zhou, Yueren; Murray, Susan; Tayob, Nabihah; Brown, Kevin K; Wells, Athol U; Schmidt, Shelley L; Martinez, Fernando J; Flaherty, Kevin R

2016-02-01

Idiopathic pulmonary fibrosis is a progressive lung disease with variable course. The Gender-Age-Physiology (GAP) Index and staging system uses clinical variables to stage mortality risk. It is unknown whether clinical staging predicts future decline in pulmonary function. We assessed whether the GAP stage predicts future pulmonary function decline and whether interval pulmonary function change predicts mortality after accounting for stage. Patients with idiopathic pulmonary fibrosis (N = 657) were identified retrospectively at three tertiary referral centers, and baseline GAP stages were assessed. Mixed models were used to describe average trajectories of FVC and diffusing capacity of the lung for carbon monoxide (Dlco). Multivariable Cox proportional hazards models were used to assess whether declines in pulmonary function ≥ 10% in 6 months predict mortality after accounting for GAP stage. Over a 2-year period, GAP stage was not associated with differences in yearly lung function decline. After accounting for stage, a 10% decrease in FVC or Dlco over 6 months independently predicted death or transplantation (FVC hazard ratio, 1.37; Dlco hazard ratio, 1.30; both, P ≤ .03). Patients with GAP stage 2 with declining pulmonary function experienced a survival profile similar to patients with GAP stage 3, with 1-year event-free survival of 59.3% (95% CI, 49.4-67.8) vs 56.9% (95% CI, 42.2-69.1). Baseline GAP stage predicted death or lung transplantation but not the rate of future pulmonary function decline. After accounting for GAP stage, a decline of ≥ 10% over 6 months independently predicted death or lung transplantation. Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Disruption of miR-29 Leads to Aberrant Differentiation of Smooth Muscle Cells Selectively Associated with Distal Lung Vasculature.

PubMed

Cushing, Leah; Costinean, Stefan; Xu, Wei; Jiang, Zhihua; Madden, Lindsey; Kuang, Pingping; Huang, Jingshu; Weisman, Alexandra; Hata, Akiko; Croce, Carlo M; Lü, Jining

2015-05-01

Differentiation of lung vascular smooth muscle cells (vSMCs) is tightly regulated during development or in response to challenges in a vessel specific manner. Aberrant vSMCs specifically associated with distal pulmonary arteries have been implicated in the pathogenesis of respiratory diseases, such as pulmonary arterial hypertension (PAH), a progressive and fatal disease, with no effective treatment. Therefore, it is highly relevant to understand the underlying mechanisms of lung vSMC differentiation. miRNAs are known to play critical roles in vSMC maturation and function of systemic vessels; however, little is known regarding the role of miRNAs in lung vSMCs. Here, we report that miR-29 family members are the most abundant miRNAs in adult mouse lungs. Moreover, high levels of miR-29 expression are selectively associated with vSMCs of distal vessels in both mouse and human lungs. Furthermore, we have shown that disruption of miR-29 in vivo leads to immature/synthetic vSMC phenotype specifically associated with distal lung vasculature, at least partially due to the derepression of KLF4, components of the PDGF pathway and ECM-related genes associated with synthetic phenotype. Moreover, we found that expression of FBXO32 in vSMCs is significantly upregulated in the distal vasculature of miR-29 null lungs. This indicates a potential important role of miR-29 in smooth muscle cell function by regulating FBXO32 and SMC protein degradation. These results are strongly supported by findings of a cell autonomous role of endogenous miR-29 in promoting SMC differentiation in vitro. Together, our findings suggested a vessel specific role of miR-29 in vSMC differentiation and function by targeting several key negative regulators.

Pulmonary Function in Children with Development Coordination Disorder

ERIC Educational Resources Information Center

Wu, Sheng K.; Cairney, John; Lin, Hsiao-Hui; Li, Yao-Chuen; Song, Tai-Fen

2011-01-01

The purpose of this study was to compare pulmonary function in children with developmental coordination disorder (DCD) with children who are typically developing (TD), and also analyze possible gender differences in pulmonary function between these groups. The Movement ABC test was used to identify the movement coordination ability of children.…

Source-specific pollution exposure and associations with pulmonary response in the Atlanta Commuters Exposure Studies.

PubMed

Krall, Jenna R; Ladva, Chandresh N; Russell, Armistead G; Golan, Rachel; Peng, Xing; Shi, Guoliang; Greenwald, Roby; Raysoni, Amit U; Waller, Lance A; Sarnat, Jeremy A

2018-06-01

Concentrations of traffic-related air pollutants are frequently higher within commuting vehicles than in ambient air. Pollutants found within vehicles may include those generated by tailpipe exhaust, brake wear, and road dust sources, as well as pollutants from in-cabin sources. Source-specific pollution, compared to total pollution, may represent regulation targets that can better protect human health. We estimated source-specific pollution exposures and corresponding pulmonary response in a panel study of commuters. We used constrained positive matrix factorization to estimate source-specific pollution factors and, subsequently, mixed effects models to estimate associations between source-specific pollution and pulmonary response. We identified four pollution factors that we named: crustal, primary tailpipe traffic, non-tailpipe traffic, and secondary. Among asthmatic subjects (N = 48), interquartile range increases in crustal and secondary pollution were associated with changes in lung function of -1.33% (95% confidence interval (CI): -2.45, -0.22) and -2.19% (95% CI: -3.46, -0.92) relative to baseline, respectively. Among non-asthmatic subjects (N = 51), non-tailpipe pollution was associated with pulmonary response only at 2.5 h post-commute. We found no significant associations between pulmonary response and primary tailpipe pollution. Health effects associated with traffic-related pollution may vary by source, and therefore some traffic pollution sources may require targeted interventions to protect health.

Caveolae, caveolin-1 and cavin-1: Emerging roles in pulmonary hypertension.

PubMed

Chettimada, Sukrutha; Yang, Jincheng; Moon, Hyung-Geun; Jin, Yang

2015-07-28

Caveolae are flask-shaped invaginations of cell membrane that play a significant structural and functional role. Caveolae harbor a variety of signaling molecules and serve to receive, concentrate and transmit extracellular signals across the membrane. Caveolins are the main structural proteins residing in the caveolae. Caveolins and another category of newly identified caveolae regulatory proteins, named cavins, are not only responsible for caveolae formation, but also interact with signaling complexes in the caveolae and regulate transmission of signals across the membrane. In the lung, two of the three caveolin isoforms, i.e ., cav-1 and -2, are expressed ubiquitously. Cavin protein family is composed of four proteins, named cavin-1 (or PTRF for polymerase Ⅰ and transcript release factor), cavin-2 (or SDPR for serum deprivation protein response), cavin-3 (or SRBC for sdr-related gene product that binds to-c-kinase) and cavin-4 (or MURC for muscle restricted coiled-coiled protein or cavin-4). All the caveolin and cavin proteins are essential regulators for caveolae dynamics. Recently, emerging evidence suggest that caveolae and its associated proteins play crucial roles in development and progression of pulmonary hypertension. The focus of this review is to outline and discuss the contrast in alteration of cav-1 (cav-1),-2 and cavin-1 (PTRF) expression and downstream signaling mechanisms between human and experimental models of pulmonary hypertension.

Lung function and pulmonary artery blood flow following prenatal maternal retinoic acid and imatinib in the nitrofen model of congenital diaphragmatic hernia.

PubMed

Burgos, Carmen Mesas; Davey, Marcus G; Riley, John S; Jia, Huimin; Flake, Alan W; Peranteau, William H

2017-12-19

Lung and pulmonary vascular maldevelopment in congenital diaphragmatic hernia (CDH) results in significant morbidity and mortality. Retinoic acid (RA) and imatinib have been shown to improve pulmonary morphology following prenatal administration in the rat nitrofen-induced CDH model. It remains unclear if these changes translate into improved function. We evaluated the effect of prenatal RA and imatinib on postnatal lung function, structure, and pulmonary artery (PA) blood flow in the rat CDH model. Olive oil or nitrofen was administered alone or in combination with RA or imatinib to pregnant rats. Pups were assessed for PA blood flow by ultrasound and pulmonary function/morphology following delivery, intubation, and short-term ventilation. Neither RA nor imatinib had a negative effect on lung and body growth. RA accelerated lung maturation indicated by increased alveoli number and thinner interalveolar septa and was associated with decreased PA resistance and improved oxygenation. With the exception of a decreased PA pulsatility index, no significant changes in morphology and pulmonary function were noted following imatinib. Prenatal treatment with RA but not imatinib was associated with improved pulmonary morphology and function, and decreased pulmonary vascular resistance. This study highlights the potential of prenatal pharmacologic therapies, such as RA, for management of CDH. Copyright © 2017 Elsevier Inc. All rights reserved.

Outflow tract septation and the aortic arch system in reptiles: lessons for understanding the mammalian heart.

PubMed

Poelmann, Robert E; Gittenberger-de Groot, Adriana C; Biermans, Marcel W M; Dolfing, Anne I; Jagessar, Armand; van Hattum, Sam; Hoogenboom, Amanda; Wisse, Lambertus J; Vicente-Steijn, Rebecca; de Bakker, Merijn A G; Vonk, Freek J; Hirasawa, Tatsuya; Kuratani, Shigeru; Richardson, Michael K

2017-01-01

Cardiac outflow tract patterning and cell contribution are studied using an evo-devo approach to reveal insight into the development of aorto-pulmonary septation. We studied embryonic stages of reptile hearts (lizard, turtle and crocodile) and compared these to avian and mammalian development. Immunohistochemistry allowed us to indicate where the essential cell components in the outflow tract and aortic sac were deployed, more specifically endocardial, neural crest and second heart field cells. The neural crest-derived aorto-pulmonary septum separates the pulmonary trunk from both aortae in reptiles, presenting with a left visceral and a right systemic aorta arising from the unseptated ventricle. Second heart field-derived cells function as flow dividers between both aortae and between the two pulmonary arteries. In birds, the left visceral aorta disappears early in development, while the right systemic aorta persists. This leads to a fusion of the aorto-pulmonary septum and the aortic flow divider (second heart field population) forming an avian aorto-pulmonary septal complex. In mammals, there is also a second heart field-derived aortic flow divider, albeit at a more distal site, while the aorto-pulmonary septum separates the aortic trunk from the pulmonary trunk. As in birds there is fusion with second heart field-derived cells albeit from the pulmonary flow divider as the right 6th pharyngeal arch artery disappears, resulting in a mammalian aorto-pulmonary septal complex. In crocodiles, birds and mammals, the main septal and parietal endocardial cushions receive neural crest cells that are functional in fusion and myocardialization of the outflow tract septum. Longer-lasting septation in crocodiles demonstrates a heterochrony in development. In other reptiles with no indication of incursion of neural crest cells, there is either no myocardialized outflow tract septum (lizard) or it is vestigial (turtle). Crocodiles are unique in bearing a central shunt, the foramen of Panizza, between the roots of both aortae. Finally, the soft-shell turtle investigated here exhibits a spongy histology of the developing carotid arteries supposedly related to regulation of blood flow during pharyngeal excretion in this species. This is the first time that is shown that an interplay of second heart field-derived flow dividers with a neural crest-derived cell population is a variable but common, denominator across all species studied for vascular patterning and outflow tract septation. The observed differences in normal development of reptiles may have impact on the understanding of development of human congenital outflow tract malformations.

Idiopathic pulmonary fibrosis (IPF) signaling pathways and protective roles of melatonin.

PubMed

Hosseinzadeh, Azam; Javad-Moosavi, Seyed Ali; Reiter, Russel J; Hemati, Karim; Ghaznavi, Habib; Mehrzadi, Saeed

2018-05-15

Idiopathic pulmonary fibrosis (IPF) is characterized by the progressive loss of lung function due to tissue scarring. A variety of pro-inflammatory and pro-fibrogenic factors including interleukin‑17A, transforming growth factor β, Wnt/β‑catenin, vascular endothelial growth factor, platelet-derived growth factor, fibroblast growth factors, endotelin‑1, renin angiotensin system and impaired caveolin‑1 function are involved in the IPF pathogenesis. Current therapies for IPF have some limitations and this highlights the need for effective therapeutic agents to treat this fatal disease. Melatonin and its metabolites are broad-spectrum antioxidants that not only remove reactive oxygen and nitrogen species by radical scavenging but also up-regulate the expression and activity of endogenous antioxidants. Via these actions, melatonin and its metabolites modulate a variety of molecular pathways in different pathophysiological conditions. Herein, we review the signaling pathways involved in the pathophysiology of IPF and the potentially protective effects of melatonin on these pathways. Copyright © 2018 Elsevier Inc. All rights reserved.

Functional morphology and patterns of blood flow in the heart of Python regius.

PubMed

Starck, J Matthias

2009-06-01

Brightness-modulated ultrasonography, continuous-wave Doppler, and pulsed-wave Doppler-echocardiography were used to analyze the functional morphology of the undisturbed heart of ball pythons. In particular, the action of the muscular ridge and the atrio-ventricular valves are key features to understand how patterns of blood flow emerge from structures directing blood into the various chambers of the heart. A step-by-step image analysis of echocardiographs shows that during ventricular diastole, the atrio-ventricular valves block the interventricular canals so that blood from the right atrium first fills the cavum venosum, and blood from the left atrium fills the cavum arteriosum. During diastole, blood from the cavum venosum crosses the muscular ridge into the cavum pulmonale. During middle to late systole the muscular ridge closes, thus prohibiting further blood flow into the cavum pulmonale. At the same time, the atrio-ventricular valves open the interventricular canal and allow blood from the cavum arteriosum to flow into the cavum venosum. In the late phase of ventricular systole, all blood from the cavum pulmonale is pressed into the pulmonary trunk; all blood from the cavum venosum is pressed into both aortas. Quantitative measures of blood flow volume showed that resting snakes bypass the pulmonary circulation and shunt about twice the blood volume into the systemic circulation as into the pulmonary circulation. When digesting, the oxygen demand of snakes increased tremendously. This is associated with shunting more blood into the pulmonary circulation. The results of this study allow the presentation of a detailed functional model of the python heart. They are also the basis for a functional hypothesis of how shunting is achieved. Further, it was shown that shunting is an active regulation process in response to changing demands of the organism (here, oxygen demand). Finally, the results of this study support earlier reports about a dual pressure circulation in Python regius.

Classification Models for Pulmonary Function using Motion Analysis from Phone Sensors.

PubMed

Cheng, Qian; Juen, Joshua; Bellam, Shashi; Fulara, Nicholas; Close, Deanna; Silverstein, Jonathan C; Schatz, Bruce

2016-01-01

Smartphones are ubiquitous, but it is unknown what physiological functions can be monitored at clinical quality. Pulmonary function is a standard measure of health status for cardiopulmonary patients. We have shown phone sensors can accurately measure walking patterns. Here we show that improved classification models can accurately measure pulmonary function, with sole inputs being sensor data from carried phones. Twenty-four cardiopulmonary patients performed six minute walk tests in pulmonary rehabilitation at a regional hospital. They carried smartphones running custom software recording phone motion. For every patient, every ten-second interval was correctly computed. The trained model perfectly computed the GOLD level 1/2/3, which is a standard categorization of pulmonary function as measured by spirometry. These results are encouraging towards field trials with passive monitors always running in the background. We expect patients can simply carry their phones during daily living, while supporting automatic computation ofpulmonary function for health monitoring.

Pulmonary function and fuel use: A population survey

PubMed Central

Saha, Asim; Mohan Rao, N; Kulkarni, PK; Majumdar, PK; Saiyed, HN

2005-01-01

Background In the backdrop of conflicting reports (some studies reported adverse outcomes of biomass fuel use whereas few studies reported absence of any association between adverse health effect and fuel use, may be due to presence of large number of confounding variables) on the respiratory health effects of biomass fuel use, this cross sectional survey was undertaken to understand the role of fuel use on pulmonary function. Method This study was conducted in a village of western India involving 369 randomly selected adult subjects (165 male and 204 female). All the subjects were interviewed and were subjected to pulmonary function test. Analysis of covariance was performed to compare the levels of different pulmonary function test parameters in relation to different fuel use taking care of the role of possible confounding factors. Results This study showed that biomass fuel use (especially wood) is an important factor for deterioration of pulmonary function (particularly in female). FEV1 (p < .05), FEV1 % (p < .01), PEFR (p < .05) and FEF25–75 (p < .01) values were significantly lower in biomass fuel using females than nonusers. Comparison of only biomass fuel use vs. only LPG (Liquefied Petroleum Gas) use and only wood vs. only LPG use has showed that LPG is a safer fuel so far as deterioration of pulmonary function is concerned. This study observes some deterioration of pulmonary function in the male subjects also, who came from biomass fuel using families. Conclusion This study concluded that traditional biomass fuels like wood have adverse effects on pulmonary function. PMID:16255784

Decreased apelin and apelin-receptor expression in the pulmonary vasculature of nitrofen-induced congenital diaphragmatic hernia.

PubMed

Hofmann, Alejandro D; Friedmacher, Florian; Takahashi, Hiromizu; Hunziker, Manuela; Gosemann, Jan-Hendrik; Puri, Prem

2014-02-01

The high morbidity and mortality in congenital diaphragmatic hernia (CDH) are attributed to severe pulmonary hypoplasia and persistent pulmonary hypertension (PH). PH is characterized by structural changes in pulmonary arteries, resulting in adventitial and medial thickness. These effects are triggered by abnormal apoptosis and proliferation of pulmonary vascular endothelial and smooth muscle cells (SMCs). Apelin (APLN), a target gene of bone morphogenic protein receptor 2 (BMPR2), is known to play an important and manifold role in regulating pulmonary homeostasis promoting endothelial cell (EC) survival, proliferation and migration. In addition to these autocrine effects of apelin, it displays a paracrine function attenuating the response of pulmonary SMCs to growth factors and promoting apoptosis. Apelin exerts its effect via its G-protein-coupled receptor (APLNR) and is solely expressed by pulmonary vascular EC, whereas APLNR is co-localized in pulmonary ECs and SMCs. Dysfunction of BMPR2 and downstream signalling have been shown to disturb the crucial balance of proliferation of SMCs contributing to the pathogenesis of human and experimentally induced PH. We designed this study to investigate the hypothesis that apelin and APLNR signalling are disrupted in the pulmonary vasculature of rats in nitrofen-induced CDH. Pregnant rats were exposed to nitrofen or vehicle on D9 of gestation. Foetuses were sacrificed on D21 and divided into nitrofen and control group (n = 32). Pulmonary RNA was extracted and mRNA levels of APLN and APLNR were determined by quantitative real-time PCR. Protein expression of apelin and APLNR was investigated by western blotting. Confocal immunofluorescence double staining for apelin, APLNR and SMCs were performed. Relative mRNA level of APLN and APLNR were significantly decreased in the CDH group compared to control lungs. Western blotting and confocal microscopy confirmed the qRT-PCR results showing decreased pulmonary protein expression of apelin and APLNR in lungs of nitrofen-exposed foetuses compared to controls. This study provides striking evidence of markedly decreased gene and protein expression of apelin and its receptor APLNR in the pulmonary vasculature of nitrofen-induced CDH. The disruption of the apelin-APLNR signalling axis in the pulmonary vasculature may lead to extensive vascular remodelling and contribute to PPH in the nitrofen-induced CDH model.

Pulmonary function and respiratory symptoms in potash workers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Graham, B.L.; Dosman, J.A.; Cotton, D.J.

1984-03-01

Over 94% of the workers in each of four Saskatchewan potash mines participated in a respiratory health surveillance program that included a questionnaire and pulmonary function tests. Compared with a nonexposed control group, potash workers had higher prevalences of cough, dyspnea, and chronic bronchitis but better pulmonary function. Prevalences of symptoms and pulmonary function abnormalities were similar among workers at the four mines tested and at the various job locations. Potash dust, diesel fumes, and other air contaminants may have an irritant effect that leads to the increased prevalences of cough and chronic bronchitis. Although no adverse effects of themore » potash mine environment on pulmonary function were found, these findings reflect a healthy worker effect or some selection process that makes the potash workers appear healthier in a cross-sectional study.« less

Pulmonary function and respiratory symptoms in potash workers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Graham, B.L.; Dosman, J.A.; Cotton, D.J.

1984-03-01

Over 94% of the workers in each of four Saskatchewan potash mines participated in a respiratory health surveillance program that included a questionnaire and pulmonary function tests. Compared with a nonexposed control group, potash workers had higher prevalences of cough, dyspnea, and chronic bronchitis but better pulmonary function. Prevalences of symptoms and pulmonary function abnormalities were similar among workers at the four mines tested and at the various job locations. Potash dust, diesel fumes, and other air contaminants may have an irritant effect that leads to the increased prevalences of cough and chronic bronchitis. Although we found no adverse effectsmore » of the potash mine environment on pulmonary function, these findings reflect a healthy worker effect or some selection process that makes the potash workers appear healthier in a cross-sectional study.« less

Up-regulation of Wnt5a gene expression in the nitrofen-induced hypoplastic lung.

PubMed

Doi, Takashi; Puri, Prem

2009-12-01

The pathogenesis of pulmonary hypoplasia in nitrofen-induced congenital diaphragmatic hernia (CDH) still remains unclear. Wnt signaling pathways play a critical role in lung development. Whereas canonical Wnt signaling regulates branching morphogenesis during early lung development, the noncanonical Wnt5a controls late lung morphogenesis, including patterning of distal airway and vascular tubulogenesis (alveolarization). Overexpression of Wnt5a in transgenic mice and in the chick has been reported to result in severe pulmonary hypoplasia. We designed this study to test the hypothesis that the pulmonary Wnt5a gene expression is up-regulated in late stages of lung morphogenesis in CDH. Pregnant rats were exposed to either olive oil or nitrofen on day 9 of gestation (D9). Fetal lungs were harvested on D15, D18, and D21 and divided into 3 groups: control; nitrofen without CDH, CDH(-); and nitrofen with CDH, CDH(+) (n = 8 at each time-point, respectively). Wnt5a pulmonary gene expression was analyzed by real-time reverse transcription polymerase chain reaction. Immunohistochemistry was performed to evaluate Wnt5a protein expression at each time-point. Pulmonary relative mRNA expression levels of Wnt5a were significantly increased in CDH(-) and CDH(+) at D18 (1.61 +/- 0.92 and 1.81 +/- 1.20, respectively) and D21 (2.40 +/- 0.74* and 2.65 +/- 0.35*, respectively) compared to controls at D18 and D21 (0.90 +/- 0.17* and 1.69 +/- 0.53**, respectively) (*P < .05, **P < .001 vs control ). Strong Wnt5a immunoreactivity was seen in the distal epithelium at D18 and D21 in nitrofen-induced hypoplastic lung compared to controls. Up-regulation of pulmonary Wnt5a gene expression in the late lung morphogenesis may interfere with patterning of alveolarization, causing pulmonary hypoplasia in the nitrofen-induced CDH.

Rationale and design of a randomized trial of home electronic symptom and lung function monitoring to detect cystic fibrosis pulmonary exacerbations: the early intervention in cystic fibrosis exacerbation (eICE) trial.

PubMed

Lechtzin, N; West, N; Allgood, S; Wilhelm, E; Khan, U; Mayer-Hamblett, N; Aitken, M L; Ramsey, B W; Boyle, M P; Mogayzel, P J; Goss, C H

2013-11-01

Acute pulmonary exacerbations are central events in the lives of individuals with cystic fibrosis (CF). Pulmonary exacerbations lead to impaired lung function, worse quality of life, and shorter survival. We hypothesized that aggressive early treatment of acute pulmonary exacerbation may improve clinical outcomes. Describe the rationale of an ongoing trial designed to determine the efficacy of home monitoring of both lung function measurements and symptoms for early detection and subsequent early treatment of acute CF pulmonary exacerbations. A randomized, non-blinded, multi-center trial in 320 individuals with CF aged 14 years and older. The study compares usual care to a twice a week assessment of home spirometry and CF respiratory symptoms using an electronic device with data transmission to the research personnel to identify and trigger early treatment of CF pulmonary exacerbation. Participants will be enrolled in the study for 12 months. The primary endpoint is change in FEV1 (L) from baseline to 12 months determined by a linear mixed effects model incorporating all quarterly FEV1 measurements. Secondary endpoints include time to first acute protocol-defined pulmonary exacerbation, number of acute pulmonary exacerbations, number of hospitalization days for acute pulmonary exacerbation, time from the end of acute pulmonary exacerbation to onset of subsequent pulmonary exacerbation, change in health related quality of life, change in treatment burden, change in CF respiratory symptoms, and adherence to the study protocol. This study is a first step in establishing alternative approaches to the care of CF pulmonary exacerbations. We hypothesize that early treatment of pulmonary exacerbations has the potential to slow lung function decline, reduce respiratory symptoms and improve the quality of life for individuals with CF. © 2013.

The effect of scoliosis surgery on pulmonary function in spinal muscular atrophy type II patients.

PubMed

Chou, Shih-Hsiang; Lin, Gau-Tyan; Shen, Po-Chih; Lue, Yi-Jing; Lu, Cheng-Chang; Tien, Yin-Chun; Lu, Yen-Mou

2017-06-01

Various results of the previous literature related to surgical effect on pulmonary function of spinal muscular atrophy (SMA) patients might be due to different SMA type, different fusion level and technique. The aim of this study was to determine the value of scoliosis surgery for SMA type II patients with regard to pulmonary function, under the same fusion level, fusion technique and average long-term follow-up. Ten SMA II patients who underwent spinal correction procedures from 1993 to 2010 were identified. Data on clinical features and pulmonary function, including forced vital capacity (FVC) and forced expiratory volume in 1st second (FEV 1 ), were collected. The data on pulmonary function were divided into preoperative, postoperative short-term (0-5 years), mid-term (5-10 years), and long-term (>10 years). Statistical comparisons were made using the Wilcoxon test for pulmonary function and body weight analysis. Questions were answered by parents on how surgery influenced the frequency of respiratory infection and the ability to sit at school. The average length of postoperative pulmonary function follow-up was 12.3 years (range 4.9-15.9 years). There was no significant difference in FVC or FEV 1 between preoperative and each postoperative period. However, a significant decline from mid-term to long-term was observed (p = 0.028). Body weight increased significantly in all postoperative periods and was moderately correlated to pulmonary function (r = 0.526 for FVC). The answers to the questionnaire revealed that 80% of the patients had obvious improvement in the frequency of respiratory infection and 100% were tolerable sitting at school. Surgical correction for scoliosis in SMA II patients results in pulmonary function being maintained during long-term follow-up. In addition, the advantages of surgery also include body weight gain, better sitting tolerance, and reduced frequency of respiratory infection.

The Relationship of Welding Fume Exposure, Smoking, and Pulmonary Function in Welders.

PubMed

Roach, Laura L

2018-01-01

The purpose of this study was to explore the relationship between occupational exposure to welding fumes and pulmonary function in an effort to add supportive evidence and clarity to the current body of research. This study utilized a retrospective chart review of pulmonary function testing and pulmonary questionnaires already available in charts from preplacement physicals to the most recent test. When comparing smokers to nonsmokers, utilizing multiple regression and controlling for age and percentage of time using a respirator, years welding was statistically significant at p = .04. Data support that smoking has a synergistic effect when combined with welding fume exposure on pulmonary decline.

High-Resolution Computed Tomography and Pulmonary Function Findings of Occupational Arsenic Exposure in Workers.

PubMed

Ergün, Recai; Evcik, Ender; Ergün, Dilek; Ergan, Begüm; Özkan, Esin; Gündüz, Özge

2017-05-05

The number of studies where non-malignant pulmonary diseases are evaluated after occupational arsenic exposure is very few. To investigate the effects of occupational arsenic exposure on the lung by high-resolution computed tomography and pulmonary function tests. Retrospective cross-sectional study. In this study, 256 workers with suspected respiratory occupational arsenic exposure were included, with an average age of 32.9±7.8 years and an average of 3.5±2.7 working years. Hair and urinary arsenic levels were analysed. High-resolution computed tomography and pulmonary function tests were done. In workers with occupational arsenic exposure, high-resolution computed tomography showed 18.8% pulmonary involvement. In pulmonary involvement, pulmonary nodule was the most frequently seen lesion (64.5%). The other findings of pulmonary involvement were 18.8% diffuse interstitial lung disease, 12.5% bronchiectasis, and 27.1% bullae-emphysema. The mean age of patients with pulmonary involvement was higher and as they smoked more. The pulmonary involvement was 5.2 times higher in patients with skin lesions because of arsenic. Diffusing capacity of lung for carbon monoxide was significantly lower in patients with pulmonary involvement. Besides lung cancer, chronic occupational inhalation of arsenic exposure may cause non-malignant pulmonary findings such as bronchiectasis, pulmonary nodules and diffuse interstitial lung disease. So, in order to detect pulmonary involvement in the early stages, workers who experience occupational arsenic exposure should be followed by diffusion test and high-resolution computed tomography.

Hydrocortisone normalizes oxygenation and cGMP regulation in lambs with persistent pulmonary hypertension of the newborn

PubMed Central

Lakshminrusimha, Satyan; Wedgwood, Stephen; Czech, Lyubov; Gugino, Sylvia F.; Russell, James A.; Farrow, Kathryn N.; Steinhorn, Robin H.

2012-01-01

In the pulmonary vasculature, cGMP levels are regulated by soluble guanylate cyclase (sGC) and phosphodiesterase 5 (PDE5). We previously reported that lambs with persistent pulmonary hypertension of the newborn (PPHN) demonstrate increased reactive oxygen species (ROS) and altered sGC and PDE5 activity, with resultant decreased cGMP. The objective of this study was to evaluate the effects of hydrocortisone on pulmonary vascular function, ROS, and cGMP in the ovine ductal ligation model of PPHN. PPHN lambs were ventilated with 100% O2 for 24 h. Six lambs received 5 mg/kg hydrocortisone every 8 h times three doses (PPHN-hiHC), five lambs received 3 mg/kg hydrocortisone followed by 1 mg·kg−1·dose−1 times two doses (PPHN-loHC), and six lambs were ventilated with O2 alone (PPHN). All groups were compared with healthy 1-day spontaneously breathing lambs (1DSB). O2 ventilation of PPHN lambs decreased sGC activity, increased PDE5 activity, and increased ROS vs. 1DSB lambs. Both hydrocortisone doses significantly improved arterial-to-alveolar ratios relative to PPHN lambs, decreased PDE5 activity, and increased cGMP relative to PPHN lambs. High-dose hydrocortisone also increased sGC activity, decreased PDE5 expression, decreased ROS, and increased total vascular SOD activity vs. PPHN lambs. These data suggest that hydrocortisone treatment in clinically relevant doses improves oxygenation and decreases hyperoxia-induced changes in sGC and PDE5 activity, increasing cGMP levels. Hydrocortisone reduces ROS levels in part by increasing SOD activity in PPHN lambs ventilated with 100% O2. We speculate that hydrocortisone increases cGMP by direct effects on sGC and PDE5 expression and by attenuating abnormalities induced by oxidant stress. PMID:22198909

STARS knockout attenuates hypoxia-induced pulmonary arterial hypertension by suppressing pulmonary arterial smooth muscle cell proliferation.

PubMed

Shi, Zhaoling; Wu, Huajie; Luo, Jianfeng; Sun, Xin

2017-03-01

STARS (STriated muscle Activator of Rho Signaling) is a sarcomeric protein, which expressed early in cardiac development and involved in pathological remodeling. Abundant evidence indicated that STARS could regulate cell proliferation, but it's exact function remains unclear. In this study, we aimed to investigate the role of STARS in the proliferation of pulmonary arterial smooth muscle cells (PASMC) and the potential effect on the progression of pulmonary arterial hypertension (PAH). In this study, we established a PAH mouse model through chronic hypoxia exposure as reflected by the increased RVSP and RVHI. Western blot and RT-qPCR detected the increased STARS protein and mRNA levels in PAH mice. Next, we cultured the primary PASMC from PAH mice. After STARS overexpression in PASMC, STARS, SRF and Egr-1 were up-regulated significantly. The MTT assay revealed an increase in cell proliferation. Flow cytometry showed a marked inhibition of cell apoptosis. However, STARS silence in PASMC exerted opposite effects with STARS overexpression. SRF siRNA transfection blocked the effects of STARS overexpression in PASMC. In order to further confirm the role of STARS in PAH mice in vivo, we exposed STARS knockout mice to hypoxia and found lower RVSP and RVHI in knockout mice as compared with controls. Our results not only suggest that STARS plays a crucial role in the development of PAH by increasing the proliferation of PASMC through activation of the SRF/Egr-1 pathway, but also provides a new mechanism for hypoxia-induced PAH. In addition, STARS may represent a potential treatment target. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Matrilysin (Matrix Metalloproteinase-7) Regulates Anti-Inflammatory and Antifibrotic Pulmonary Dendritic Cells That Express CD103 (αEβ7-Integrin)

PubMed Central

Manicone, Anne M.; Huizar, Isham; McGuire, John K.

2009-01-01

The E-cadherin receptor CD103 (αEβ7-integrin) is expressed on specific populations of pulmonary dendritic cells (DC) and T cells. However, CD103 function in the lung is not well understood. Matrilysin (MMP-7) expression is increased in lung injury and cleaves E-cadherin from injured lung epithelium. Thus, to assess matrilysin effects on CD103-E-cadherin interactions in lung injury, wild-type, CD103−/−, and Mmp7−/− mice, in which E-cadherin isn’t cleaved in the lung, were treated with bleomycin or bleomycin with nFMLP to reverse the defect in acute neutrophil influx seen in Mmp7−/− mice. Pulmonary CD103+ DC were significantly increased in injured wild-type compared with Mmp7−/− mice, and CD103+ leukocytes showed significantly enhanced interaction with E-cadherin on injured wild-type epithelium than with Mmp7−/− epithelium in vitro and in vivo. Bleomycin-treated CD103−/− mice had persistent neutrophilic inflammation, increased fibrosis, and increased mortality compared with wild-type mice, a phenotype that was partially recapitulated in bleomycin/nFMLP-treated Mmp7−/− mice. Soluble E-cadherin increased IL-12 and IL-10 and reduced IL-6 mRNA expression in wild-type bone marrow-derived DC but not in CD103−/− bone marrow-derived DC. Similar mRNA patterns were seen in lungs of bleomycin-injured wild-type, but not CD103−/− or Mmp7−/−, mice. In conclusion, matrilysin regulates pulmonary localization of DC that express CD103, and E-cadherin cleavage may activate CD103+ DC to limit inflammation and inhibit fibrosis. PMID:19893044

Comparison of Flow and Volume Incentive Spirometry on Pulmonary Function and Exercise Tolerance in Open Abdominal Surgery: A Randomized Clinical Trial.

PubMed

Kumar, Amaravadi Sampath; Alaparthi, Gopala Krishna; Augustine, Alfred Joseph; Pazhyaottayil, Zulfeequer Chundaanveetil; Ramakrishna, Anand; Krishnakumar, Shyam Krishnan

2016-01-01

Surgical procedures in abdominal area lead to changes in pulmonary function, respiratory mechanics and impaired physical capacity leading to postoperative pulmonary complications, which can affect up to 80% of upper abdominal surgery. To evaluate the effects of flow and volume incentive spirometry on pulmonary function and exercise tolerance in patients undergoing open abdominal surgery. A randomized clinical trial was conducted in a hospital of Mangalore city in Southern India. Thirty-seven males and thirteen females who were undergoing abdominal surgeries were included and allocated into flow and volume incentive spirometry groups by block randomization. All subjects underwent evaluations of pulmonary function with measurement of Forced Vital Capacity (FVC), Forced Expiratory Volume in the first second (FEV1), Peak Expiratory Flow (PEF). Preoperative and postoperative measurements were taken up to day 5 for both groups. Exercise tolerance measured by Six- Minute Walk Test during preoperative period and measured again at the time of discharge for both groups. Pulmonary function was analysed by post-hoc analysis and carried out using Bonferroni's 't'-test. Exercise tolerance was analysed by Paired 'T'-test. Pulmonary function (FVC, FEV1, and PEFR) was found to be significantly decreased in 1(st), 2(nd) and 3(rd) postoperative day when compared with preoperative day. On 4(th) and 5(th) postoperative day the pulmonary function (FVC, FEV1, and PEFR) was found to be better preserved in both flow and volume incentive spirometry groups. The Six-Minute Walk Test showed a statistically significant improvement in pulmonary function on the day of discharge than in the preoperative period. In terms of distance covered, the volume- incentive spirometry group showed a greater statistically significant improvement from the preoperative period to the time of discharge than was exhibited by the flow incentive spirometry group. Flow and volume incentive spirometry can be safely recommended to patients undergoing open abdominal surgery as there have been no adverse events recorded. Also, these led to a demonstrable improvement in pulmonary function and exercise tolerance.

Comparison of Flow and Volume Incentive Spirometry on Pulmonary Function and Exercise Tolerance in Open Abdominal Surgery: A Randomized Clinical Trial

PubMed Central

Kumar, Amaravadi Sampath; Augustine, Alfred Joseph; Pazhyaottayil, Zulfeequer Chundaanveetil; Ramakrishna, Anand; Krishnakumar, Shyam Krishnan

2016-01-01

Introduction Surgical procedures in abdominal area lead to changes in pulmonary function, respiratory mechanics and impaired physical capacity leading to postoperative pulmonary complications, which can affect up to 80% of upper abdominal surgery. Aim To evaluate the effects of flow and volume incentive spirometry on pulmonary function and exercise tolerance in patients undergoing open abdominal surgery. Materials and Methods A randomized clinical trial was conducted in a hospital of Mangalore city in Southern India. Thirty-seven males and thirteen females who were undergoing abdominal surgeries were included and allocated into flow and volume incentive spirometry groups by block randomization. All subjects underwent evaluations of pulmonary function with measurement of Forced Vital Capacity (FVC), Forced Expiratory Volume in the first second (FEV1), Peak Expiratory Flow (PEF). Preoperative and postoperative measurements were taken up to day 5 for both groups. Exercise tolerance measured by Six- Minute Walk Test during preoperative period and measured again at the time of discharge for both groups. Pulmonary function was analysed by post-hoc analysis and carried out using Bonferroni’s ‘t’-test. Exercise tolerance was analysed by Paired ‘T’-test. Results Pulmonary function (FVC, FEV1, and PEFR) was found to be significantly decreased in 1st, 2nd and 3rd postoperative day when compared with preoperative day. On 4th and 5th postoperative day the pulmonary function (FVC, FEV1, and PEFR) was found to be better preserved in both flow and volume incentive spirometry groups. The Six-Minute Walk Test showed a statistically significant improvement in pulmonary function on the day of discharge than in the preoperative period. In terms of distance covered, the volume- incentive spirometry group showed a greater statistically significant improvement from the preoperative period to the time of discharge than was exhibited by the flow incentive spirometry group. Conclusion Flow and volume incentive spirometry can be safely recommended to patients undergoing open abdominal surgery as there have been no adverse events recorded. Also, these led to a demonstrable improvement in pulmonary function and exercise tolerance. PMID:26894090

Stress Transmission within the Cell

PubMed Central

Stamenović, Dimitrije; Wang, Ning

2014-01-01

An outstanding problem in cell biology is how cells sense mechanical forces and how those forces affect cellular functions. During past decades, it has become evident that the deformable cytoskeleton (CSK), an intracellular network of various filamentous biopolymers, provides a physical basis for transducing mechanical signals into biochemical responses. To understand how mechanical forces regulate cellular functions, it is necessary to first understand how the CSK develops mechanical stresses in response to applied forces, and how those stresses are propagated through the CSK where various signaling molecules are immobilized. New experimental techniques have been developed to quantify cytoskeletal mechanics, which together with new computational approaches have given rise to new theories and models for describing mechanics of living cells. In this article, we discuss current understanding of cell biomechanics by focusing on the biophysical mechanisms that are responsible for the development and transmission of mechanical stresses in the cell and their effect on cellular functions. We compare and contrast various theories and models of cytoskeletal mechanics, emphasizing common mechanisms that those theories are built upon, while not ignoring irreconcilable differences. We highlight most recent advances in the understanding of mechanotransduction in the cytoplasm of living cells and the central role of the cytoskeletal prestress in propagating mechanical forces along the cytoskeletal filaments to activate cytoplasmic enzymes. It is anticipated that advances in cell mechanics will help developing novel therapeutics to treat pulmonary diseases like asthma, pulmonary fibrosis, and chronic obstructive pulmonary disease. PMID:23737186

Decrease in pulmonary function and oxygenation after lung resection

PubMed Central

Westerdahl, Elisabeth; Langer, Daniel; Souza, Domingos S.R.; Andreasen, Jan Jesper

2018-01-01

Respiratory deficits are common following curative intent lung cancer surgery and may reduce the patient's ability to be physically active. We evaluated the influence of surgery on pulmonary function, respiratory muscle strength and physical performance after lung resection. Pulmonary function, respiratory muscle strength (maximal inspiratory/expiratory pressure) and 6-min walk test (6MWT) were assessed pre-operatively, 2 weeks post-operatively and 6 months post-operatively in 80 patients (age 68±9 years). Video-assisted thoracoscopic surgery was performed in 58% of cases. Two weeks post-operatively, we found a significant decline in pulmonary function (forced vital capacity −0.6±0.6 L and forced expiratory volume in 1 s −0.43±0.4 L; both p<0.0001), 6MWT (−37.6±74.8 m; p<0.0001) and oxygenation (−2.9±4.7 units; p<0.001), while maximal inspiratory and maximal expiratory pressure were unaffected. At 6 months post-operatively, pulmonary function and oxygenation remained significantly decreased (p<0.001), whereas 6MWT was recovered. We conclude that lung resection has a significant short- and long-term impact on pulmonary function and oxygenation, but not on respiratory muscle strength. Future research should focus on mechanisms negatively influencing post-operative pulmonary function other than impaired respiratory muscle strength. PMID:29362707

Decrease in pulmonary function and oxygenation after lung resection.

PubMed

Brocki, Barbara Cristina; Westerdahl, Elisabeth; Langer, Daniel; Souza, Domingos S R; Andreasen, Jan Jesper

2018-01-01

Respiratory deficits are common following curative intent lung cancer surgery and may reduce the patient's ability to be physically active. We evaluated the influence of surgery on pulmonary function, respiratory muscle strength and physical performance after lung resection. Pulmonary function, respiratory muscle strength (maximal inspiratory/expiratory pressure) and 6-min walk test (6MWT) were assessed pre-operatively, 2 weeks post-operatively and 6 months post-operatively in 80 patients (age 68±9 years). Video-assisted thoracoscopic surgery was performed in 58% of cases. Two weeks post-operatively, we found a significant decline in pulmonary function (forced vital capacity -0.6±0.6 L and forced expiratory volume in 1 s -0.43±0.4 L; both p<0.0001), 6MWT (-37.6±74.8 m; p<0.0001) and oxygenation (-2.9±4.7 units; p<0.001), while maximal inspiratory and maximal expiratory pressure were unaffected. At 6 months post-operatively, pulmonary function and oxygenation remained significantly decreased (p<0.001), whereas 6MWT was recovered. We conclude that lung resection has a significant short- and long-term impact on pulmonary function and oxygenation, but not on respiratory muscle strength. Future research should focus on mechanisms negatively influencing post-operative pulmonary function other than impaired respiratory muscle strength.

Key Role of ROS in the Process of 15-Lipoxygenase/15-Hydroxyeicosatetraenoiccid-Induced Pulmonary Vascular Remodeling in Hypoxia Pulmonary Hypertension

PubMed Central

Qiu, Yanli; Liu, Gaofeng; Sheng, Tingting; Yu, Xiufeng; Wang, Shuang; Zhu, Daling

2016-01-01

We previously reported that 15-lipoxygenase (15-LO) and its metabolite 15-hydroxyeicosatetraenoic acid (15-HETE) were up-regulated in pulmonary arterial cells from both pulmonary artery hypertension patients and hypoxic rats and that these factors mediated the progression of pulmonary hypertension (PH) by affecting the proliferation and apoptosis of pulmonary arterial (PA) cells. However, the underlying mechanisms of the remodeling induced by 15-HETE have remained unclear. As reactive oxygen species (ROS) and 15-LO are both induced by hypoxia, it is possible that ROS are involved in the events of hypoxia-induced 15-LO expression that lead to PH. We employed immunohistochemistry, tube formation assays, bromodeoxyuridine (BrdU) incorporation assays, and cell cycle analyses to explore the role of ROS in the process of 15-HETE-mediated hypoxic pulmonary hypertension (HPH). We found that exogenous 15-HETE facilitated the generation of ROS and that this effect was mainly localized to mitochondria. In particular, the mitochondrial electron transport chain and nicotinamide-adenine dinucleotide phosphate oxidase 4 (Nox4) were responsible for the significant 15-HETE-stimulated increase in ROS production. Moreover, ROS induced by 15-HETE stimulated endothelial cell (EC) migration and promoted pulmonary artery smooth muscle cell (PASMC) proliferation under hypoxia via the p38 MAPK pathway. These results indicated that 15-HETE-regulated ROS mediated hypoxia-induced pulmonary vascular remodeling (PVR) via the p38 MAPK pathway. PMID:26871724

PPAR-gamma pathways attenuate pulmonary granuloma formation in a carbon nanotube induced murine model of sarcoidosis.

PubMed

McPeek, Matthew; Malur, Anagha; Tokarz, Debra A; Murray, Gina; Barna, Barbara P; Thomassen, Mary Jane

2018-06-15

Peroxisome proliferator activated receptor gamma (PPARγ), a ligand activated nuclear transcription factor, is constitutively expressed in alveolar macrophages of healthy individuals. PPARγ deficiencies have been noted in several lung diseases including the alveolar macrophages of pulmonary sarcoidosis patients. We have previously described a murine model of multiwall carbon nanotubes (MWCNT) induced pulmonary granulomatous inflammation which bears striking similarities to pulmonary sarcoidosis, including the deficiency of alveolar macrophage PPARγ. Further studies demonstrate alveolar macrophage PPARγ deficiency exacerbates MWCNT-induced pulmonary granulomas. Based on these observations we hypothesized that activation of PPARγ via administration of the PPARγ-specific ligand rosiglitazone would limit MWCNT-induced granuloma formation and promote PPARγ-dependent pathways. Results presented here show that rosiglitazone significantly limits the frequency and severity of MWCNT-induced pulmonary granulomas. Furthermore, rosiglitazone attenuates alveolar macrophage NF-κB activity and downregulates the expression of the pro-inflammatory mediators, CCL2 and osteopontin. PPARγ activation via rosiglitazone also prevents the MWCNT-induced deficiency of PPARγ-regulated ATP-binding cassette lipid transporter-G1 (ABCG1) expression. ABCG1 is crucial to pulmonary lipid homeostasis. ABCG1 deficiency results in lipid accumulation which promotes pro-inflammatory macrophage activation. Our results indicate that restoration of homeostatic ABCG1 levels by rosiglitazone correlates with both reduced pulmonary lipid accumulation, and decreased alveolar macrophage activation. These data confirm and further support our previous observations that PPARγ pathways are critical in regulating MWCNT-induced pulmonary granulomatous inflammation. Copyright © 2018 Elsevier Inc. All rights reserved.

Redox Regulation of the Superoxide Dismutases SOD3 and SOD2 in the Pulmonary Circulation.

PubMed

Hernandez-Saavedra, Daniel; Swain, Kalin; Tuder, Rubin; Petersen, Steen V; Nozik-Grayck, Eva

2017-01-01

When evaluating the role of redox-regulating signaling in pulmonary vascular diseases, it is intriguing to consider the modulation of key antioxidant enzymes like superoxide dismutase (SOD) because SOD isoforms are regulated by redox reactions, and, in turn, modulate downstream redox sensitive processes. The emerging field of redox biology is built upon understanding the regulation and consequences of tightly controlled and specific reduction-oxidation reactions that are critical for diverse cellular processes including cell signaling. Of relevance, both the site of production of specific reactive oxygen and nitrogen species and the site of the antioxidant defenses are highly compartmentalized within the cell. For example, superoxide is generated during oxidative phosphorylation in the mitochondria as well as by a number of enzymatic sources within the cytosol and at the cell membrane. In the pulmonary circulation, these sources include the mitochondrial electron transport chain, NADPH oxidases (NOX1-4, Duox1,2), nitric oxide synthases, and xanthine oxidase; this important topic has been thoroughly reviewed recently [1]. In parallel with these different cellular sites of superoxide production, the three SOD isoforms are also specifically localized to the cytosol (SOD1), mitochondria (SOD2) or extracellular compartment (SOD3). This chapter focuses on the role of redox mechanisms regulating SOD2 and SOD3, with an emphasis on these processes in the setting of pulmonary hypertension.

Maintenance of pulmonary vasculature tone by blood derived from the inferior vena cava in a rabbit model of cavopulmonary shunt.

PubMed

Ikai, Akio; Shirai, Mikiyasu; Nishimura, Kazunobu; Ikeda, Tadashi; Kameyama, Takayuki; Ueyama, Koji; Komeda, Masashi

2005-01-01

After cavopulmonary shunt in which the superior vena cava is anastomosed to the right pulmonary artery, the right lung is in a unique condition without flow pulsatility and hepatic venous effluent. In a previous study, we reported that hypoxic pulmonary vasoconstriction disappeared in the pulmonary circulation after cavopulmonary shunt. In this study, however, to investigate the influence of pulsatility and hepatic venous effluent on hypoxic pulmonary vasoconstriction in the pulmonary circulation, we developed an alternative cavopulmonary shunt rabbit model that included hepatic venous effluent in the pulmonary circulation and reduced the pulsatility of the pulmonary arterial blood flow. We then observed the physiologic characteristics of the peripheral pulmonary artery after cavopulmonary shunt, specifically the disappearance of hypoxic pulmonary vasoconstriction. Sixteen Japanese white rabbits (12-16 weeks old) were used in this study. With general anesthesia, a cavopulmonary shunt was established by anastomosing the right superior vena cava to the right pulmonary artery in an end-to-side fashion. Of the 16 rabbits for the study, the proximal right pulmonary artery was completely ligated in 5 (atresia group) and partially ligated in 6 (stenosis group). Sham operation was performed in the remaining 5 rabbits. Two weeks later, we analyzed the response of the pulmonary artery (which was divided into three categories: segmental, lobular, and acinar level artery) to hypoxia (8% oxygen inhalation) with a specially designed video radiographic system. Morphometric analysis of the resistance pulmonary artery was done in each group after angiography. Mean pressure and pulse pressure in the right pulmonary artery were not significantly different between the atresia and stenosis groups. The mean pulmonary artery pressures in the atresia and stenosis groups were 8 and 11 mm Hg, respectively. However, the pulse pressure was less than 2 mm Hg in both groups. The baseline internal diameter of the resistance pulmonary artery of the atresia group was significantly different from those of the stenosis and sham groups. In the atresia group, the resistance pulmonary arteries did not respond to hypoxia. In contrast, significant constriction (as assessed by percentage change of internal diameter of the resistance pulmonary arteries in the acinar and lobular level arteries) was observed in the pulmonary arteries of the sham and stenosis groups (atresia vs stenosis vs sham 0.4% vs - 19.0% vs - 18.8%, P = .01). In our morphometric study, we observed vasodilation of the resistance pulmonary artery with a thinner medial layer in the atresia group, consistent with the result of microangiography. We developed a cavopulmonary shunt rabbit model in which the inferior vena caval blood was derived from the right ventricle. Hypoxic pulmonary vasoconstriction was maintained in the model with the blood flow from the right ventricle. When the blood flow was not maintained, however, hypoxic pulmonary vasoconstriction disappeared. This phenomenon strongly suggests that a substance in hepatic venous effluent partially regulates the physiological pulmonary vascular function in the rabbit lung.

Effects of atorvastatin and losartan on monocrotaline-induced pulmonary artery remodeling in rats.

PubMed

Xie, Liangdi; Lin, Peisen; Xie, Hong; Xu, Changsheng

2010-01-01

Structural remodeling of pulmonary artery plays an important role in maintaining sustained pulmonary arterial hypertension (PAH). The anti-remodeling effects of statins have been reported in systemic hypertension. In this study, we studied the effects of atovastatin (Ato) or losartan (Los) in monocrotaline (MCL)-induced pulmonary artery remodeling using a rat model. Forty Sprague-Dawley (SD) rats were randomly assigned into four groups (n = 10): normal control (Ctr), PAH, PAH treated with Los, and PAH treated with Ato. We found that in the Los- or Ato-treated group, the mean pulmonary arterial pressure, right heart hypertrophy index, ratio of wall/lumen thickness (WT%), as well as the wall/lumen area (WA%) were significantly reduced compared to the PAH group. Also in pulmonary arteries dissected from rats in the Ato- or Los-treated group, in both mRNA and protein levels, the expression of α1C subunit of voltage-gated calcium channel (Ca(v)α1c) was downregulated, while sarcoplasmic/endoplasmic reticulum calcium-ATPase (SERCA-2a) and inositol 1,4,5 triphosphate receptor 1 (IP3R-1) upregulated. However, the mRNA level of RyR-3 subunit of calcium regulating channel was increased, whereas its protein level was reduced in the treated groups. Our results suggest that atorvastatin or losartan may regress the remodeling of the pulmonary artery in pulmonary hypertensive rats, with differential expression of calcium regulating channels.

Colchicine Depolymerizes Microtubules, Increases Junctophilin-2, and Improves Right Ventricular Function in Experimental Pulmonary Arterial Hypertension.

PubMed

Prins, Kurt W; Tian, Lian; Wu, Danchen; Thenappan, Thenappan; Metzger, Joseph M; Archer, Stephen L

2017-05-31

Pulmonary arterial hypertension (PAH) is a lethal disease characterized by obstructive pulmonary vascular remodeling and right ventricular (RV) dysfunction. Although RV function predicts outcomes in PAH, mechanisms of RV dysfunction are poorly understood, and RV-targeted therapies are lacking. We hypothesized that in PAH, abnormal microtubular structure in RV cardiomyocytes impairs RV function by reducing junctophilin-2 (JPH2) expression, resulting in t-tubule derangements. Conversely, we assessed whether colchicine, a microtubule-depolymerizing agent, could increase JPH2 expression and enhance RV function in monocrotaline-induced PAH. Immunoblots, confocal microscopy, echocardiography, cardiac catheterization, and treadmill testing were used to examine colchicine's (0.5 mg/kg 3 times/week) effects on pulmonary hemodynamics, RV function, and functional capacity. Rats were treated with saline (n=28) or colchicine (n=24) for 3 weeks, beginning 1 week after monocrotaline (60 mg/kg, subcutaneous). In the monocrotaline RV, but not the left ventricle, microtubule density is increased, and JPH2 expression is reduced, with loss of t-tubule localization and t-tubule disarray. Colchicine reduces microtubule density, increases JPH2 expression, and improves t-tubule morphology in RV cardiomyocytes. Colchicine therapy diminishes RV hypertrophy, improves RV function, and enhances RV-pulmonary artery coupling. Colchicine reduces small pulmonary arteriolar thickness and improves pulmonary hemodynamics. Finally, colchicine increases exercise capacity. Monocrotaline-induced PAH causes RV-specific derangement of microtubules marked by reduction in JPH2 and t-tubule disarray. Colchicine reduces microtubule density, increases JPH2 expression, and improves both t-tubule architecture and RV function. Colchicine also reduces adverse pulmonary vascular remodeling. These results provide biological plausibility for a clinical trial to repurpose colchicine as a RV-directed therapy for PAH. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Prediction of post-operative pulmonary function after lobectomy for primary lung cancer: A comparison among counting method, effective lobar volume, and lobar collapsibility using inspiratory/expiratory CT.

PubMed

Yabuuchi, Hidetake; Kawanami, Satoshi; Kamitani, Takeshi; Yonezawa, Masato; Yamasaki, Yuzo; Yamanouchi, Torahiko; Nagao, Michinobu; Okamoto, Tatsuro; Honda, Hiroshi

2016-11-01

To compare the predictabilities of postoperative pulmonary function after lobectomy for primary lung cancer among counting method, effective lobar volume, and lobar collapsibility. Forty-nine patients who underwent lobectomy for primary lung cancer were enrolled. All patients underwent inspiratory/expiratory CT and pulmonary function tests 2 weeks before surgery and postoperative pulmonary function tests 6-7 months after surgery. Pulmonary function losses (ΔFEV 1.0 and ΔVC) were calculated from the pulmonary function tests. Predictive postoperative pulmonary function losses (ppoΔFEV 1.0 and ppoΔVC) were calculated using counting method, effective volume, and lobar collapsibility. Correlations and agreements between ΔFEV 1.0 and ppoFEV 1.0 and those between ΔVC and ppoΔVC were tested among three methods using Spearman's correlation coefficient and Bland-Altman plots. ΔFEV 1.0 and ppoΔFEV 1.0insp-exp were strongly correlated (r=0.72), whereas ΔFEV 1.0 and ppoΔFEV 1.0count and ΔFEV 1.0 and Pred. ΔFEV 1.0eff.vol. were moderately correlated (r=0.50, 0.56). ΔVC and ppoΔVC eff.vol. (r=0.71) were strongly correlated, whereas ΔVC and ppoΔVC count , and ΔVC and ppoΔVC insp-exp were moderately correlated (r=0.55, 0.42). Volumetry from inspiratory/expiratory CT data could be useful to predict postoperative pulmonary function after lobectomy for primary lung cancer. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Yin yang 1 is a novel regulator of pulmonary fibrosis.

PubMed

Lin, Xin; Sime, Patricia J; Xu, Haodong; Williams, Marc A; LaRussa, Larry; Georas, Steve N; Guo, Jia

2011-06-15

The differentiation of fibroblasts into myofibroblasts is a cardinal feature of idiopathic pulmonary fibrosis (IPF). The transcription factor Yin Yang 1 (YY1) plays a role in the proliferation and differentiation of diverse cell types, but its role in fibrotic lung diseases is not known. To elucidate the mechanism by which YY1 regulates fibroblast differentiation and lung fibrosis. Lung fibroblasts were cultured with transforming growth factor (TGF)-β or tumor necrosis factor-α. Nuclear factor (NF)-κB, YY1, and α-smooth muscle actin (SMA) were determined in protein, mRNA, and promoter reporter level. Lung fibroblasts and lung fibrosis were assessed in a partial YY1-deficient mouse and a YY1(f/f) conditional knockout mouse after being exposed to silica or bleomycin. TGF-β and tumor necrosis factor-α up-regulated YY1 expression in lung fibroblasts. TGF-β-induced YY1 expression was dramatically decreased by an inhibitor of NF-κB, which blocked I-κB degradation. YY1 is significantly overexpressed in both human IPF and murine models of lung fibrosis, including in the aggregated pulmonary fibroblasts of fibrotic foci. Furthermore, the mechanism of fibrogenesis is that YY1 can up-regulate α-SMA expression in pulmonary fibroblasts. YY1-deficient (YY1(+/-)) mice were significantly protected from lung fibrosis, which was associated with attenuated α-SMA and collagen expression. Finally, decreasing YY1 expression through instilled adenovirus-cre in floxed-YY1(f/f) mice reduced lung fibrosis. YY1 is overexpressed in fibroblasts in both human IPF and murine models in a NF-κB-dependent manner, and YY1 regulates fibrogenesis at least in part by increasing α-SMA and collagen expression. Decreasing YY1 expression may provide a new therapeutic strategy for pulmonary fibrosis.

The sGC activator inhibits the proliferation and migration, promotes the apoptosis of human pulmonary arterial smooth muscle cells via the up regulation of plasminogen activator inhibitor-2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Shuai; Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders, 8 Gongti South Rd, Beijing; Zou, Lihui

Background: Different types of pulmonary hypertension (PH) share the same process of pulmonary vascular remodeling, the molecular mechanism of which is not entirely clarified by far. The abnormal biological behaviors of pulmonary arterial smooth muscle cells (PASMCs) play an important role in this process. Objectives: We investigated the regulation of plasminogen activator inhibitor-2 (PAI-2) by the sGC activator, and explored the effect of PAI-2 on PASMCs proliferation, apoptosis and migration. Methods: After the transfection with PAI-2 overexpression vector and specific siRNAs or treatment with BAY 41-2272 (an activator of sGC), the mRNA and protein levels of PAI-2 in cultured humanmore » PASMCs were detected, and the proliferation, apoptosis and migration of PASMCs were investigated. Results: BAY 41-2272 up regulated the endogenous PAI-2 in PASMCs, on the mRNA and protein level. In PAI-2 overexpression group, the proliferation and migration of PASMCs were inhibited significantly, and the apoptosis of PASMCs was increased. In contrast, PAI-2 knockdown with siRNA increased PASMCs proliferation and migration, inhibited the apoptosis. Conclusions: PAI-2 overexpression inhibits the proliferation and migration and promotes the apoptosis of human PASMCs. Therefore, sGC activator might alleviate or reverse vascular remodeling in PH through the up-regulation of PAI-2. - Highlights: • sGC activator BAY41-2272 up regulated PAI-2 in PASMCs, on the mRNA and protein level. • PAI-2 overexpression inhibits the proliferation and migration of human PASMCs. • PAI-2 overexpression promotes the apoptosis of human PASMCs. • sGC activator might alleviate the vascular remodeling in pulmonary hypertension.« less

Nitrated fatty acids reverse pulmonary fibrosis by dedifferentiating myofibroblasts and promoting collagen uptake by alveolar macrophages

PubMed Central

Reddy, Aravind T.; Lakshmi, Sowmya P.; Zhang, Yingze; Reddy, Raju C.

2014-01-01

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disease, thought to be largely transforming growth factor β (TGFβ) driven, for which there is no effective therapy. We assessed the potential benefits in IPF of nitrated fatty acids (NFAs), which are unique endogenous agonists of peroxisome proliferator-activated receptor γ (PPARγ), a nuclear hormone receptor that exhibits wound-healing and antifibrotic properties potentially useful for IPF therapy. We found that pulmonary PPARγ is down-regulated in patients with IPF. In vitro, knockdown or knockout of PPARγ expression in isolated human and mouse lung fibroblasts induced a profibrotic phenotype, whereas treating human fibroblasts with NFAs up-regulated PPARγ and blocked TGFβ signaling and actions. NFAs also converted TGFβ to inactive monomers in cell-free solution, suggesting an additional mechanism through which they may inhibit TGFβ. In vivo, treating mice bearing experimental pulmonary fibrosis with NFAs reduced disease severity. Also, NFAs up-regulated the collagen-targeting factor milk fat globule-EGF factor 8 (MFG-E8), stimulated collagen uptake and degradation by alveolar macrophages, and promoted myofibroblast dedifferentiation. Moreover, treating mice with established pulmonary fibrosis using NFAs reversed their existing myofibroblast differentiation and collagen deposition. These findings raise the prospect of treating IPF with NFAs to halt and perhaps even reverse the progress of IPF.—Reddy, A. T., Lakshmi, S. P., Zhang, Y., Reddy, R. C. Nitrated fatty acids reverse pulmonary fibrosis by dedifferentiating myofibroblasts and promoting collagen uptake by alveolar macrophages. PMID:25252739

Upregulation of endothelin receptors A and B in the nitrofen induced hypoplastic lung occurs early in gestation.

PubMed

Dingemann, Jens; Doi, Takashi; Ruttenstock, Elke; Puri, Prem

2010-01-01

Pulmonary hypoplasia and persistent pulmonary hypertension (PPH) aggravate clinical courses in congenital diaphragmatic hernia (CDH). Endothelin 1 enhances PPH by vasoconstriction and proliferation of vessel walls. Up-regulation of pulmonary Endothelin Receptors A and B (EDNRA, EDNRB) has been reported in human CDH and animal models, but the onset of those alterations during lung development remains unclear. We hypothesized that pulmonary expression of EDNRA and EDNRB is up-regulated at early gestational stages in the nitrofen model. Pregnant rats were exposed to nitrofen or vehicle on gestational day 9 (D9). Embryos were sacrificed on D15, D18 and D21 and divided into nitrofen- and control group. Pulmonary RNA was extracted and mRNA levels of EDNRA and EDNRB were determined by real-time PCR. Immunohistochemistry for protein expression of both receptors was performed. mRNA levels of EDNRA and EDNRB were significantly increased in the nitrofen group on D15, D18 and D21. Immunohistochemistry revealed increased pulmonary vascular expression of EDNRA and EDNRB compared to controls. Altered expression of EDNRA and EDNRB is an early event in lung morphogenesis in the nitrofen model. We speculate that pulmonary arteries in CDH become excessively muscularised in early fetal life, becoming unable to adapt normally at birth.

Impact of Pulmonary Artery Pressure on Exercise Function in Severe COPD

PubMed Central

Sims, Michael W.; Margolis, David J.; Localio, A. Russell; Panettieri, Reynold A.; Kawut, Steven M.; Christie, Jason D.

2009-01-01

Background: Although pulmonary hypertension commonly complicates COPD, the functional consequences of increased pulmonary artery pressures in patients with this condition remain poorly defined. Methods: We conducted a cross-sectional analysis of a cohort of 362 patients with severe COPD who were evaluated for lung transplantation. Patients with pulmonary hemodynamics measured by cardiac catheterization and available 6-min walk test results were included. The association of mean pulmonary artery pressure (mPAP) with pulmonary function, echocardiographic variables, and 6-min walk distance was assessed. Results: The prevalence of pulmonary hypertension (mPAP, > 25 mm Hg; pulmonary artery occlusion pressure [PAOP], < 16 mm Hg) was 23% (95% confidence interval, 19 to 27%). In bivariate analysis, higher mPAP was associated with lower FVC and FEV1, higher Pco2 and lower Po2 in arterial blood, and more right heart dysfunction. Multivariate analysis demonstrated that higher mPAP was associated with shorter distance walked in 6 min, even after adjustment for age, gender, race, height, weight, FEV1, and PAOP (−11 m for every 5 mm Hg rise in mPAP; 95% confidence interval, −21 to −0.7; p = 0.04). Conclusions: Higher pulmonary artery pressures are associated with reduced exercise function in patients with severe COPD, even after controlling for demographics, anthropomorphics, severity of airflow obstruction, and PAOP. Whether treatments aimed at lowering pulmonary artery pressures may improve clinical outcomes in COPD, however, remains unknown. PMID:19318664

Pulmonary function derangements in isolated or predominant mitral stenosis - Preoperative evaluation with clinico-hemodynamic correlation.

PubMed

Parvathy, Usha T; Rajan, Rajesh; Faybushevich, Alexander Georgevich

2014-06-01

It is well known that mitral stenosis (MS) is complicated by pulmonary hypertension (PH) of varying degrees. The hemodynamic derangement is associated with structural changes in the pulmonary vessels and parenchyma and also functional derangements. This article analyzes the pulmonary function derangements in 25 patients with isolated/predominant mitral stenosis of varying severity. THE AIM OF THE STUDY WAS TO CORRELATE THE PULMONARY FUNCTION TEST (PFT) DERANGEMENTS (DONE BY SIMPLE METHODS) WITH: a) patient demographics and clinical profile, b) severity of the mitral stenosis, and c) severity of pulmonary artery hypertension (PAH) and d) to evaluate its significance in preoperative assessment. This cross-sectional study was conducted in 25 patients with mitral stenosis who were selected for mitral valve (MV) surgery. The patients were evaluated for clinical class, echocardiographic severity of mitral stenosis and pulmonary hypertension, and with simple methods of assessment of pulmonary function with spirometry and blood gas analysis. The diagnosis and classification were made on standardized criteria. The associations and correlations of parameters, and the difference in groups of severity were analyzed statistically with Statistical Package for Social Sciences (SPSS), using nonparametric measures. THE SPIROMETRIC PARAMETERS SHOWED SIGNIFICANT CORRELATION WITH INCREASING NEW YORK HEART ASSOCIATION (NYHA) FUNCTIONAL CLASS (FC): forced vital capacity (FVC, r = -0.4*, p = 0.04), forced expiratory volume in one second (FEV1, r = -0.5*, p = 0.01), FEV1/FVC (r = -0.44*, p = 0.02), and with pulmonary venous congestion (PVC): FVC (r = -0.41*, p = 0.04) and FEV1 (r = -0.41*, p = 0.04). Cardiothoracic ratio (CTR) correlated only with FEV1 (r = -0.461*, p = 0.02) and peripheral saturation of oxygen (SPO2, r = -0.401*, p = 0.04). There was no linear correlation to duration of symptoms, mitral valve orifice area, or pulmonary hypertension, except for MV gradient with PCO2 (r = 0.594**, p = 0.002). The decreased oxygenation status correlated significantly with FC, CTR, PVC, and with deranged spirometry (r = 0.495*, p = 0.02). PFT derangements are seen in all grades of severity of MS and correlate well with the functional class, though no significant linear correlation with grades of severity of stenosis or pulmonary hypertension. Even the early or mild derangements in pulmonary function such as small airway obstruction in the less severe cases of normal or mild PH can be detected by simple and inexpensive methods when the conventional parameters are normal. The supplementary data from baseline arterial blood gas analysis is informative and relevant. This reclassified pulmonary function status might be prognostically predictive.

Impaired pulmonary function after treatment for tuberculosis: the end of the disease?

PubMed

Chushkin, Mikhail Ivanovich; Ots, Oleg Nikolayevich

2017-01-01

To evaluate the prevalence of pulmonary function abnormalities and to investigate the factors affecting lung function in patients treated for pulmonary tuberculosis. A total of 214 consecutive patients (132 men and 82 women; 20-82 years of age), treated for pulmonary tuberculosis and followed at a local dispensary, underwent spirometry and plethysmography at least one year after treatment. Pulmonary impairment was present in 102 (47.7%) of the 214 patients evaluated. The most common functional alteration was obstructive lung disease (seen in 34.6%). Of the 214 patients, 60 (28.0%) showed reduced pulmonary function (FEV1 below the lower limit of normal). Risk factors for reduced pulmonary function were having had culture-positive pulmonary tuberculosis in the past, being over 50 years of age, having recurrent tuberculosis, and having a lower level of education. Nearly half of all tuberculosis patients evolve to impaired pulmonary function. That underscores the need for pulmonary function testing after the end of treatment. Avaliar a prevalência de alterações da função pulmonar e investigar os fatores que afetam a função pulmonar em pacientes tratados para tuberculose pulmonar. Um total de 214 pacientes consecutivos (132 homens e 82 mulheres; 20-82 anos de idade), tratados para tuberculose pulmonar e acompanhados em um dispensário local, foi submetido a espirometria e pletismografia pelo menos um ano após o tratamento. O comprometimento pulmonar estava presente em 102 (47,7%) dos 214 pacientes avaliados. A alteração funcional mais comum foi o distúrbio ventilatório obstrutivo (observado em 34,6%). Dos 214 pacientes, 60 (28,0%) apresentaram função pulmonar reduzida (VEF1 abaixo do limite inferior de normalidade). Os fatores de risco para função pulmonar reduzida foram tuberculose pulmonar com cultura positiva no passado, idade acima de 50 anos, recidiva de tuberculose e menor nível de escolaridade. Quase metade de todos os pacientes com tuberculose evolui com comprometimento da função pulmonar. Isso reforça a necessidade de testes de função pulmonar após o término do tratamento.

Role of Circulating miRNAs as Biomarkers in Idiopathic Pulmonary Arterial Hypertension: Possible Relevance of miR-23a

PubMed Central

Sarrion, Irene; Milian, Lara; Juan, G.; Ramon, Mercedes; Furest, Idelfonso; Carda, Carmen; Cortijo Gimeno, Julio; Mata Roig, Manuel

2015-01-01

Idiopathic pulmonary hypertension (IPAH) is a rare disease characterized by a progressive increase in pulmonary vascular resistance leading to heart failure. MicroRNAs (miRNAs) are small noncoding RNAs that control the expression of genes, including some involved in the progression of IPAH, as studied in animals and lung tissue. These molecules circulate freely in the blood and their expression is associated with the progression of different vascular pathologies. Here, we studied the expression profile of circulating miRNAs in 12 well-characterized IPAH patients using microarrays. We found significant changes in 61 miRNAs, of which the expression of miR23a was correlated with the patients' pulmonary function. We also studied the expression profile of circulating messenger RNA (mRNAs) and found that miR23a controlled 17% of the significantly changed mRNA, including PGC1α, which was recently associated with the progression of IPAH. Finally we found that silencing of miR23a resulted in an increase of the expression of PGC1α, as well as in its well-known regulated genes CYC, SOD, NRF2, and HO1. The results point to the utility of circulating miRNA expression as a biomarker of disease progression. PMID:25815108

[Clinical, hemodynamic and angiographic results of total cavo-pulmonary connection].

PubMed

Jimenez, A C; Neville, P; Chamboux, C; Crenn, R; Vaillant, M C; Marchand, M; Chantepie, A

1998-05-01

The aim of the study was to assess the short and medium term results of total cavo-pulmonary connection based on analysis of the functional status, the cavo-pulmonary circulation and the surgical techniques, and the hepatic consequences. Fifteen patients with congenital defects beyond repair were treated by total cavo-pulmonary connection at Tours between March 1st 1992 and July 30th 1996. There were 12 children (mean age: 6.3 years) and 3 adults aged 25 to 28. Results were assessed by clinical examination, hepatic function tests and cardiovascular investigations including right heart catheterisation with angiography in 14 patients. There were no fatalities. Seven patients were in functional Class I and 8 in Class II at medium term (average follow-up of 33 months). Hepatic function was mildly abnormal in all patients with an increase in serum bilirubin and gamma GT, and a decrease in the coagulation factors. The mean pressures in the atrial channel were 12 mmHg (9-16 mmHg), in the superior vena 13.2 mmHg (10-18 mmHg), in the right pulmonary artery 9.5 mmHg (7-15 mmHg) and 11.6 mmHg (8-16 mmHg) in the left pulmonary artery. Significant residual stenosis of a pulmonary branch was observed in 2 cases. The cavo-pulmonary anastomoses were out of line, one from the other, in all cases. The atrial channel was tubular in 9 cases and dilated with slight stagnation of the contrast medium in its inferior region in 5 cases. Total cavo-pulmonary connection transformed the clinical status of these patients but was associated with minor abnormalities of liver function. The quality of the cavo-pulmonary circulation and the surgical anastomoses was estimated to be satisfactory in the majority of cases.

Pulmonary Morbidity in Infancy after Exposure to Chorioamnionitis in Late Preterm Infants.

PubMed

McDowell, Karen M; Jobe, Alan H; Fenchel, Matthew; Hardie, William D; Gisslen, Tate; Young, Lisa R; Chougnet, Claire A; Davis, Stephanie D; Kallapur, Suhas G

2016-06-01

Chorioamnionitis is an important cause of preterm birth, but its impact on postnatal outcomes is understudied. To evaluate whether fetal exposure to inflammation is associated with adverse pulmonary outcomes at 6 to 12 months' chronological age in infants born moderate to late preterm. Infants born between 32 and 36 weeks' gestational age were prospectively recruited (N = 184). Chorioamnionitis was diagnosed by placenta and umbilical cord histology. Select cytokines were measured in samples of cord blood. Validated pulmonary questionnaires were administered (n = 184), and infant pulmonary function testing was performed (n = 69) between 6 and 12 months' chronological age by the raised volume rapid thoracoabdominal compression technique. A total of 25% of participants had chorioamnionitis. Although infant pulmonary function testing variables were lower in infants born preterm compared with historical normative data for term infants, there were no differences between infants with chorioamnionitis (n = 20) and those without (n = 49). Boys and black infants had lower infant pulmonary function testing measurements than girls and white infants, respectively. Chorioamnionitis exposure was associated independently with wheeze (odds ratio [OR], 2.08) and respiratory-related physician visits (OR, 3.18) in the first year of life. Infants exposed to severe chorioamnionitis had increased levels of cord blood IL-6 and greater pulmonary morbidity at age 6 to 12 months than those exposed to mild chorioamnionitis. Elevated IL-6 was associated with significantly more respiratory problems (OR, 3.23). In infants born moderate or late preterm, elevated cord blood IL-6 and exposure to histologically identified chorioamnionitis was associated with respiratory morbidity during infancy without significant changes in infant pulmonary function testing measurements. Black compared with white and boy compared with girl infants had lower infant pulmonary function testing measurements and worse pulmonary outcomes.

Pulmonary functions in plastic factory workers: a preliminary study.

PubMed

Khaliq, Farah; Singh, Pawan; Chandra, Prakash; Gupta, Keshav; Vaney, Neelam

2011-01-01

Exposure to long term air pollution in the work environment may result in decreased lung functions and various other health problems. A significant occupational hazard to lung functions is experienced by plastic factory workers. The present study is planned to assess the pulmonary functions of workers in the plastic factory where recycling of pastic material was done. These workers were constantly exposed to fumes of various chemicals throughout the day. Thirty one workers of plastic factory were assessed for their pulmonary functions. Parameters were compared with 31 age and sex matched controls not exposed to the same environment. The pulmonary function tests were done using Sibelmed Datospir 120 B portable spirometer. A significant decrease in most of the flow rates (MEF 25%, MEF 50%, MEF 75% and FEF 25-75%) and most of the lung volumes and capacities (FVC, FEV1, VC, TV, ERV, MVV) were observed in the workers. Smoking and duration of exposure were not affecting the lung functions as the non smokers also showed a similar decrement in pulmonary functions. Similarly the workers working for less than 5 years also had decrement in pulmonary functions indicating that their lungs are being affected even if they have worked for one year. Exposure to the organic dust in the work environment should be controlled by adequate engineering measures, complemented by effective personal respiratory protection.

Role of the inflammasome in chronic obstructive pulmonary disease (COPD).

PubMed

Colarusso, Chiara; Terlizzi, Michela; Molino, Antonio; Pinto, Aldo; Sorrentino, Rosalinda

2017-10-10

Inflammation is central to the development of chronic obstructive pulmonary disease (COPD), a pulmonary disorder characterized by chronic bronchitis, chronic airway obstruction, emphysema, associated to progressive and irreversible decline of lung function. Emerging genetic and pharmacological evidence suggests that IL-1-like cytokines are highly detected in the sputum and broncho-alveolar lavage (BAL) of COPD patients, implying the involvement of the multiprotein complex inflammasome. So far, scientific evidence has focused on nucleotide-binding oligomerization domain-like receptors protein 3 (NLRP3) inflammasome, a specialized inflammatory signaling platform that governs the maturation and secretion of IL-1-like cytokines through the regulation of caspase-1-dependent proteolytic processing. Some studies revealed that it is involved during airway inflammation typical of COPD. Based on the influence of cigarette smoke in various respiratory diseases, including COPD, in this view we report its effects in inflammatory and immune responses in COPD mouse models and in human subjects affected by COPD. In sharp contrast to what reported on experimental and clinical studies, randomized clinical trials show that indirect inflammasome inhibitors did not have any beneficial effect in moderate to severe COPD patients.

Effect of Exercise on Pulmonary Function Tests in Obese Malaysian Patients.

PubMed

Christopher, L K S; Kosai, N R; Reynu, R; Levin, K B; Taher, M M; Sutton, P A; Sukor, N; Das, S

2015-01-01

Obesity has taken the 21st century by storm, posing negative effects on of the various facades of health, healthcare and global economy. With regards to pulmonary performance, numerous studies have proven the detrimental effects of obesity while reinstating the positive effects of weight loss on overall pulmonary function. However, effects of exercise on pulmonary function and correlation between changes in pulmonary function test with weight loss have yet to be described. We performed a prospective interventional study to determine the effects of regular exercise on Pulmonary Function Tests (PFT) and ascertain the relationship between weight loss and change in PFT in obese patients. Twenty-five obese patients were enrolled, giving an 80% power of study. Baseline weight and PFT consisting of FEV1, FVC, TLC, mean ERV and VC were recorded prior to commencement of the 8 week long Standard Exercise Regimen (SER). PFT and weight were recorded again at the end of 8 weeks. All parameters of the PFT studied improved significantly with exercise. The participants lost an average of 1kg of body weight post-exercise (p<0.0005). The correlations between mean changes in weight and PFT were negligible. A period of supervised regular exercise improves the pulmonary function of obese patients and this improvement is independent of the amount of weight loss. Hence, SER should be recommended to all obese patients, especially when bariatric surgery is desired.

Glycogen synthase kinase-3 (GSK-3) regulates TGF-β1-induced differentiation of pulmonary fibroblasts

PubMed Central

Baarsma, Hoeke A; Engelbertink, Lilian HJM; van Hees, Lonneke J; Menzen, Mark H; Meurs, Herman; Timens, Wim; Postma, Dirkje S; Kerstjens, Huib AM; Gosens, Reinoud

2013-01-01

Background Chronic lung diseases such as asthma, COPD and pulmonary fibrosis are characterized by abnormal extracellular matrix (ECM) turnover. TGF-β is a key mediator stimulating ECM production by recruiting and activating lung fibroblasts and initiating their differentiation process into more active myofibroblasts. Glycogen synthase kinase-3 (GSK-3) regulates various intracellular signalling pathways; its role in TGF-β1-induced myofibroblast differentiation is currently largely unknown. Purpose To determine the contribution of GSK-3 signalling in TGF-β1-induced myofibroblast differentiation. Experimental Approach We used MRC5 human lung fibroblasts and primary pulmonary fibroblasts of individuals with and without COPD. Protein and mRNA expression were determined by immunoblotting and RT-PCR analysis respectively. Results Stimulation of MRC5 and primary human lung fibroblasts with TGF-β1 resulted in time- and dose-dependent increases of α-sm-actin and fibronectin expression, indicative of myofibroblast differentiation. Pharmacological inhibition of GSK-3 by SB216763 dose-dependently attenuated TGF-β1-induced expression of these myofibroblasts markers. Moreover, silencing of GSK-3 by siRNA or pharmacological inhibition by CT/CHIR99021 fully inhibited the TGF-β1-induced expression of α-sm-actin and fibronectin. The effect of GSK-3 inhibition on α-sm-actin expression was similar in fibroblasts from individuals with and without COPD. Neither smad, NF-κB nor ERK1/2 were involved in the inhibitory actions of GSK-3 inhibition by SB126763 on myofibroblast differentiation. Rather, SB216763 increased the phosphorylation of CREB, which in its phosphorylated form acts as a functional antagonist of TGF-β/smad signalling. Conclusion and Implication We demonstrate that GSK-3 signalling regulates TGF-β1-induced myofibroblast differentiation by regulating CREB phosphorylation. GSK-3 may constitute a useful target for treatment of chronic lung diseases. PMID:23297769

Sleep and pulmonary outcomes for clinical trials of airway plexiform neurofibromas in NF1.

PubMed

Plotkin, Scott R; Davis, Stephanie D; Robertson, Kent A; Akshintala, Srivandana; Allen, Julian; Fisher, Michael J; Blakeley, Jaishri O; Widemann, Brigitte C; Ferner, Rosalie E; Marcus, Carole L

2016-08-16

Plexiform neurofibromas (PNs) are complex, benign nerve sheath tumors that occur in approximately 25%-50% of individuals with neurofibromatosis type 1 (NF1). PNs that cause airway compromise or pulmonary dysfunction are uncommon but clinically important. Because improvement in sleep quality or airway function represents direct clinical benefit, measures of sleep and pulmonary function may be more meaningful than tumor size as endpoints in therapeutic clinical trials targeting airway PN. The Response Evaluation in Neurofibromatosis and Schwannomatosis functional outcomes group reviewed currently available endpoints for sleep and pulmonary outcomes and developed consensus recommendations for response evaluation in NF clinical trials. For patients with airway PNs, polysomnography, impulse oscillometry, and spirometry should be performed to identify abnormal function that will be targeted by the agent under clinical investigation. The functional group endorsed the use of the apnea hypopnea index (AHI) as the primary sleep endpoint, and pulmonary resistance at 10 Hz (R10) or forced expiratory volume in 1 or 0.75 seconds (FEV1 or FEV0.75) as primary pulmonary endpoints. The group defined minimum changes in AHI, R10, and FEV1 or FEV0.75 for response criteria. Secondary sleep outcomes include desaturation and hypercapnia during sleep and arousal index. Secondary pulmonary outcomes include pulmonary resistance and reactance measurements at 5, 10, and 20 Hz; forced vital capacity; peak expiratory flow; and forced expiratory flows. These recommended sleep and pulmonary evaluations are intended to provide researchers with a standardized set of clinically meaningful endpoints for response evaluation in trials of NF1-related airway PNs. © 2016 American Academy of Neurology.

Pulmonary MR imaging with ultra-short TEs: utility for disease severity assessment of connective tissue disease patients.

PubMed

Ohno, Yoshiharu; Nishio, Mizuho; Koyama, Hisanobu; Takenaka, Daisuke; Takahashi, Masaya; Yoshikawa, Takeshi; Matsumoto, Sumiaki; Obara, Makoto; van Cauteren, Marc; Sugimura, Kazuro

2013-08-01

To evaluate the utility of pulmonary magnetic resonance (MR) imaging with ultra-short echo times (UTEs) at a 3.0 T MR system for pulmonary functional loss and disease severity assessments of connective tissue disease (CTD) patients with interstitial lung disease (ILD). This prospective study was approved by the institutional review board, and written informed consent was obtained from 18 CTD patients (eight men and ten women) and eight normal subjects with suspected chest disease (three men and five women). All subjects underwent thin-section MDCT, pulmonary MR imaging with UTEs, pulmonary function test and serum KL-6. Regional T2 maps were generated from each MR data set, and mean T2 values were determined from ROI measurements. From each thin-section MDCT data set, CT-based disease severity was evaluated with a visual scoring system. Mean T2 values for normal and CTD subjects were statistically compared by using Student's t-test. To assess capability for pulmonary functional loss and disease severity assessments, mean T2 values were statistically correlated with pulmonary functional parameters, serum KL-6 and CT-based disease severity. Mean T2 values for normal and CTD subjects were significantly different (p=0.0019) and showed significant correlations with %VC, %DLCO, serum KL-6 and CT-based disease severity of CTD patients (p<0.05). Pulmonary MR imaging with UTEs is useful for pulmonary functional loss and disease severity assessments of CTD patients with ILD. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Correlation between pulmonary function and brain volume in healthy elderly subjects.

PubMed

Taki, Yasuyuki; Kinomura, Shigeo; Ebihara, Satoru; Thyreau, Benjamin; Sato, Kazunori; Goto, Ryoi; Kakizaki, Masako; Tsuji, Ichiro; Kawashima, Ryuta; Fukuda, Hiroshi

2013-06-01

Cigarette smoking decreases brain regional gray matter volume and is related to chronic obstructive lung disease (COPD). COPD leads to decreased pulmonary function, which is represented by forced expiratory volume in one second percentage (FEV1.0 %); however, it is unclear if decreased pulmonary function is directly related to brain gray matter volume decline. Because there is a link between COPD and cognitive decline, revealing a direct relationship between pulmonary function and brain structure is important to better understand how pulmonary function affects brain structure and cognitive function. Therefore, the purpose of this study was to analyze whether there were significant correlations between FEV1.0 % and brain regional gray and white matter volumes using brain magnetic resonance (MR) image data from 109 community-dwelling healthy elderly individuals. Brain MR images were processed with voxel-based morphometry using a custom template by applying diffeomorphic anatomical registration using the exponentiated lie algebra procedure. We found a significant positive correlation between the regional white matter volume of the cerebellum and FEV1.0 % after adjusting for age, sex, and intracranial volume. Our results suggest that elderly individuals who have a lower FEV1.0 % have decreased regional white matter volume in the cerebellum. Therefore, preventing decreased pulmonary function is important for cerebellar white matter volume in the healthy elderly population.

The IDO-AhR Axis Controls Th17/Treg Immunity in a Pulmonary Model of Fungal Infection.

PubMed

de Araújo, Eliseu Frank; Feriotti, Claudia; Galdino, Nayane Alves de Lima; Preite, Nycolas Willian; Calich, Vera Lúcia Garcia; Loures, Flávio Vieira

2017-01-01

In infectious diseases, the enzyme indoleamine 2,3 dioxygenase-1 (IDO1) that catalyzes the tryptophan (Trp) degradation along the kynurenines (Kyn) pathway has two main functions, the control of pathogen growth by reducing available Trp and immune regulation mediated by the Kyn-mediated expansion of regulatory T (Treg) cells via aryl hydrocarbon receptor (AhR). In pulmonary paracoccidioidomycosis (PCM) caused by the dimorphic fungus Paracoccidioides brasiliensis , IDO1 was shown to control the disease severity of both resistant and susceptible mice to the infection; however, only in resistant mice, IDO1 is induced by TGF-β signaling that confers a stable tolerogenic phenotype to dendritic cells (DCs). In addition, in pulmonary PCM, the tolerogenic function of plasmacytoid dendritic cells was linked to the IDO1 activity. To further evaluate the function of IDO1 in pulmonary PCM, IDO1-deficient (IDO1 -/- ) C57BL/6 mice were intratracheally infected with P. brasiliensis yeasts and the infection analyzed at three postinfection periods regarding several parameters of disease severity and immune response. The fungal loads and tissue pathology of IDO1 -/- mice were higher than their wild-type controls resulting in increased mortality rates. The evaluation of innate lymphoid cells showed an upregulated differentiation of the innate lymphoid cell 3 phenotype accompanied by a decreased expansion of ILC1 and NK cells in the lungs of infected IDO1 -/- mice. DCs from these mice expressed elevated levels of costimulatory molecules and cytokine IL-6 associated with reduced production of IL-12, TNF-α, IL-1β, TGF-β, and IL-10. This response was concomitant with a marked reduction in AhR production. The absence of IDO1 expression caused an increased influx of activated Th17 cells to the lungs with a simultaneous reduction in Th1 and Treg cells. Accordingly, the suppressive cytokines IL-10, TGF-β, IL-27, and IL-35 appeared in reduced levels in the lungs of IDO1 -/- mice. In conclusion, the immunological balance mediated by the axis IDO/AhR is fundamental to determine the balance between Th17/Treg cells and control the severity of pulmonary PCM.

Association between high-density lipoprotein cholesterol level and pulmonary function in healthy Korean adolescents: the JS high school study.

PubMed

Park, Ji Hye; Mun, Seyeon; Choi, Dong Phil; Lee, Joo Young; Kim, Hyeon Chang

2017-12-11

Accumulating evidence suggests that high-density lipoprotein (HDL) cholesterol is associated with pulmonary function and pulmonary disorders. The aim of this study was to evaluate the association between HDL cholesterol and pulmonary function in healthy adolescents. This cross-sectional study was based on data collected for the JS High School study. The analysis included 644 adolescents (318 male and 326 female) aged 15-16 years old and free from asthma or chronic obstructive pulmonary disease. Fasting blood samples were collected for hematologic and biochemical assessment. Forced vital capacity volume (FVC) and forced expiratory volume in the 1 s (FEV1) were measured using dry-rolling-seal spirometry. The associations between HDL cholesterol and pulmonary function were analyzed using multiple linear regression models. Among male adolescents, an increase of 1.0 mg/dL in HDL cholesterol was associated with 10 mL decrease in FVC (p = 0.013) and FEV1 (p = 0.013) after adjusting for age, height, weight, alcohol drinking, smoking, physical activity, systolic blood pressure, total cholesterol, triglyceride, and monthly household income. Percent predicted values of FVC (p = 0.036) and FEV1 (p = 0.017) were also inversely associated with HDL cholesterol. However, among female adolescents, HDL cholesterol level was not significantly associated with absolute or percent predictive value of FVC and FEV1. Higher HDL cholesterol level may be associated with decreased pulmonary function among healthy male adolescents. The sex differences observed in the association between HDL cholesterol and pulmonary function need further investigation.

Microarray expression profile of circular RNAs in chronic thromboembolic pulmonary hypertension

PubMed Central

Miao, Ran; Wang, Ying; Wan, Jun; Leng, Dong; Gong, Juanni; Li, Jifeng; Liang, Yan; Zhai, Zhenguo; Yang, Yuanhua

2017-01-01

Abstract Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare but debilitating and life-threatening complication of acute pulmonary embolism. Circular RNAs (circRNAs), presenting as covalently closed continuous loops, are RNA molecules with covalently joined 3′- and 5′-ends formed by back-splicing events. circRNAs may be significant biological molecules to understand disease mechanisms and to identify biomarkers for disease diagnosis and therapy. The aim of this study was to investigate the potential roles of circRNAs in CTEPH. Methods: Ten human blood samples (5 each from CTEPH and control groups) were included in the Agilent circRNA chip. The differentially expressed circRNAs were evaluated using t test, with significance set at a P value of < .05. A functional enrichment analysis for differentially expressed circRNAs was performed using DAVID online tools, and a Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis for target genes of miRNAs was performed using the R package clusterProfiler. Furthermore, miRNAs that interacted with differentially expressed circRNAs were predicted using the miRanda package. mRNAs that had clear biological functions and were regulated by miRNAs were predicted using miRWalk2.0 and then combined into a circRNA–miRNA–mRNA network. Results: In total, 351 differentially expressed circRNAs (122 upregulated and 229 downregulated) between CTEPH and control groups were obtained; among these circRNAs, hsa_circ_0002062 and hsa_circ_0022342 might be important because they can regulate 761 (e.g., hsa-miR-942–5p) and 453 (e.g., hsa-miR-940) miRNAs, respectively. Target genes (e.g., cyclin-dependent kinase 6) of hsa-miR-942–5p were mainly enriched in cancer-related pathways, whereas target genes (e.g., CRK-Like Proto-Oncogene, Adaptor Protein) of hsa-miR-940 were enriched in the ErbB signaling pathway. Therefore, these pathways are potentially important in CTEPH. Conclusions: Our findings suggested that hsa_circ_0002062 and hsa_circ_0022342 may be key circRNAs for CTEPH development and that their targeted regulation may be an effective approach for treating CTEPH. PMID:28682884

Right ventricular morphology and function in chronic obstructive pulmonary disease patients living at high altitude.

PubMed

Güvenç, Tolga Sinan; Erer, Hatice Betül; Kul, Seref; Perinçek, Gökhan; Ilhan, Sami; Sayar, Nurten; Yıldırım, Binnaz Zeynep; Doğan, Coşkun; Karabağ, Yavuz; Balcı, Bahattin; Eren, Mehmet

2013-01-01

Pulmonary vasculature is affected in patients with chronic pulmonary obstructive disease (COPD). As a result of increased pulmonary resistance, right ventricular morphology and function are altered in COPD patients. High altitude and related hypoxia causes pulmonary vasoconstriction, thereby affecting the right ventricle. We aimed to investigate the combined effects of COPD and altitude-related chronic hypoxia on right ventricular morphology and function. Forty COPD patients living at high altitude (1768 m) and 41 COPD patients living at sea level were enrolled in the study. All participants were diagnosed as COPD by a pulmonary diseases specialist depending on symptoms, radiologic findings and pulmonary function test results. Detailed two-dimensional echocardiography was performed by a cardiologist at both study locations. Oxygen saturation and mean pulmonary artery pressure were higher in the high altitude group. Right ventricular end diastolic diameter, end systolic diameter, height and end systolic area were significantly higher in the high altitude group compared to the sea level group. Parameters of systolic function, including tricuspid annular systolic excursion, systolic velocity of tricuspid annulus and right ventricular isovolumic acceleration were similar between groups, while fractional area change was significantly higher in the sea level groups compared to the high altitude group. Indices of diastolic function and myocardial performance index were similar between groups. An increase in mean pulmonary artery pressure and right ventricular dimensions are observed in COPD patients living at high altitude. Despite this increase, systolic and diastolic functions of the right ventricle, as well as global right ventricular performance are similar in COPD patients living at high altitude and sea level. Altitude-related adaptation to chronic hypoxia could explain these findings. Copyright © 2012 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.

Pulmonary Function in Middle-Aged Patients With Idiopathic Scoliosis With Onset Before the Age of 10 Years.

PubMed

Danielsson, Aina J; Ekerljung, Linda; Hallerman, Kerstin Lofdahl

2015-09-01

Consecutive patients with idiopathic scoliosis diagnosed before age 10 attended a clinical follow-up at least 10 years after treatment. To evaluate the pulmonary function in adulthood after treatment with brace or surgery before maturity. Long-term studies of these patients have not been published. One hundred twenty-four patients (69% of the original group) underwent radiography, spirometry, and answered symptom questionnaires. A total of 73 patients had spirometries before treatment enabling longitudinal evaluation. Overall, 68 braced only (BT) and 56 surgically treated (ST) were analyzed in detail. A population-based control group was used. At follow-up, the mean age was 41.5 years and the mean curve size 36 degrees (26% of the curves >45 degrees). The full patient group had a significantly reduced pulmonary function (as measured by the forced vital capacity [FVC], percentage of predicted) compared with the control group, mean 85% versus 102% (p < .0001). Both subgroups of BT and ST patients showed a significant reduction, more in the ST than the BT group (means 79% and 90%, respectively, p = .0003). The most important risk factor for a low lung function at follow-up was a low initial FVC value. Initial curve size correlated with pulmonary function both before treatment and at follow-up. Most surgically treated patients, who had larger curves before treatment, did not improve their pulmonary function after surgery. Both braced and surgically treated patients had reduced pulmonary function at the age of around 40 years. The pulmonary function did not worsen over time in most patients. There was no difference in terms of symptoms between patient groups and controls. Initial curve size was found to be of great importance for pulmonary function. Initial spirometry and follow-up in selected patients is important. III. Copyright © 2015 Scoliosis Research Society. Published by Elsevier Inc. All rights reserved.

Implantation of the Medtronic Harmony Transcatheter Pulmonary Valve Improves Right Ventricular Size and Function in an Ovine Model of Postoperative Chronic Pulmonary Insufficiency.

PubMed

Schoonbeek, Rosanne C; Takebayashi, Satoshi; Aoki, Chikashi; Shimaoka, Toru; Harris, Matthew A; Fu, Gregory L; Kim, Timothy S; Dori, Yoav; McGarvey, Jeremy; Litt, Harold; Bouma, Wobbe; Zsido, Gerald; Glatz, Andrew C; Rome, Jonathan J; Gorman, Robert C; Gorman, Joseph H; Gillespie, Matthew J

2016-10-01

Pulmonary insufficiency is the nexus of late morbidity and mortality after transannular patch repair of tetralogy of Fallot. This study aimed to establish the feasibility of implantation of the novel Medtronic Harmony transcatheter pulmonary valve (hTPV) and to assess its effect on pulmonary insufficiency and ventricular function in an ovine model of chronic postoperative pulmonary insufficiency. Thirteen sheep underwent baseline cardiac magnetic resonance imaging, surgical pulmonary valvectomy, and transannular patch repair. One month after transannular patch repair, the hTPV was implanted, followed by serial magnetic resonance imaging and computed tomography imaging at 1, 5, and 8 month(s). hTPV implantation was successful in 11 animals (85%). There were 2 procedural deaths related to ventricular fibrillation. Seven animals survived the entire follow-up protocol, 5 with functioning hTPV devices. Two animals had occlusion of hTPV with aneurysm of main pulmonary artery. A strong decline in pulmonary regurgitant fraction was observed after hTPV implantation (40.5% versus 8.3%; P=0.011). Right ventricular end diastolic volume increased by 49.4% after transannular patch repair (62.3-93.1 mL/m 2 ; P=0.028) but was reversed to baseline values after hTPV implantation (to 65.1 mL/m 2 at 8 months, P=0.045). Both right ventricular ejection fraction and left ventricular ejection fraction were preserved after hTPV implantation. hTPV implantation is feasible, significantly reduces pulmonary regurgitant fraction, facilitates right ventricular volume improvements, and preserves biventricular function in an ovine model of chronic pulmonary insufficiency. This percutaneous strategy could potentially offer an alternative for standard surgical pulmonary valve replacement in dilated right ventricular outflow tracts, permitting lower risk, nonsurgical pulmonary valve replacement in previously prohibitive anatomies. © 2016 American Heart Association, Inc.

Down-regulated peroxisome proliferator-activated receptor γ (PPARγ) in lung epithelial cells promotes a PPARγ agonist-reversible proinflammatory phenotype in chronic obstructive pulmonary disease (COPD).

PubMed

Lakshmi, Sowmya P; Reddy, Aravind T; Zhang, Yingze; Sciurba, Frank C; Mallampalli, Rama K; Duncan, Steven R; Reddy, Raju C

2014-03-07

Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory condition and a leading cause of death, with no available cure. We assessed the actions in pulmonary epithelial cells of peroxisome proliferator-activated receptor γ (PPARγ), a nuclear hormone receptor with anti-inflammatory effects, whose role in COPD is largely unknown. We found that PPARγ was down-regulated in lung tissue and epithelial cells of COPD patients, via both reduced expression and phosphorylation-mediated inhibition, whereas pro-inflammatory nuclear factor-κB (NF-κB) activity was increased. Cigarette smoking is the main risk factor for COPD, and exposing airway epithelial cells to cigarette smoke extract (CSE) likewise down-regulated PPARγ and activated NF-κB. CSE also down-regulated and post-translationally inhibited the glucocorticoid receptor (GR-α) and histone deacetylase 2 (HDAC2), a corepressor important for glucocorticoid action and whose down-regulation is thought to cause glucocorticoid insensitivity in COPD. Treating epithelial cells with synthetic (rosiglitazone) or endogenous (10-nitro-oleic acid) PPARγ agonists strongly up-regulated PPARγ expression and activity, suppressed CSE-induced production and secretion of inflammatory cytokines, and reversed its activation of NF-κB by inhibiting the IκB kinase pathway and by promoting direct inhibitory binding of PPARγ to NF-κB. In contrast, PPARγ knockdown via siRNA augmented CSE-induced chemokine release and decreases in HDAC activity, suggesting a potential anti-inflammatory role of endogenous PPARγ. The results imply that down-regulation of pulmonary epithelial PPARγ by cigarette smoke promotes inflammatory pathways and diminishes glucocorticoid responsiveness, thereby contributing to COPD pathogenesis, and further suggest that PPARγ agonists may be useful for COPD treatment.

Ghrelin and the cardiovascular system.

PubMed

Tokudome, Takeshi; Kishimoto, Ichiro; Miyazato, Mikiya; Kangawa, Kenj

2014-01-01

Ghrelin is a peptide that was originally isolated from the stomach. It exerts potent growth hormone (GH)-releasing and orexigenic activities. Several studies have highlighted the therapeutic benefits of ghrelin for the treatment of cardiovascular disease. In animal models of chronic heart failure, the administration of ghrelin improved cardiac function and remodeling; these findings were replicated in human patients with heart failure. Moreover, in an animal study, ghrelin administration effectively reduced pulmonary hypertension induced by chronic hypoxia. In addition, repeated administration of ghrelin to cachectic patients with chronic obstructive pulmonary disease had positive effects on overall body function, including muscle wasting, functional capacity and sympathetic activity. The administration of ghrelin early after myocardial infarction (MI) reduced fatal arrhythmia and related mortality. In ghrelin-deficient mice, both exogenous and endogenous ghrelin were protective against fatal arrhythmia and promoted remodeling after MI. Although the mechanisms underlying the effects of ghrelin on the cardiovascular system remain unclear, there are indications that its beneficial effects are mediated through both direct physiological actions, including increased GH levels, improved energy balance and direct actions on cardiovascular cells, and regulation of autonomic nervous system activity. Therefore, ghrelin is a promising novel therapeutic agent for cardiovascular disease. © 2014 S. Karger AG, Basel.

International spinal cord injury pulmonary function basic data set.

PubMed

Biering-Sørensen, F; Krassioukov, A; Alexander, M S; Donovan, W; Karlsson, A-K; Mueller, G; Perkash, I; Sheel, A William; Wecht, J; Schilero, G J

2012-06-01

To develop the International Spinal Cord Injury (SCI) Pulmonary Function Basic Data Set within the framework of the International SCI Data Sets in order to facilitate consistent collection and reporting of basic bronchopulmonary findings in the SCI population. International. The SCI Pulmonary Function Data Set was developed by an international working group. The initial data set document was revised on the basis of suggestions from members of the Executive Committee of the International SCI Standards and Data Sets, the International Spinal Cord Society (ISCoS) Executive and Scientific Committees, American Spinal Injury Association (ASIA) Board, other interested organizations and societies and individual reviewers. In addition, the data set was posted for 2 months on ISCoS and ASIA websites for comments. The final International SCI Pulmonary Function Data Set contains questions on the pulmonary conditions diagnosed before spinal cord lesion,if available, to be obtained only once; smoking history; pulmonary complications and conditions after the spinal cord lesion, which may be collected at any time. These data include information on pneumonia, asthma, chronic obstructive pulmonary disease and sleep apnea. Current utilization of ventilator assistance including mechanical ventilation, diaphragmatic pacing, phrenic nerve stimulation and Bi-level positive airway pressure can be reported, as well as results from pulmonary function testing includes: forced vital capacity, forced expiratory volume in one second and peak expiratory flow. The complete instructions for data collection and the data sheet itself are freely available on the website of ISCoS (http://www.iscos.org.uk).

Caveolin-1 siRNA increases the pulmonary microvascular and alveolar epithelial permeability in rats.

PubMed

Gao, Chengjin; Li, Rongrong; Huan, Jingning; Li, Wei

2011-01-01

Increased pulmonary microvascular and epithelial permeability are important contributors to pulmonary edema in acute lung injury. In this study, we used small interfering RNA (siRNA) to knock down caveolin-1 expression in rat lungs and to confirm the important role of caveolin-1 in regulating pulmonary edema. After pulmonary injection of siRNA against caveolin-1 messenger RNA incorporated in liposomes with three concentrations of 0.4, 0.8, and 1.2 mg/kg, the gene silencing rate and the effects of caveolin-1 siRNA on aquaporin (AQP)-1, AQP-5, and epithelial sodium channel (ENaC) were detected. For pulmonary permeability analysis, Evans blue fluorimetry, ratios of albumin concentrations between blood and bronchoalveolar lavage, and wet/dry weight ratios were measured. The impacts of caveolin-1 suppression on interendothelial junctions were evaluated by the performance of electron microscopy and the analysis of vascular endothelial (VE)-cadherin Western blot. Alveolar wall thickness analysis and chest fluoroscopy were performed to determine the pulmonary edema degree. After 72 hours of injection, the gene silencing rate of caveolin-1 siRNA is about 87%. AQP-1, AQP-5, ENaC-α, ENaC-β, ENaC-γ, and VE-cadherin protein levels were decreased by 63%, 66%, 80%, 90%, 89%, and 50%, respectively. Caveolin-1 siRNA also resulted in increasing microvascular and epithelial permeability and pulmonary edema. These data suggest that caveolin-1 plays an important part in regulating the pulmonary permeability by modifying AQP-1, AQP-5, ENaC, and VE-cadherin.

Optical techniques in pulmonary medicine. SPIE photonics West.

PubMed

Suter, Melissa J; Lam, Stephen; Brenner, Matthew

2012-04-01

There is ongoing interest in the emerging field of pulmonary photonic-based diagnostics. Potential clinical need areas that are being actively investigated at this time include airway and peripheral lung cancer diagnostics, pulmonary parenchymal and interstitial disorders, alveolar structure function, inhalation injury, ciliary function analysis, asthma and obstructive lung diseases.

Leaving Moderate Tricuspid Valve Regurgitation Alone at the Time of Pulmonary Valve Replacement: A Worthwhile Approach.

PubMed

Kogon, Brian; Mori, Makoto; Alsoufi, Bahaaldin; Kanter, Kirk; Oster, Matt

2015-06-01

Pulmonary valve disruption in patients with tetralogy of Fallot and congenital pulmonary stenosis often results in pulmonary insufficiency, right ventricular dilation, and tricuspid valve regurgitation. Management of functional tricuspid regurgitation at the time of subsequent pulmonary valve replacement remains controversial. Our aims were to (1) analyze tricuspid valve function after pulmonary valve replacement through midterm follow-up and (2) determine the benefits, if any, of concomitant tricuspid annuloplasty. Thirty-five patients with tetralogy of Fallot or congenital pulmonary stenosis were analyzed. All patients had been palliated in childhood by disrupting the pulmonary valve, and all patients had at least moderate tricuspid valve regurgitation at the time of subsequent pulmonary valve replacement. Preoperative and serial postoperative echocardiograms were analyzed. Pulmonary and tricuspid regurgitation, along with right ventricular dilation and dysfunction were scored as 0 (none), 1 (mild), 2 (moderate), and 3 (severe). Right ventricular volume and area were also calculated. Comparisons were made between patients who underwent pulmonary valve replacement alone and those who underwent concomitant tricuspid valve annuloplasty. At 1 month after pulmonary valve replacement, there were significant reductions in pulmonary valve regurgitation (mean 3 vs 0.39, p < 0.0001), tricuspid valve regurgitation (mean 2.33 vs 1.3, p < 0.0001), and in right ventricular dilation, volume, and area. There was no difference in the degree of tricuspid regurgitation 1 month postoperatively between patients who underwent concomitant tricuspid annuloplasty and those who underwent pulmonary valve replacement alone (mean 1.31 vs 1.29, p = 0.81). However, at latest follow-up (mean 7.0 ± 2.8 years), the degree of tricuspid regurgitation was significantly higher in the concomitant annuloplasty group (mean 1.87 vs 1.12, p = 0.005). In patients with at least moderate tricuspid valve regurgitation, significant improvement in tricuspid valve function and right ventricular size occurs in the first postoperative month after pulmonary valve replacement, irrespective of concomitant tricuspid valve annuloplasty. The tricuspid valve appears to function better over the midterm if annuloplasty is not performed. Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

The Expression of NOX4 in Smooth Muscles of Small Airway Correlates with the Disease Severity of COPD

PubMed Central

2016-01-01

Airway smooth muscle (ASM) remodeling is a hallmark in chronic obstructive pulmonary disease (COPD), and nicotinamide-adenine dinucleotide phosphate (NADPH) oxidases (NOXs) produced reactive oxygen species (ROS) play a crucial role in COPD pathogenesis. In the present study, the expression of NOX4 and its correlation with the ASM hypertrophy/hyperplasia, clinical pulmonary functions, and the expression of transforming growth factor β (TGF-β) in the ASM of COPD small airways were investigated by semiquantitative morphological and/or immunohistochemistry staining methods. The results showed that an elevated expression of NOX4 and TGF-β, along with an increased volume of ASM mass, was found in the ASM of small airways in COPD patients. The abundance of NOX4 protein in the ASM was increased with disease severity and inversely correlated with the pulmonary functions in COPD patients. In addition, the expression of NOX4 and ASM marker α-SMA was colocalized, and the increased NOX4 expression was found to accompany an upregulated expression of TGF-β in the ASM of small airways of COPD lung. These results indicate that NOX4 may be a key regulator in ASM remodeling of small airway, in part through a mechanism interacting with TGF-β signaling in the pathogenesis of COPD, which warrants further investigation. PMID:27656649

A minireview of E4BP4/NFIL3 in heart failure.

PubMed

Velmurugan, Bharath Kumar; Chang, Ruey-Lin; Marthandam Asokan, Shibu; Chang, Chih-Fen; Day, Cecilia-Hsuan; Lin, Yueh-Min; Lin, Yuan-Chuan; Kuo, Wei-Wen; Huang, Chih-Yang

2018-06-01

Heart failure (HF) remains a major cause of morbidity and mortality worldwide. The primary cause identified for HF is impaired left ventricular myocardial function, and clinical manifestations may lead to severe conditions like pulmonary congestion, splanchnic congestion, and peripheral edema. Development of new therapeutic strategies remains the need of the hour for controlling the problem of HF worldwide. Deeper insights into the molecular mechanisms involved in etiopathology of HF indicate the significant role of calcium signaling, autocrine signaling pathways, and insulin-like growth factor-1 signaling that regulates the physiologic functions of heart growth and development such as contraction, metabolism, hypertrophy, cytokine signaling, and apoptosis. In view of these facts, a transcription factor (TF) regulating the myriad of these signaling pathways may prove as a lead candidate for development of therapeutics. Adenovirus E4 promoter-binding protein (E4BP4), also known as nuclear-factor, interleukin 3 regulated (NFIL3), a type of basic leucine zipper TF, is known to regulate the signaling processes involved in the functioning of heart. The current review discusses about the expression, structure, and functional role of E4BP4 in signaling processes with emphasis on calcium signaling mechanisms, autocrine signaling, and insulin-like growth factor II receptor-mediated processes regulated by E4BP4 that may regulate the pathogenesis of HF. We propose that E4BP4, being the critical component for the regulation of the above signaling processes, may serve as a novel therapeutic target for HF, and scientific investigations are merited in this direction. © 2018 Wiley Periodicals, Inc.

Pulmonary function and respiratory symptoms of school children exposed to ambient air pollution

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Yoon Shin; Ko, Ung Ring

1996-12-31

This study was undertaken to evaluate the health effect of air pollution on pulmonary function and respiratory symptoms of Korean school children between 7 and 10 years of age during November 1995-January 1996. A standard respiratory symptom questionnaire was administered and spirometry was performed to examine pulmonary function of 121 children in an urban polluted area, Seoul, and of 119 children in non-polluted area, Sokcho, respectively. There was significant difference in the level of pulmonary function [forced expiratory volume in second (FEV{sub 1.0}) and forced vital capacity (FVC)] between exposed groups to polluted area and non-polluted area. Parental smoking wasmore » significantly related to respiratory symptoms of cough, phlegm, and the level of pulmonary function. The observed changes in FEV{sub 1.0} and FVC seemed to relate to home cooking fuel, not to respiratory symptoms. The additional longitudinal work that carefully monitors ambient and indoor air pollution and health effects data should be conducted to confirm these results.« less

Pulmonary function outcomes for assessing cystic fibrosis care.

PubMed

Wagener, Jeffrey S; Elkin, Eric P; Pasta, David J; Schechter, Michael S; Konstan, Michael W; Morgan, Wayne J

2015-05-01

Assessing cystic fibrosis (CF) patient quality of care requires the choice of an appropriate outcome measure. We looked systematically and in detail at pulmonary function outcomes that potentially reflect clinical practice patterns. Epidemiologic Study of Cystic Fibrosis data were used to evaluate six potential outcome variables (2002 best FVC, FEV(1), and FEF(25-75) and rate of decline for each from 2000 to 2002). We ranked CF care sites by outcome measure and then assessed any association with practice patterns and follow-up pulmonary function. Sites ranked in the top quartile had more frequent monitoring, treatment of exacerbations, and use of chronic therapies and oral corticosteroids. The follow-up rate of pulmonary function decline was not predicted by site ranking. Different pulmonary function outcomes associate slightly differently with practice patterns, although annual FEV(1) is at least as good as any other measure. Current site ranking only moderately predicts future ranking. Copyright © 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Hyperpolarized Gas MRI: Technique and Applications

PubMed Central

McAdams, Holman P.; Kaushik, S. Sivaram; Driehuys, Bastiaan

2015-01-01

Synopsis Functional imaging today offers a rich world of information that is more sensitive to changes in lung structure and function than traditionally obtained pulmonary function tests. Hyperpolarized helium (3He) and xenon (129Xe) MR imaging of the lungs provided new sensitive contrast mechanisms to probe changes in pulmonary ventilation, microstructure and gas exchange. With the recent scarcity in the supply of 3He the field of hyperpolarized gas imaging shifted to the use of cheaper and naturally available 129Xe. Xenon is well tolerated and recent technical advances have ensured that the 129Xe image quality is on par with that of 3He. The added advantage of 129Xe is its solubility in pulmonary tissue, which allows exploring specific lung function characteristics involved in gas exchange and alveolar oxygenation. With a plethora of contrast mechanisms, hyperpolarized gases and 129Xe in particular, stands to be an excellent probe of pulmonary structure and function, and provide sensitive and non-invasive biomarkers for a wide variety of pulmonary diseases. PMID:25952516

Lipocalin-2 Promotes Endoplasmic Reticulum Stress and Proliferation by Augmenting Intracellular Iron in Human Pulmonary Arterial Smooth Muscle Cells

PubMed Central

Wang, Guoliang; Liu, Shenghua; Wang, Li; Meng, Liukun; Cui, Chuanjue; Zhang, Hao; Hu, Shengshou; Ma, Ning; Wei, Yingjie

2017-01-01

Endoplasmic reticulum (ER) stress, a feature of many conditions associated with pulmonary hypertension (PH), is increasingly recognized as a common response to promote proliferation in the walls of pulmonary arteries. Increased expression of Lipocalin-2 in PH led us to test the hypothesis that Lipocalin-2, a protein known to sequester iron and regulate it intracellularly, might facilitate the ER stress and proliferation in pulmonary arterial smooth muscle cells (PASMCs). In this study, we observed greatly increased Lcn2 expression accompanied with increased ATF6 cleavage in a standard rat model of pulmonary hypertension induced by monocrotaline. In cultured human PASMCs, Lcn2 significantly promoted ER stress (determined by augmented cleavage and nuclear localization of ATF6, up-regulated transcription of GRP78 and NOGO, increased expression of SOD2, and mild augmented mitochondrial membrane potential) and proliferation (assessed by Ki67 staining and BrdU incorporation). Lcn2 promoted ER stress accompanied with augmented intracellular iron levels in human PASMCs. Treatment human PASMCs with FeSO4 induced the similar ER stress and proliferation response and iron chelator (deferoxamine) abrogated the ER stress and proliferation induced by Lcn2 in cultured human PASMCs. In conclusion, Lcn2 significantly promoted human PASMC ER stress and proliferation by augmenting intracellular iron. The up-regulation of Lcn2 probably involved in the pathogenesis and progression of PH. PMID:28255266

[Clinical analysis of nasal resistance and pulmonary function testing in patients with chronic nasal-sinusitis and nasal polyps].

PubMed

Liao, Hua; Shen, Ying; Wang, Pengjun

2015-05-01

To study the pulmonary function and nasal resistance characteristics of patients with chronic nose-sinusitis and nasal polyps (CRSwNP), to explore the evaluation role of nasal resistance in nasal ventilation function and the effect of endoscopic sinus surgery on pulmonary function in patients with CRSwNP. Fifty CRSwNP patients that met the study criteria were selected . The patients were performed endoscopic surgeries according to Messerklinger surgical procedures under general anesthesia. Extent of surgery was based on preoperative CT showing the range of the lesion of disease and endoscopic findings. Perioperative treatments contained intranasal corticosteroids, cephalosporin or penicillin antibiotics, nasal irrigation and other treatments. Main outcome measures included visual analog scale (VAS), endoscopic Lind-Kennedy scores, nasal resistence, pulmonary function in patientsone week before and after surgery, three months and six months after surgery. Pulmonary function includes forced expiratory volume in one second (FEV1), forced vital capacity FEV1/FVC and peak expiratory flow (PEF). The study found that there were significantly positive correlations among VAS score, Lund-Kennedy score and nasal resistance (P < 0.05) in CRSwNP patients, but there is a significantly negative correlation between VAS score, Lund-Kennedy score, nasal resistance and pulmonary function indexes of FEV1, FVC and PEF (P < 0.05). The VAS score, Lund-Kennedy score and nasal resistance values of CRSwNP patients were decreased significantly after comprehensive treatments with nasal endoscopic operation as the major one, the difference was statistically different (P < 0.05). And the pulmonary function indexs (FEV1, FVC, PEF) were significantly increased after surgery in CRSwNP patients. The nasal resistance can objectively and reliably reflect the degree of nasal congestion and the recovery of nasal function in CRSwNP patients after endoscopic sinus surgery. The detection method of nasal resistance is simple. Functional endoscopic sinus surgery can effectively improve the pulmonary ventilation function in CRSwNP patients, providing some clinical references about the prevention and treatment of CRS related lower respiratory disease.

Exercise capacity before and after an 8-week multidisciplinary inpatient rehabilitation program in lung cancer patients: a pilot study.

PubMed

Spruit, Martijn A; Janssen, Paul P; Willemsen, Sonja C P; Hochstenbag, Monique M H; Wouters, Emiel F M

2006-05-01

Although lung cancer is a highly prevalent type of cancer, the effects of an inpatient multidisciplinary rehabilitation program on pulmonary function and exercise capacity have never been studied in these patients. Pulmonary function, 6-min walking distance and peak exercise capacity of 10 patients with a severely impaired pulmonary function following treatment of lung cancer were assessed in this pilot study before and after an 8-week inpatient multidisciplinary rehabilitation program. At baseline, patients had a restrictive pulmonary function and an apparent exercise intolerance (median 6-min walking distance: 63.6% predicted; median peak cycling load: 58.5% predicted). Despite the lack of change in median pulmonary function [FEV1: -0.01L, p = 0.5469], functional exercise capacity [145 m; 43.2% of the initial values, p=0.0020] and peak exercise capacity [26 W; 34.4% of the initial values, p = 0.0078] improved significantly compared to baseline. Future trials have to corroborate the present findings. Nevertheless, patients with lung cancer have a clear indication to start a comprehensive rehabilitation program following intensive treatment of their disease. In fact, based on the results of the present pilot study it appears that these patients are good candidates for pulmonary rehabilitation programs.

Mediating pathways from central obesity to childhood asthma: a population-based longitudinal study.

PubMed

Chih, An-Hsuan; Chen, Yang-Ching; Tu, Yu-Kang; Huang, Kuo-Chin; Chiu, Tai-Yuan; Lee, Yungling Leo

2016-09-01

The mediating pathways linking obesity and asthma are largely unknown. We aimed to investigate the mediating pathways and to search for the most prominent pathological mechanism between central obesity and childhood asthma.In the Taiwan Children Health Study, we collected data on an open cohort of children aged 9-13 years. Children's respiratory outcomes, atopic conditions, obesity measures and pulmonary function were surveyed annually between 2010 and 2012. Exhaled nitric oxide fraction concentrations were recorded in 2012. Generalised estimating equations and general linear models were used to examine the associations between central obesity, possible mediators and asthma. Structural equation models were applied to investigate the pathways that mediate the link between central obesity and asthma.Central obesity (waist-to-hip ratio) most accurately predicted childhood asthma. In the active asthma model, the percentage of mediation was 28.6% for pulmonary function, 18.1% for atopy and 5.7% for airway inflammation. The percentage of mediation for pulmonary function was 40.2% in the lifetime wheeze model. Pulmonary function was responsible for the greatest percentage of mediation among the three mediators in both models.Decline in pulmonary function is the most important pathway in central obesity related asthma. Pulmonary function screening should be applied to obese children for asthma risk prediction. Copyright ©ERS 2016.

Protective mechanical ventilation during general anesthesia for open abdominal surgery improves postoperative pulmonary function.

PubMed

Severgnini, Paolo; Selmo, Gabriele; Lanza, Christian; Chiesa, Alessandro; Frigerio, Alice; Bacuzzi, Alessandro; Dionigi, Gianlorenzo; Novario, Raffaele; Gregoretti, Cesare; de Abreu, Marcelo Gama; Schultz, Marcus J; Jaber, Samir; Futier, Emmanuel; Chiaranda, Maurizio; Pelosi, Paolo

2013-06-01

The impact of intraoperative ventilation on postoperative pulmonary complications is not defined. The authors aimed at determining the effectiveness of protective mechanical ventilation during open abdominal surgery on a modified Clinical Pulmonary Infection Score as primary outcome and postoperative pulmonary function. Prospective randomized, open-label, clinical trial performed in 56 patients scheduled to undergo elective open abdominal surgery lasting more than 2 h. Patients were assigned by envelopes to mechanical ventilation with tidal volume of 9 ml/kg ideal body weight and zero-positive end-expiratory pressure (standard ventilation strategy) or tidal volumes of 7 ml/kg ideal body weight, 10 cm H2O positive end-expiratory pressure, and recruitment maneuvers (protective ventilation strategy). Modified Clinical Pulmonary Infection Score, gas exchange, and pulmonary functional tests were measured preoperatively, as well as at days 1, 3, and 5 after surgery. Patients ventilated protectively showed better pulmonary functional tests up to day 5, fewer alterations on chest x-ray up to day 3 and higher arterial oxygenation in air at days 1, 3, and 5 (mmHg; mean ± SD): 77.1 ± 13.0 versus 64.9 ± 11.3 (P = 0.0006), 80.5 ± 10.1 versus 69.7 ± 9.3 (P = 0.0002), and 82.1 ± 10.7 versus 78.5 ± 21.7 (P = 0.44) respectively. The modified Clinical Pulmonary Infection Score was lower in the protective ventilation strategy at days 1 and 3. The percentage of patients in hospital at day 28 after surgery was not different between groups (7 vs. 15% respectively, P = 0.42). A protective ventilation strategy during abdominal surgery lasting more than 2 h improved respiratory function and reduced the modified Clinical Pulmonary Infection Score without affecting length of hospital stay.

Screening and identification of lncRNAs as potential biomarkers for pulmonary tuberculosis.

PubMed

Chen, Zhong-Liang; Wei, Li-Liang; Shi, Li-Ying; Li, Meng; Jiang, Ting-Ting; Chen, Jing; Liu, Chang-Ming; Yang, Su; Tu, Hui-Hui; Hu, Yu-Ting; Gan, Lin; Mao, Lian-Gen; Wang, Chong; Li, Ji-Cheng

2017-12-01

Pulmonary tuberculosis (TB) is among the diseases with the highest morbidity and mortality worldwide. Effective diagnostic methods for TB are lacking. In this study, we investigated long non-coding RNAs (lncRNAs) in plasma using microarray and the potential diagnostic value of lncRNAs for TB. We found a total of 163 up-regulated lncRNAs and 348 down-regulated lncRNAs. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and coding-noncoding co-expression (CNC) analyses showed that functions of differentially expressed lncRNAs were mainly enriched in the regulation of alpha-beta T cell activation and the T cell receptor signalling pathway. Four differentially expressed lncRNAs, NR_038221 (fold change = 3.79, P < 0.01), NR_003142 (fold change = 1.69, P < 0.05), ENST00000570366 (fold change = 3.04, P < 0.05), and ENST00000422183 (fold change = 2.11, P < 0.001), were verified using RT-qPCR. Among those, NR_038221, NR_003142, and ENST00000570366 were found to be up-regulated, while ENST00000422183 was down-regulated. The value of the area under the curve (AUC) for the diagnostic model consisting of the four lncRNAs was 0.845 (sensitivity = 79.2%, specificity = 75%). We further predicted 85 mRNAs and 404 miRNAs that potentially interact with these lncRNAs. Our study revealed the potential value of lncRNAs as biomarkers for early diagnosis of TB and the underlying mechanisms of these abnormally expressed lncRNAs in the pathogenesis of TB.

Pulmonary 3 T MRI with ultrashort TEs: influence of ultrashort echo time interval on pulmonary functional and clinical stage assessments of smokers.

PubMed

Ohno, Yoshiharu; Nishio, Mizuho; Koyama, Hisanobu; Yoshikawa, Takeshi; Matsumoto, Sumiaki; Seki, Shinichiro; Obara, Makoto; van Cauteren, Marc; Takahashi, Masaya; Sugimura, Kazuro

2014-04-01

To assess the influence of ultrashort TE (UTE) intervals on pulmonary magnetic resonance imaging (MRI) with UTEs (UTE-MRI) for pulmonary functional loss assessment and clinical stage classification of smokers. A total 60 consecutive smokers (43 men and 17 women; mean age 70 years) with and without COPD underwent thin-section multidetector row computed tomography (MDCT), UTE-MRI, and pulmonary functional measurements. For each smoker, UTE-MRI was performed with three different UTE intervals (UTE-MRI A: 0.5 msec, UTE-MRI B: 1.0 msec, UTE-MRI C: 1.5 msec). By using the GOLD guidelines, the subjects were classified as: "smokers without COPD," "mild COPD," "moderate COPD," and "severe or very severe COPD." Then the mean T2* value from each UTE-MRI and CT-based functional lung volume (FLV) were correlated with pulmonary function test. Finally, Fisher's PLSD test was used to evaluate differences in each index among the four clinical stages. Each index correlated significantly with pulmonary function test results (P < 0.05). CT-based FLV and mean T2* values obtained from UTE-MRI A and B showed significant differences among all groups except between "smokers without COPD" and "mild COPD" groups (P < 0.05). UTE-MRI has a potential for management of smokers and the UTE interval is suggested as an important parameter in this setting. Copyright © 2013 Wiley Periodicals, Inc.

Update on diagnosis and treatment of idiopathic pulmonary fibrosis

PubMed Central

Baddini-Martinez, José; Baldi, Bruno Guedes; da Costa, Cláudia Henrique; Jezler, Sérgio; Lima, Mariana Silva; Rufino, Rogério

2015-01-01

Idiopathic pulmonary fibrosis is a type of chronic fibrosing interstitial pneumonia, of unknown etiology, which is associated with a progressive decrease in pulmonary function and with high mortality rates. Interest in and knowledge of this disorder have grown substantially in recent years. In this review article, we broadly discuss distinct aspects related to the diagnosis and treatment of idiopathic pulmonary fibrosis. We list the current diagnostic criteria and describe the therapeutic approaches currently available, symptomatic treatments, the action of new drugs that are effective in slowing the decline in pulmonary function, and indications for lung transplantation. PMID:26578138

PREOPERATIVE PREDICTION OF LUNG FUNCTION IN PNEUMONECTOMY BY SPIROMETRY AND LUNG PERFUSION SCINTIGRAPHY

PubMed Central

Cukic, Vesna

2012-01-01

Introduction: Nowadays an increasing number of lung resections are being done because of the rising prevalence of lung cancer that occurs mainly in patients with limited lung function, what is caused by common etiologic factor - smoking cigarettes. Loss of lung tissue in such patients can worsen much the postoperative pulmonary function. So it is necessary to asses the postoperative pulmonary function especially after maximal resection, i.e. pneumonectomy. Objective: To check over the accuracy of preoperative prognosis of postoperative lung function after pneumonectomy using spirometry and lung perfusion scinigraphy. Material and methods: The study was done on 17 patients operated at the Clinic for thoracic surgery, who were treated previously at the Clinic for Pulmonary Diseases “Podhrastovi” in the period from 01. 12. 2008. to 01. 06. 2011. Postoperative pulmonary function expressed as ppoFEV1 (predicted postoperative forced expiratory volume in one second) was prognosticated preoperatively using spirometry, i.e.. simple calculation according to the number of the pulmonary segments to be removed and perfusion lung scintigraphy. Results: There is no significant deviation of postoperative achieved values of FEV1 from predicted ones obtained by both methods, and there is no significant differences between predicted values (ppoFEV1) obtained by spirometry and perfusion scintigraphy. Conclusion: It is necessary to asses the postoperative pulmonary function before lung resection to avoid postoperative respiratory failure and other cardiopulmonary complications. It is absolutely necessary for pneumonectomy, i.e.. maximal pulmonary resection. It can be done with great possibility using spirometry or perfusion lung scintigraphy. PMID:23378687

Pulmonary adverse effects of welding fume in automobile assembly welders.

PubMed

Sharifian, Seyed Akbar; Loukzadeh, Ziba; Shojaoddiny-Ardekani, Ahmad; Aminian, Omid

2011-01-01

Welding is one of the key components of numerous manufacturing industries, which has potential physical and chemical health hazards. Many components of welding fumes can potentially affect the lung function. This study investigates the effects of welding fumes on lung function and respiratory symptoms among welders of an automobile manufacturing plant in Iran. This historical cohort study assesses 43 male welders and 129 office workers by a questionnaire to record demographic data, smoking habits, work history and respiratory symptoms as well as lung function status by spirometry. The average pulmonary function values of welders were lower relative to controls with dose-effect relationship between work duration and pulmonary function impairment. The prevalence of chronic bronchitis was higher in welders than controls. Our findings suggest that welders are at risk for pulmonary disease.

Airway and Pulmonary β2-Adrenergic Vasodilatory Function in Current Smokers and Never Smokers.

PubMed

Hurwitz, Barry E; Mendes, Eliana S; Schmid, Andreas; Parker, Meela; Arana, Johana; Gonzalez, Alex; Wanner, Adam

2017-03-01

Cigarette smoking has been associated with diminished vasodilatory function in the airway circulation. It is possible that cigarette smoking similarly affects the pulmonary circulation before resting pulmonary circulatory abnormalities become manifested. The aim of this study was to compare the acute effect of inhaled albuterol on airway and pulmonary hemodynamic function as an index of β 2 -adrenoceptor-mediated vasodilation in smokers and never smokers. In 30 adults, airway and pulmonary vascular function was assessed before and 15 min after albuterol inhalation (270 μg). From mean systemic arterial pressure, cardiac output, airway blood flow, and mean pulmonary arterial pressure, airway vascular resistance (AVR) and pulmonary vascular resistance (PVR) were derived. Albuterol induced a substantial drop in mean (± SE) PVR (-67.2% ± 5%), with no difference between groups. In contrast, the albuterol-induced decrease in AVR was significantly greater in never smokers than in smokers (-28.6% ± 3% vs -3.1% ± 6%; P < .02). These results are consistent with a dysfunction in a β 2 -adrenergic signaling pathway mediating vasorelaxation in the airway circulation of current smokers. The vasodilatory deficit in the airway circulation but not in the pulmonary circulation could be related to local differences in the impact of cigarette smoke on the vascular endothelium. Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

[Analysis of clinical features in patients with pneumoconiosis complicated with pulmonary emphysema].

PubMed

Li, X; Dai, W R; Li, L; Liu, W F; Yang, Z X; Xie, L

2017-11-20

Objective: To investigate the clinical features of pneumoconiosis complicated with pulmo-nary emphysema. Methods: selected 868 patients with pneumoconiosis were selected from December 2015 to December 2016 in Hunan occupational disease prevention and treatment hospital. Collected the results of high-resolution spiral CT, arterial blood gas, ECG, pulmonary function and MRC score. The subjects were divided into pneumoconiosis complicated with pulmonary emphysema group and simple pneumoconiosis group accord-ing to the results of HRCT. The smoking, MRC score, pulmonary function, blood gas and complications were compared. Results: A total of 868 patients were enrolled in the study. Emphysema 232 people, accounting for 26.73%. The incidence of emphysema in the first phase of pneumoconiosis was 12.69%, and the incidence rate of emphysema in pneumoconiosis was 17.03%, The incidence of three Stage pneumoconiosis was highest, up to 60.76%, the incidence of emphysema increased with the increase of stages of pneumoconiosis ( P =0.000) .The smoking index of pneumoconiosis combined with emphysema group was significantly higher than that of simple pneumoconiosis group ( P <0.01) . The MRC score of pneumoconiosis complicated with pulmonary em-physema group was higher than that of simple pneumoconiosis group ( P =0.000) . In pneumoconiosis complicat-ed with pulmonary emphysema group the FEV(1.0)%, FVC%, FEV(1.0)/FVC, DLCO%, oxygen partial pressure were significantly lower than that of simple pneumoconiosis group ( P ≤0.05) . The combined rate of Bullae of lung in pneumoconiosis complicated with pulmonary emphysema group was higher than that of simple pneumo-coniosis group ( P <0.01) . Conclusion: pneumoconiosis stage and smoking. Patients with pneumoconiosis com-plicated with pulmonary emphysema had heavier breathing difficulties, more serious pulmonary function and active endurance, the degree of hypoxia is more serious, and had a higher incidence of complications. The pul-monary function of pneumoconiosis complicated with pulmonary emphysema is not consistent with the typical CPFE.

Spatiotemporal alterations in Sprouty-2 expression and tyrosine phosphorylation in nitrofen-induced pulmonary hypoplasia.

PubMed

Friedmacher, Florian; Gosemann, Jan-Hendrik; Fujiwara, Naho; Alvarez, Luis A J; Corcionivoschi, Nicolae; Puri, Prem

2013-11-01

Pulmonary hypoplasia (PH) is a life-threatening condition of newborns presenting with congenital diaphragmatic hernia (CDH). Sprouty-2 functions as a key regulator of fibroblast growth factor receptor (FGFR) signalling in developing foetal lungs. It has been reported that FGFR-mediated alveolarization is disrupted in nitrofen-induced PH. Sprouty-2 knockouts show severe defects in lung morphogenesis similar to nitrofen-induced PH. Upon FGFR stimulation, Sprouty-2 is tyrosine-phosphorylated, which is essential for its physiological function during foetal lung development. We hypothesized that Sprouty-2 expression and tyrosine phosphorylation are altered in nitrofen-induced PH. Time-pregnant rats received either nitrofen or vehicle on gestation day 9 (D9). Foetal lungs were dissected on D18 and D21. Pulmonary Sprouty-2 gene and protein expression levels were analyzed by qRT-PCR, Western blotting and immunohistochemical staining. Relative mRNA expression of Sprouty-2 was significantly decreased in hypoplastic lungs without CDH (0.1050±0.01 vs. 0.3125±0.01; P<.0001) and with CDH (0.1671±0.01 vs. 0.3125±0.01; P<.0001) compared to controls on D18. Protein levels of Sprouty-2 were markedly decreased in hypoplastic lungs on D18 with decreased tyrosine phosphorylation levels on D18 and D21 detected at the molecular weight of Sprouty-2 consistent with Sprouty-2 tyrosine phosphorylation. Sprouty-2 immunoreactivity was markedly decreased in hypoplastic lungs on D18 and D21. Spatiotemporal alterations in pulmonary Sprouty-2 expression and tyrosine phosphorylation during the late stages of foetal lung development may interfere with FGFR-mediated alveolarization in nitrofen-induced PH. © 2013.

Inhibition of mitochondrial fission prevents hypoxia-induced metabolic shift and cellular proliferation of pulmonary arterial smooth muscle cells.

PubMed

Parra, Valentina; Bravo-Sagua, Roberto; Norambuena-Soto, Ignacio; Hernández-Fuentes, Carolina P; Gómez-Contreras, Andrés G; Verdejo, Hugo E; Mellado, Rosemarie; Chiong, Mario; Lavandero, Sergio; Castro, Pablo F

2017-11-01

Chronic hypoxia exacerbates proliferation of pulmonary arterial smooth muscle cells (PASMC), thereby reducing the lumen of pulmonary arteries. This leads to poor blood oxygenation and cardiac work overload, which are the basis of diseases such as pulmonary artery hypertension (PAH). Recent studies revealed an emerging role of mitochondria in PAH pathogenesis, as key regulators of cell survival and metabolism. In this work, we assessed whether hypoxia-induced mitochondrial fragmentation contributes to the alterations of both PASMC death and proliferation. In previous work in cardiac myocytes, we showed that trimetazidine (TMZ), a partial inhibitor of lipid oxidation, stimulates mitochondrial fusion and preserves mitochondrial function. Thus, here we evaluated whether TMZ-induced mitochondrial fusion can prevent human PASMC proliferation in an in vitro hypoxic model. Using confocal fluorescence microscopy, we showed that prolonged hypoxia (48h) induces mitochondrial fragmentation along with higher levels of the mitochondrial fission protein DRP1. Concomitantly, both mitochondrial potential and respiratory rates decreased, indicative of mitochondrial dysfunction. In accordance with a metabolic shift towards non-mitochondrial ATP generation, mRNA levels of glycolytic markers HK2, PFKFB2 and GLUT1 increased during hypoxia. Incubation of PASMC with TMZ, prior to hypoxia, prevented all these changes and precluded the increase in PASMC proliferation. These findings were also observed using Mdivi-1 (a pharmacological DRP1 inhibitor) or a dominant negative DRP1 K38A as pre-treatments. Altogether, our data indicate that TMZ exerts a protective role against hypoxia-induced PASMC proliferation, by preserving mitochondrial function, thus highlighting DRP1-dependent morphology as a novel therapeutic approach for diseases such as PAH. Copyright © 2017 Elsevier B.V. All rights reserved.

Role of pulmonary diseases and physical condition in the regulation of vasoactive hormones.

PubMed

Hietanen, E; Marniemi, J; Liippo, K; Seppänen, A; Hartiala, J; Viinamäki, O

1988-12-01

Lungs have many non-respiratory metabolic functions, of which some take place in the capillary endothelium, while others are in parenchymal lung tissue. We have studied the role of the lungs in the metabolism of vasoactive and some other hormones by comparing patients who have undergone lung resection to those having various obstructive or fibrotic lung diseases. We have also compared these groups with persons in good physical health. The data suggested that lung resection patients had low angiotensin II levels in plasma but the response of angiotensin II to exercise was normal. Also adrenalin concentration was low in the lung resection group while dopamine did not show any significant difference between the groups. When hormone levels were correlated to the exercise data, renin levels were especially related to physical condition. Serum post-exercise renin values were inversely related to the uneven distribution of lung perfusion, possibly thus reflecting the diminished pulmonary vascularization. A negative association was found between angiotensin II and diffusion capacity. Thus, the angiotensin II levels may preferably be controlled by the non-circulatory functions of the lungs.

Correlation of 68Ga Ventilation-Perfusion PET/CT with Pulmonary Function Test Indices for Assessing Lung Function.

PubMed

Le Roux, Pierre-Yves; Siva, Shankar; Steinfort, Daniel P; Callahan, Jason; Eu, Peter; Irving, Lou B; Hicks, Rodney J; Hofman, Michael S

2015-11-01

Pulmonary function tests (PFTs) are routinely used to assess lung function, but they do not provide information about regional pulmonary dysfunction. We aimed to assess correlation of quantitative ventilation-perfusion (V/Q) PET/CT with PFT indices. Thirty patients underwent V/Q PET/CT and PFT. Respiration-gated images were acquired after inhalation of (68)Ga-carbon nanoparticles and administration of (68)Ga-macroaggregated albumin. Functional volumes were calculated by dividing the volume of normal ventilated and perfused (%NVQ), unmatched and matched defects by the total lung volume. These functional volumes were correlated with forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC, and diffusing capacity for carbon monoxide (DLCO). All functional volumes were significantly different in patients with chronic obstructive pulmonary disease (P < 0.05). FEV1/FVC and %NVQ had the highest correlation (r = 0.82). FEV1 was also best correlated with %NVQ (r = 0.64). DLCO was best correlated with the volume of unmatched defects (r = -0.55). Considering %NVQ only, a cutoff value of 90% correctly categorized 28 of 30 patients with or without significant pulmonary function impairment. Our study demonstrates strong correlations between V/Q PET/CT functional volumes and PFT parameters. Because V/Q PET/CT is able to assess regional lung function, these data support the feasibility of its use in radiation therapy and preoperative planning and assessing pulmonary dysfunction in a variety of respiratory diseases. © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

[The repercussions of pulmonary congestion on ventilatory volumes, capacities and flows].

PubMed

Carmo, M M; Ferreira, T; Lousada, N; Bárbara, C; Neves, P R; Correia, J M; Rendas, A B

1994-10-01

To evaluate the effects of pulmonary congestion on pulmonary function. Prospective study performed in patients with left ventricular failure or mitral stenosis. Forty-eight hospitalized patients were included suffering from pulmonary congestion either from left ventricular failure or mitral stenosis. While in hospital all patients were submitted to right heart catheterization by the Swan-Ganz method and also to an echocardiographic examination. Within 48 hours after the patients were submitted to the following lung function studies: lung volumes and capacities by the multi-breath helium dilution method and airway flows by pneumotachography. Respiratory symptoms were evaluated by the Medical Research Council Questionnaire and the functional class classified according to the NYHA. Correlations were made between the functional and clinical data. Regarding the cardiac evaluation patients presented with a mean pulmonary wedge pressure of 19.9 +/- 8.6 mmHg, a cardiac index of 2.5 +/- 0.8 l/min/m2, an end diastolic dimension of the left ventricle of 65.9 +/- 10.1 mm, and end systolic dimension of 51.2 +/- 12.2 mm, with a shortening fraction of 21.8 +/- 9.5%. The pulmonary evaluation showed a restrictive syndrome with a reduction in the mean values of the following parameters: total pulmonary capacity 71 +/- 14.4% of the predicted value (pv), forced vital capacity (FVC) 69.8 +/- 20.5% pv, and forced expiratory volume (FEV1) of 64 +/- 21.8% vp. The index FEV1/FVC was within the normal value of 72.7 +/- 9.7%. These lung function results did not correlate significantly with either the clinical, the hemodynamic or echocardiographic findings. In these group of patients pulmonary congestion led to the development of a restrictive syndrome which failed to correlate in severity with the duration of the disease, the pulmonary wedge pressure and the left ventricular function.

Pulmonary Morbidity in Infancy after Exposure to Chorioamnionitis in Late Preterm Infants

PubMed Central

McDowell, Karen M.; Jobe, Alan H.; Fenchel, Matthew; Hardie, William D.; Gisslen, Tate; Young, Lisa R.; Chougnet, Claire A.; Davis, Stephanie D.

2016-01-01

Rationale: Chorioamnionitis is an important cause of preterm birth, but its impact on postnatal outcomes is understudied. Objectives: To evaluate whether fetal exposure to inflammation is associated with adverse pulmonary outcomes at 6 to 12 months’ chronological age in infants born moderate to late preterm. Methods: Infants born between 32 and 36 weeks’ gestational age were prospectively recruited (N = 184). Chorioamnionitis was diagnosed by placenta and umbilical cord histology. Select cytokines were measured in samples of cord blood. Validated pulmonary questionnaires were administered (n = 184), and infant pulmonary function testing was performed (n = 69) between 6 and 12 months’ chronological age by the raised volume rapid thoracoabdominal compression technique. Measurements and Main Results: A total of 25% of participants had chorioamnionitis. Although infant pulmonary function testing variables were lower in infants born preterm compared with historical normative data for term infants, there were no differences between infants with chorioamnionitis (n = 20) and those without (n = 49). Boys and black infants had lower infant pulmonary function testing measurements than girls and white infants, respectively. Chorioamnionitis exposure was associated independently with wheeze (odds ratio [OR], 2.08) and respiratory-related physician visits (OR, 3.18) in the first year of life. Infants exposed to severe chorioamnionitis had increased levels of cord blood IL-6 and greater pulmonary morbidity at age 6 to 12 months than those exposed to mild chorioamnionitis. Elevated IL-6 was associated with significantly more respiratory problems (OR, 3.23). Conclusions: In infants born moderate or late preterm, elevated cord blood IL-6 and exposure to histologically identified chorioamnionitis was associated with respiratory morbidity during infancy without significant changes in infant pulmonary function testing measurements. Black compared with white and boy compared with girl infants had lower infant pulmonary function testing measurements and worse pulmonary outcomes. PMID:27015030

Recent advances in arginine metabolism: roles and regulation of the arginases

PubMed Central

Morris, Sidney M

2009-01-01

As arginine can serve as precursor to a wide range of compounds, including nitric oxide, creatine, urea, polyamines, proline, glutamate and agmatine, there is considerable interest in elucidating mechanisms underlying regulation of its metabolism. It is now becoming apparent that the two isoforms of arginase in mammals play key roles in regulation of most aspects of arginine metabolism in health and disease. In particular, work over the past several years has focused on the roles and regulation of the arginases in vascular disease, pulmonary disease, infectious disease, immune cell function and cancer. As most of these topics have been considered in recent review articles, this review will focus more closely on results of recent studies on expression of the arginases in endothelial and vascular smooth muscle cells, post-translational modulation of arginase activity and applications of arginase inhibitors in vivo. PMID:19508396

Increased activation of NADPH oxidase 4 in the pulmonary vasculature in experimental diaphragmatic hernia.

PubMed

Gosemann, Jan-H; Friedmacher, Florian; Hunziker, Manuela; Alvarez, Luis; Corcionivoschi, Nicolae; Puri, Prem

2013-01-01

Persistent pulmonary hypertension remains a major cause of mortality and morbidity in congenital diaphragmatic hernia (CDH). NADPH oxidases (Nox) are the main source of superoxide production in vasculature. Nox4 is highly expressed in the smooth muscle and endothelial cells of the vascular wall and increased activity has been reported in the pulmonary vasculature of both experimental and human pulmonary hypertension. Peroxisome proliferator-activated receptor (PPARγ) is a key regulator of Nox4 expression. Targeted depletion of PPARγ results in pulmonary hypertension phenotype whereas activation of PPARγ attenuates pulmonary hypertension and reduces Nox4 production. The nitrofen-induced CDH model is an established model to study the pathogenesis of pulmonary hypertension in CDH. It has been previously reported that PPARγ-signaling is disrupted during late gestation and H(2)O(2) production is increased in nitrofen-induced CDH. We designed this study to investigate the hypothesis that Nox4 expression and activation is increased and vascular PPARγ is decreased in nitrofen-induced CDH. Pregnant rats were treated with either nitrofen or vehicle on gestational day 9 (D9). Fetuses were sacrificed on D21 and divided into control and CDH. RT-PCR, western blotting and confocal-immunofluorescence-double-staining were performed to determine pulmonary expression levels of PPARγ, Nox4 and Nox4-activation (p22(phox)). There was a marked increase in medial and adventitial thickness in pulmonary arteries of all sizes in CDH compared to controls. Pulmonary Nox4 levels were significantly increased whereas PPARγ levels were decreased in nitrofen-induced CDH compared to controls. Western blotting revealed increased pulmonary protein expression of the Nox4-activating subunit p22(phox) and decreased protein expression of PPARγ in CDH compared to controls. Confocal-microscopy confirmed markedly increased pulmonary expression of the Nox4 activating subunit p22(phox) accompanied by decreased perivascular PPARγ expression in lungs of nitrofen-exposed fetuses compared to controls. To our knowledge, the present study is the first to report increased Nox4 production in the pulmonary vasculature of nitrofen-induced CDH. Down-regulation of the PPARγ-signaling pathway may lead to increased superoxide production, resulting in pulmonary vascular dysfunction and contributing to pulmonary hypertension in the nitrofen-induced CDH model. PPARγ-activation inhibiting Nox4 production may therefore represent a potential therapeutic approach for the treatment of pulmonary hypertension in CDH.

Trans-plasma membrane electron transport in mammals: functional significance in health and disease.

PubMed

Del Principe, Domenico; Avigliano, Luciana; Savini, Isabella; Catani, Maria Valeria

2011-06-01

Trans-plasma membrane electron transport (t-PMET) has been established since the 1960s, but it has only been subject to more intensive research in the last decade. The discovery and characterization at the molecular level of its novel components has increased our understanding of how t-PMET regulates distinct cellular functions. This review will give an update on t-PMET, with particular emphasis on how its malfunction relates to some diseases, such as cancer, abnormal cell death, cardiovascular diseases, aging, obesity, neurodegenerative diseases, pulmonary fibrosis, asthma, and genetically linked pathologies. Understanding these relationships may provide novel therapeutic approaches for pathologies associated with unbalanced redox state.

[Functional respiratory evolution in two patients with emphysema and pulmonary fibrosis].

PubMed

Arce, Santiago C; Molinari, Luciana; De Vito, Eduardo L

2009-01-01

Combined pulmonary fibrosis and emphysema (CPFE) is a frequently under-diagnosed condition. Isolated pulmonary function tests (PFT) can give rise to misinterpretations. We have found no reports on these patients' spirometric progression. We describe two cases of CPFE, showing long-term functional evolution to have a more accurate understanding of current spirometric values. The most relevant findings are: 1) spirometry with discrete functional alterations in the presence of a marked dyspnea and the need, in one patient, for chronic oxygen therapy; and 2) functional evolution reflecting "pseudonormalisation" of the initial obstructive spirometric pattern, possibly as a result of fibrosis development. A mild obstructive defect in a patient with chronic airflow limitation and marked impairment of his/her clinical status and functional class should alert on the possibility of associated pulmonary fibrosis. A computed tomography (CT) and previous PFTs will allow a better understanding of this condition.

Modification of hemi-Fontan operation for patients with functional single ventricle and anomalous pulmonary venous connection to the superior vena cava: mid-term results†

PubMed Central

Ito, Hiroki; Murata, Masaya; Ide, Yujiro; Sugano, Mikio; Kanno, Kazuyoshi; Imai, Kenta; Ishido, Motonori; Fukuba, Ryohei; Sakamoto, Kisaburo

2016-01-01

OBJECTIVES Fontan candidates with mixed totally anomalous pulmonary venous connection often have postoperative pulmonary venous obstruction after cavopulmonary anastomosis. Because some pulmonary venous obstructions have no intimal hypertrophy at reoperation, we considered such pulmonary venous obstructions to be caused by 3D deformities arising from dissection or mobilization of the vessels, and hypothesized that keeping the pulmonary venous branches in a natural position could avoid such obstruction. Here, we evaluated a modified hemi-Fontan strategy consisting of minimal dissection with no division of vessels and patch separation between systemic and pulmonary venous flow. METHODS We retrospectively reviewed clinical records of infants with a functional single ventricle and supracardiac anomalous pulmonary venous connection who had undergone this procedure between 2002 and 2012. RESULTS Nine infants underwent this procedure (median age, 5.6 months; range 3.2–30), all with right atrial isomerism and several pulmonary venous branches directly and separately connecting to the superior vena cava. In 5 patients, all pulmonary veins drained into the superior vena cava; in 1, the right pulmonary veins drained into the superior vena cava and in 3, a pulmonary venous branch drained into the superior vena cava. The median follow-up was 6.9 years (0.8–13 years). Three patients underwent reoperation for postoperative pulmonary venous obstruction caused by intimal hypertrophy; however, we confirmed no pulmonary venous obstruction caused by 3D deformities on the pulmonary venous branches connecting separately to the superior vena cava. Although 2 patients were effectively relieved from pulmonary venous obstruction, 1 died due to recurrent pulmonary venous obstruction. There was no late death and no sinus-node dysfunction. Eight patients underwent successful Fontan operation and catheterization. The median interval from the Fontan operation to the latest catheterization was 3.7 years (0.9–3.7 years). The median arterial oxygen saturation was 94% (91–97%) and the central venous pressure was 12 mmHg (8–14 mmHg); no deficiency of pulmonary arteries and veins was noted. CONCLUSIONS For patients with functional single ventricle and anomalous pulmonary venous connections to the superior vena cava, our novel strategy of second-stage palliation could avoid postoperative pulmonary venous obstruction caused by 3D deformities, but may not eliminate pulmonary venous obstruction caused by intimal hypertrophy. PMID:26860898

Targeting the renin-angiotensin system as novel therapeutic strategy for pulmonary diseases.

PubMed

Tan, Wan Shun Daniel; Liao, Wupeng; Zhou, Shuo; Mei, Dan; Wong, Wai-Shiu Fred

2017-12-27

The renin-angiotensin system (RAS) plays a major role in regulating electrolyte balance and blood pressure. RAS has also been implicated in the regulation of inflammation, proliferation and fibrosis in pulmonary diseases such as asthma, acute lung injury (ALI), chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) and pulmonary arterial hypertension (PAH). Current therapeutics suffer from some drawbacks like steroid resistance, limited efficacies and side effects. Novel intervention is definitely needed to offer optimal therapeutic strategy and clinical outcome. This review compiles and analyses recent investigations targeting RAS for the treatment of inflammatory lung diseases. Inhibition of the upstream angiotensin (Ang) I/Ang II/angiotensin receptor type 1 (AT 1 R) pathway and activation of the downstream angiotensin-converting enzyme 2 (ACE2)/Ang (1-7)/Mas receptor pathway are two feasible strategies demonstrating efficacies in various pulmonary disease models. More recent studies favor the development of targeting the downstream ACE2/Ang (1-7)/Mas receptor pathway, in which diminazene aceturate, an ACE2 activator, GSK2586881, a recombinant ACE2, and AV0991, a Mas receptor agonist, showed much potential for further development. As the pathogenesis of pulmonary diseases is so complex that RAS modulation may be used alone or in combination with existing drugs like corticosteroids, pirfenidone/nintedanib or endothelin receptor antagonists for different pulmonary diseases. Personalized medicine through genetic screening and phenotyping for angiotensinogen or ACE would aid treatment especially for non-responsive patients. This review serves to provide an update on the latest development in the field of RAS targeting for pulmonary diseases, and offer some insights into future direction. Copyright © 2017 Elsevier Ltd. All rights reserved.

The Cystic Fibrosis Transmembrane Conductance Regulator Potentiator Ivacaftor Augments Mucociliary Clearance Abrogating Cystic Fibrosis Transmembrane Conductance Regulator Inhibition by Cigarette Smoke.

PubMed

Raju, S Vamsee; Lin, Vivian Y; Liu, Limbo; McNicholas, Carmel M; Karki, Suman; Sloane, Peter A; Tang, Liping; Jackson, Patricia L; Wang, Wei; Wilson, Landon; Macon, Kevin J; Mazur, Marina; Kappes, John C; DeLucas, Lawrence J; Barnes, Stephen; Kirk, Kevin; Tearney, Guillermo J; Rowe, Steven M

2017-01-01

Acquired cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction may contribute to chronic obstructive pulmonary disease pathogenesis and is a potential therapeutic target. We sought to determine the acute effects of cigarette smoke on ion transport and the mucociliary transport apparatus, their mechanistic basis, and whether deleterious effects could be reversed with the CFTR potentiator ivacaftor (VX-770). Primary human bronchial epithelial (HBE) cells and human bronchi were exposed to cigarette smoke extract (CSE) and/or ivacaftor. CFTR function and expression were measured in Ussing chambers and by surface biotinylation. CSE-derived acrolein modifications on CFTR were determined by mass spectroscopic analysis of purified protein, and the functional microanatomy of the airway epithelia was measured by 1-μm resolution optical coherence tomography. CSE reduced CFTR-dependent current in HBE cells (P < 0.05) and human bronchi (P < 0.05) within minutes of exposure. The mechanism involved CSE-induced reduction of CFTR gating, decreasing CFTR open-channel probability by approximately 75% immediately after exposure (P < 0.05), whereas surface CFTR expression was partially reduced with chronic exposure, but was stable acutely. CSE treatment of purified CFTR resulted in acrolein modifications on lysine and cysteine residues that likely disrupt CFTR gating. In primary HBE cells, CSE reduced airway surface liquid depth (P < 0.05) and ciliary beat frequency (P < 0.05) within 60 minutes that was restored by coadministration with ivacaftor (P < 0.005). Cigarette smoking transmits acute reductions in CFTR activity, adversely affecting the airway surface. These effects are reversible by a CFTR potentiator in vitro, representing a potential therapeutic strategy in patients with chronic obstructive pulmonary disease with chronic bronchitis.

[Consequences of short term fluctuations of environmental temperatures in calves--Part 1: Immediate reactions of the respiratory system, the cardiovascular system, metabolism and thermal regulation].

PubMed

Elmer, S; Reinhold, P

2002-04-01

Clinically healthy calves (aged 3-6 weeks) were exposed to defined ambient temperature for 4 hours (cold: 5 degrees C, 60% humidity, n = 12; warm: 35 degrees C, 60% humidity, n = 11). During the exposure of each animal in a climatic chamber, certain parameters of lung function, respiratory mechanics, blood gas analysis, circulation, metabolism and thermal regulation were registered simultaneously in order to study immediate physiological consequences of different environmental conditions. In comparison to control calves (18-20 degrees C, 60% humidity, n = 13) an insufficient adaptation of these young calves was noticed in both cold and warm conditions. At 5 degrees C, marked changes in lung function were observed, i.e. airway constriction, pulmonary hypertension, and ventilation-perfusion-mismatching leading to hypoxemia and hypercapnia. Due to compensation by the circulatory system, a sufficient O2-consumption of the organism as well as an unchanged body temperature were maintained. At 35 degrees C, the respiratory pattern changed to panting and a higher dead space ventilation. No changes were observed in pulmonary gas exchange and blood arterialisation. Due to hyperventilation, the partial pressure for CO2 decreased in blood. Since the body temperature increased continuously, thermal regulation was insufficient. This situation would have led to animals collapsing after a period of heat stress lasting longer than 4 hours. In conclusion, young calves up to the age of 6 weeks were not able to tolerate acute changes in ambient temperature. This was true for cold conditions (5 degrees C) as well as for hot conditions (35 degrees C). The results of this study should be taken into account in order to optimise transport and farming conditions.

Normal Physiological Values for Conscious Pigs Used in Biomedical Research

DTIC Science & Technology

1989-05-01

6. Cardiovascular and Pulmonary Functions........... 18 TABLE 7. Bioenergetics..................................... 19 TABLE 8. Renal Function...procedure developed in our laboratory. Plasma concentrations of aldosterone, cortisol, total T3, total T4, free T4, insulin and glucagon were...pulmonary vascular resistance , alveolar ventilation, alveolar ventilation/perfusion ratio, arterial 02 transport, tissue 02 extraction ratio, pulmonary

Pulmonary function studies in young healthy Malaysians of Kelantan, Malaysia.

PubMed

Bandyopadhyay, Amit

2011-11-01

Pulmonary function tests have been evolved as clinical tools in diagnosis, management and follow up of respiratory diseases as it provides objective information about the status of an individual's respiratory system. The present study was aimed to evaluate pulmonary function among the male and female young Kelantanese Malaysians of Kota Bharu, Malaysia, and to compare the data with other populations. A total of 128 (64 males, 64 females) non-smoking healthy young subjects were randomly sampled for the study from the Kelantanese students' population of the University Sains Malaysia, Kota Bharu Campus, Kelantan, Malaysia. The study population (20-25 yr age group) had similar socio-economic background. Each subject filled up the ATS (1978) questionnaire to record their personal demographic data, health status and consent to participate in the study. Subjects with any history of pulmonary diseases were excluded from the study. The pulmonary function measurements exhibited significantly higher values among males than the females. FEV 1% did not show any significant inter-group variation probably because the parameter expresses FEV 1 as a percentage of FVC. FVC and FEV 1 exhibited significant correlations with body height and body mass among males whereas in the females exhibited significant correlation with body mass, body weight and also with age. FEV 1% exhibited significant correlation with body height and body mass among males and with body height in females. FEF 25-75% did not show any significant correlation except with body height among females. However, PEFR exhibited significant positive correlation with all the physical parameters except with age among the females. On the basis of the existence of significant correlation between different physical parameters and pulmonary function variables, simple and multiple regression norms have been computed. From the present investigation it can be concluded that Kelantanese Malaysian youths have normal range of pulmonary function in both the sexes and the computed regression norms may be used to predict the pulmonary function values in the studied population.

Pulmonary function studies in young healthy Malaysians of Kelantan, Malaysia

PubMed Central

Bandyopadhyay, Amit

2011-01-01

Background & objectives: Pulmonary function tests have been evolved as clinical tools in diagnosis, management and follow up of respiratory diseases as it provides objective information about the status of an individual's respiratory system. The present study was aimed to evaluate pulmonary function among the male and female young Kelantanese Malaysians of Kota Bharu, Malaysia, and to compare the data with other populations. Methods: A total of 128 (64 males, 64 females) non-smoking healthy young subjects were randomly sampled for the study from the Kelantanese students’ population of the University Sains Malaysia, Kota Bharu Campus, Kelantan, Malaysia. The study population (20-25 yr age group) had similar socio-economic background. Each subject filled up the ATS (1978) questionnaire to record their personal demographic data, health status and consent to participate in the study. Subjects with any history of pulmonary diseases were excluded from the study. Results: The pulmonary function measurements exhibited significantly higher values among males than the females. FEV1% did not show any significant inter-group variation probably because the parameter expresses FEV1 as a percentage of FVC. FVC and FEV1 exhibited significant correlations with body height and body mass among males whereas in the females exhibited significant correlation with body mass, body weight and also with age. FEV1% exhibited significant correlation with body height and body mass among males and with body height in females. FEF25-75% did not show any significant correlation except with body height among females. However, PEFR exhibited significant positive correlation with all the physical parameters except with age among the females. On the basis of the existence of significant correlation between different physical parameters and pulmonary function variables, simple and multiple regression norms have been computed. Interpretation & conclusions: From the present investigation it can be concluded that Kelantanese Malaysian youths have normal range of pulmonary function in both the sexes and the computed regression norms may be used to predict the pulmonary function values in the studied population. PMID:22199104

Isthmin is a novel vascular permeability inducer that functions through cell-surface GRP78-mediated Src activation.

PubMed

Venugopal, Shruthi; Chen, Mo; Liao, Wupeng; Er, Shi Yin; Wong, Wai-Shiu Fred; Ge, Ruowen

2015-07-01

Isthmin (ISM) is a recently identified 60 kDa secreted angiogenesis inhibitor. Two cell-surface receptors for ISM have been defined, the high-affinity glucose-regulated protein 78 kDa (GRP78) and the low-affinity αvβ5 integrin. As αvβ5 integrin plays an important role in pulmonary vascular permeability (VP) and ISM is highly expressed in mouse lung, we sought to clarify the role of ISM in VP. Recombinant ISM (rISM) dose-dependently enhances endothelial monolayer permeability in vitro and local dermal VP when administered intradermally in mice. Systemic rISM administration through intravenous injection leads to profound lung vascular hyperpermeability but not in other organs. Mechanistic investigations using molecular, biochemical approaches and specific chemical inhibitors revealed that ISM-GRP78 interaction triggers a direct interaction between GRP78 and Src, leading to Src activation and subsequent phosphorylation of adherens junction proteins and loss of junctional proteins from inter-endothelial junctions, resulting in enhanced VP. Dynamic studies of Src activation, VP and apoptosis revealed that ISM induces VP directly via Src activation while apoptosis contributes indirectly only after prolonged treatment. Furthermore, ISM is significantly up-regulated in lipopolysaccharide (LPS)-treated mouse lung. Blocking cell-surface GRP78 by systemic infusion of anti-GRP78 antibody significantly attenuates pulmonary vascular hyperpermeability in LPS-induced acute lung injury (ALI) in mice. ISM is a novel VP inducer that functions through cell-surface GRP78-mediated Src activation as well as induction of apoptosis. It induces a direct GRP78-Src interaction, leading to cytoplasmic Src activation. ISM contributes to pulmonary vascular hyperpermeability of LPS-induced ALI in mice. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

Intravenous injection of pharmaceutical tablets presenting as multiple pulmonary nodules and declining pulmonary function in an adolescent with cystic fibrosis.

PubMed

Smith, Kelly J; Elidemir, Okan; Dishop, Megan K; Eldin, Karen W; Tatevian, Nina; Moore, Robert H

2006-09-01

Here we present the unusual case of an adolescent with cystic fibrosis presenting with declining pulmonary function and diffuse micronodular pulmonary disease. This case illustrates the radiographic and pathologic findings associated with the intravenous injection and pulmonary arterial embolization of insoluble pharmaceutical-tablet constituents. The number of first-time users reporting nonmedical use of prescription pain relievers is increasing dramatically, especially in adolescents. Recognition of both the diagnostic imaging features and histologic features on lung biopsy are critical steps for early diagnosis, intervention, and potential prevention of sudden death in these at-risk patients.

Environmentally persistent free radicals induce airway hyperresponsiveness in neonatal rat lungs

PubMed Central

2011-01-01

Background Increased asthma risk/exacerbation in children and infants is associated with exposure to elevated levels of ultrafine particulate matter (PM). The presence of a newly realized class of pollutants, environmentally persistent free radicals (EPFRs), in PM from combustion sources suggests a potentially unrecognized risk factor for the development and/or exacerbation of asthma. Methods Neonatal rats (7-days of age) were exposed to EPFR-containing combustion generated ultrafine particles (CGUFP), non-EPFR containing CGUFP, or air for 20 minutes per day for one week. Pulmonary function was assessed in exposed rats and age matched controls. Lavage fluid was isolated and assayed for cellularity and cytokines and in vivo indicators of oxidative stress. Pulmonary histopathology and characterization of differential protein expression in lung homogenates was also performed. Results Neonates exposed to EPFR-containing CGUFP developed significant pulmonary inflammation, and airway hyperreactivity. This correlated with increased levels of oxidative stress in the lungs. Using differential two-dimensional electrophoresis, we identified 16 differentially expressed proteins between control and CGUFP exposed groups. In the rats exposed to EPFR-containing CGUFP; peroxiredoxin-6, cofilin1, and annexin A8 were upregulated. Conclusions Exposure of neonates to EPFR-containing CGUFP induced pulmonary oxidative stress and lung dysfunction. This correlated with alterations in the expression of various proteins associated with the response to oxidative stress and the regulation of glucocorticoid receptor translocation in T lymphocytes. PMID:21388553

Comparison of Diaphragmatic Breathing Exercise, Volume and Flow Incentive Spirometry, on Diaphragm Excursion and Pulmonary Function in Patients Undergoing Laparoscopic Surgery: A Randomized Controlled Trial

PubMed Central

Anand, R.

2016-01-01

Objective. To evaluate the effects of diaphragmatic breathing exercises and flow and volume-oriented incentive spirometry on pulmonary function and diaphragm excursion in patients undergoing laparoscopic abdominal surgery. Methodology. We selected 260 patients posted for laparoscopic abdominal surgery and they were block randomization as follows: 65 patients performed diaphragmatic breathing exercises, 65 patients performed flow incentive spirometry, 65 patients performed volume incentive spirometry, and 65 patients participated as a control group. All of them underwent evaluation of pulmonary function with measurement of Forced Vital Capacity (FVC), Forced Expiratory Volume in the first second (FEV1), Peak Expiratory Flow Rate (PEFR), and diaphragm excursion measurement by ultrasonography before the operation and on the first and second postoperative days. With the level of significance set at p < 0.05. Results. Pulmonary function and diaphragm excursion showed a significant decrease on the first postoperative day in all four groups (p < 0.001) but was evident more in the control group than in the experimental groups. On the second postoperative day pulmonary function (Forced Vital Capacity) and diaphragm excursion were found to be better preserved in volume incentive spirometry and diaphragmatic breathing exercise group than in the flow incentive spirometry group and the control group. Pulmonary function (Forced Vital Capacity) and diaphragm excursion showed statistically significant differences between volume incentive spirometry and diaphragmatic breathing exercise group (p < 0.05) as compared to that flow incentive spirometry group and the control group. Conclusion. Volume incentive spirometry and diaphragmatic breathing exercise can be recommended as an intervention for all patients pre- and postoperatively, over flow-oriented incentive spirometry for the generation and sustenance of pulmonary function and diaphragm excursion in the management of laparoscopic abdominal surgery. PMID:27525116

Comparison of Diaphragmatic Breathing Exercise, Volume and Flow Incentive Spirometry, on Diaphragm Excursion and Pulmonary Function in Patients Undergoing Laparoscopic Surgery: A Randomized Controlled Trial.

PubMed

Alaparthi, Gopala Krishna; Augustine, Alfred Joseph; Anand, R; Mahale, Ajith

2016-01-01

Objective. To evaluate the effects of diaphragmatic breathing exercises and flow and volume-oriented incentive spirometry on pulmonary function and diaphragm excursion in patients undergoing laparoscopic abdominal surgery. Methodology. We selected 260 patients posted for laparoscopic abdominal surgery and they were block randomization as follows: 65 patients performed diaphragmatic breathing exercises, 65 patients performed flow incentive spirometry, 65 patients performed volume incentive spirometry, and 65 patients participated as a control group. All of them underwent evaluation of pulmonary function with measurement of Forced Vital Capacity (FVC), Forced Expiratory Volume in the first second (FEV1), Peak Expiratory Flow Rate (PEFR), and diaphragm excursion measurement by ultrasonography before the operation and on the first and second postoperative days. With the level of significance set at p < 0.05. Results. Pulmonary function and diaphragm excursion showed a significant decrease on the first postoperative day in all four groups (p < 0.001) but was evident more in the control group than in the experimental groups. On the second postoperative day pulmonary function (Forced Vital Capacity) and diaphragm excursion were found to be better preserved in volume incentive spirometry and diaphragmatic breathing exercise group than in the flow incentive spirometry group and the control group. Pulmonary function (Forced Vital Capacity) and diaphragm excursion showed statistically significant differences between volume incentive spirometry and diaphragmatic breathing exercise group (p < 0.05) as compared to that flow incentive spirometry group and the control group. Conclusion. Volume incentive spirometry and diaphragmatic breathing exercise can be recommended as an intervention for all patients pre- and postoperatively, over flow-oriented incentive spirometry for the generation and sustenance of pulmonary function and diaphragm excursion in the management of laparoscopic abdominal surgery.

Respiratory health status of gilsonite workers.

PubMed

Keimig, D G; Castellan, R M; Kullman, G J; Kinsley, K B

1987-01-01

Gilsonite, a solidified hydrocarbon used in the manufacture of automotive body seam sealers, is mined only in the Uinta Basin of Eastern Utah and Western Colorado. Health effects of gilsonite dust exposure have not previously been published and exposure to gilsonite dust is not regulated. To examine potential respiratory health effects associated with gilsonite dust exposures, this cross-sectional study surveyed the 100 current male employees who had been exposed to gilsonite dust at 3 existing gilsonite companies. Total dust exposures up to 28 times the nuisance dust standard were found, and 5 of 99 (5%) workers had chest radiographs consistent with pneumoconiosis of low profusion. Increased prevalences of cough and phlegm were found in workers with high-exposure jobs, but no evidence for dust-related pulmonary function impairment was noted. To prevent pulmonary health effects, we recommend reducing dust exposures for those workers in jobs currently characterized by relatively high dust exposures.

Inapparent pulmonary vascular disease in an ex-heroin user

DOE Office of Scientific and Technical Information (OSTI.GOV)

Antonelli Incalzi, R.; Ludovico Maini, C.; Giuliano Bonetti, M.

1986-04-01

A severe pulmonary vascular derangement, usually reported in drug addicts, was diagnosed in a 28-year-old asymptomatic ex-heroin user by means of fortuitously performed pulmonary perfusion imaging. Neither physical findings nor pulmonary function tests, aroused suspicion of the diagnosis. A search for asymptomatic pulmonary vascular disease probably should be undertaken in drug addicts.

Roles of preoperative arterial blood gas tests in the surgical treatment of scoliosis with moderate or severe pulmonary dysfunction.

PubMed

Liu, Jia-Ming; Shen, Jian-Xiong; Zhang, Jian-Guo; Zhao, Hong; Li, Shu-Gang; Zhao, Yu; Qiu, Giu-Xing

2012-01-01

It has been stated that preoperative pulmonary function tests are essential to assess the surgical risk in patients with scoliosis. Arterial blood gas tests have also been used to evaluate pulmonary function before scoliotic surgery. However, few studies have been reported. The aim of this study was to investigate the roles of preoperative arterial blood gas tests in the surgical treatment of scoliosis with moderate or severe pulmonary dysfunction. This study involved scoliotic patients with moderate or severe pulmonary dysfunction (forced vital capacity < 60%) who underwent surgical treatment between January 2002 and April 2010. A total of 73 scoliotic patients (23 males and 50 females) with moderate or severe pulmonary dysfunction were included. The average age of the patients was 16.53 years (ranged 10 - 44). The demographic distribution, medical records, and radiographs of all patients were collected. All patients received arterial blood gas tests and pulmonary function tests before surgery. The arterial blood gas tests included five parameters: partial pressure of arterial oxygen, partial pressure of arterial carbon dioxide, alveolar-arterial oxygen tension gradient, pH, and standard bases excess. The pulmonary function tests included three parameters: forced expiratory volume in 1 second ratio, forced vital capacity ratio, and peak expiratory flow ratio. All five parameters of the arterial blood gas tests were compared between the two groups with or without postoperative pulmonary complications by variance analysis. Similarly, all three parameters of the pulmonary function tests were compared. The average coronal Cobb angle before surgery was 97.42° (range, 50° - 180°). A total of 15 (20.5%) patients had postoperative pulmonary complications, including hypoxemia in 5 cases (33.3%), increased requirement for postoperative ventilatory support in 4 (26.7%), pneumonia in 2 (13.3%), atelectasis in 2 (13.3%), pneumothorax in 1 (6.7%), and hydrothorax in 1 (6.7%). No significant differences in demographic characteristics or perioperative factors (P > 0.05) existed between the two groups with or without postoperative pulmonary complications. According to the variance analysis, there were no statistically significant differences in any parameter of the arterial blood gas tests between the two groups. No significant correlation between the results of the preoperative arterial blood gas tests and postoperative pulmonary complications existed in scoliotic patients with moderate or severe pulmonary dysfunction. However, the postoperative complications tended to increase with the decrease of partial pressure of arterial oxygen in the arterial blood gas tests.

Expression Profiling Identifies Klf15 as a Glucocorticoid Target That Regulates Airway Hyperresponsiveness

PubMed Central

Masuno, Kiriko; Haldar, Saptarsi M.; Jeyaraj, Darwin; Mailloux, Christina M.; Huang, Xiaozhu; Panettieri, Rey A.; Jain, Mukesh K.

2011-01-01

Glucocorticoids (GCs), which activate GC receptor (GR) signaling and thus modulate gene expression, are widely used to treat asthma. GCs exert their therapeutic effects in part through modulating airway smooth muscle (ASM) structure and function. However, the effects of genes that are regulated by GCs on airway function are not fully understood. We therefore used transcription profiling to study the effects of a potent GC, dexamethasone, on human ASM (HASM) gene expression at 4 and 24 hours. After 24 hours of dexamethasone treatment, nearly 7,500 genes had statistically distinguishable changes in expression; quantitative PCR validation of a 40-gene subset of putative GR-regulated genes in 6 HASM cell lines suggested that the early transcriptional targets of GR signaling are similar in independent HASM lines. Gene ontology analysis implicated GR targets in controlling multiple aspects of ASM function. One GR-regulated gene, the transcription factor, Kruppel-like factor 15 (Klf15), was already known to modulate vascular smooth and cardiac muscle function, but had no known role in the lung. We therefore analyzed the pulmonary phenotype of Klf15−/− mice after ovalbumin sensitization and challenge. We found diminished airway responses to acetylcholine in ovalbumin-challenged Klf15−/− mice without a significant change in the induction of asthmatic inflammation. In cultured cells, overexpression of Klf15 reduced proliferation of HASM cells, whereas apoptosis in Klf15−/− murine ASM cells was increased. Together, these results further characterize the GR-regulated gene network in ASM and establish a novel role for the GR target, Klf15, in modulating airway function. PMID:21257922

Quantitative computed tomography of pulmonary emphysema and ventricular function in chronic obstructive pulmonary disease patients with pulmonary hypertension.

PubMed

Huang, Yu-Sen; Hsu, Hsao-Hsun; Chen, Jo-Yu; Tai, Mei-Hwa; Jaw, Fu-Shan; Chang, Yeun-Chung

2014-01-01

This study strived to evaluate the relationship between degree of pulmonary emphysema and cardiac ventricular function in chronic obstructive pulmonary disease (COPD) patients with pulmonary hypertension (PH) using electrocardiographic-gated multidetector computed tomography (CT). Lung transplantation candidates with the diagnosis of COPD and PH were chosen for the study population, and a total of 15 patients were included. The extent of emphysema is defined as the percentage of voxels below -910 Hounsfield units in the lung windows in whole lung CT without intravenous contrast. Heart function parameters were measured by electrocardiographic-gated CT angiography. Linear regression analysis was conducted to examine the associations between percent emphysema and heart function indicators. Significant correlations were found between percent emphysema and right ventricular (RV) measurements, including RV end-diastolic volume (R(2) = 0.340, p = 0.023), RV stroke volume (R(2) = 0.406, p = 0.011), and RV cardiac output (R(2) = 0.382, p = 0.014); the correlations between percent emphysema and left ventricular function indicators were not observed. The study revealed that percent emphysema is correlated with RV dysfunction among COPD patients with PH. Based on our findings, percent emphysema can be considered for use as an indicator to predict the severity of right ventricular dysfunction among COPD patients.

Lung volumes, ventricular function and pulmonary arterial flow in children operated on for left-sided congenital diaphragmatic hernia: long-term results.

PubMed

Abolmaali, Nasreddin; Koch, Arne; Götzelt, Knut; Hahn, Gabriele; Fitze, Guido; Vogelberg, Christian

2010-07-01

To compare MRI-based functional pulmonary and cardiac measurements in the long-term follow-up of children operated on for left-sided congenital diaphragmatic hernia (CDH) with age- and body size-matched healthy controls. Twelve children who received immediate postnatal surgery for closure of isolated left-sided CDH were included and received basic medical examinations, pulmonary function testing and echocardiography. MRI included measurement of lung volume, ventricular function assessment and velocity-encoded imaging of the pulmonary arteries and was compared with the data for 12 healthy children matched for age and body size. While patients' clinical test results were not suspicious, comparison between the MRI data for patients and those for healthy controls revealed significant differences. In patients, the volumes of the left lungs were increased and the tidal volume was larger on the right side. While the stroke volumes of both ventricles were reduced, heart rate and ejection fraction were increased. Flow, acceleration time and cross-sectional area of the left pulmonary artery were reduced. Functional MRI detected pulmonary and cardiac findings in the late follow-up of CDH children which may be missed by standard clinical methods and might be relevant for decisions regarding late outcome and treatment.

mTOR and vascular remodeling in lung diseases: current challenges and therapeutic prospects.

PubMed

Goncharova, Elena A

2013-05-01

Mammalian target of rapamycin (mTOR) is a major regulator of cellular metabolism, proliferation, and survival that is implicated in various proliferative and metabolic diseases, including obesity, type 2 diabetes, hamartoma syndromes, and cancer. Emerging evidence suggests a potential critical role of mTOR signaling in pulmonary vascular remodeling. Remodeling of small pulmonary arteries due to increased proliferation, resistance to apoptosis, and altered metabolism of cells forming the pulmonary vascular wall is a key currently irreversible pathological feature of pulmonary hypertension, a progressive pulmonary vascular disorder with high morbidity and mortality. In addition to rare familial and idiopathic forms, pulmonary hypertension is also a life-threatening complication of several lung diseases associated with hypoxia. This review aims to summarize our current knowledge and recent advances in understanding the role of the mTOR pathway in pulmonary vascular remodeling, with a specific focus on the hypoxia component, a confirmed shared trigger of pulmonary hypertension in lung diseases. We also discuss the emerging role of mTOR as a promising therapeutic target and mTOR inhibitors as potential pharmacological approaches to treat pulmonary vascular remodeling in pulmonary hypertension.

A novel role of Yin-Yang-1 in pulmonary tuberculosis through the regulation of the chemokine CCL4.

PubMed

Rangel-Santiago, Jesus F; Baay-Guzman, Guillermina J; Duran-Padilla, Marco A; Lopez-Bochm, Karla A; Garcia-Romero, Beatriz L; Hernandez-Cueto, Daniel D; Pantoja-Escobar, Gerardo; Vega, Mario I; Hernandez-Pando, Rogelio; Huerta-Yepez, Sara

2016-01-01

Mycobacterium tuberculosis (M. tb) is the etiological agent of pulmonary tuberculosis (TB); this disease remains a worldwide health problem. Yin-Yang-1 (YY1) plays a major role in the maintenance and progression of some pulmonary diseases, including pulmonary fibrosis. However, the role of YY1 in TB remains unknown. The aim of this study was to elucidate the role of YY1 in the regulation of CCL4 and its implication in TB. We determined whether YY1 regulates CCL4 using reporter plasmids, ChIP and siRNA assays. Immunohistochemistry and digital pathology were used to measure the expression of YY1 and CCL4 in a mouse model of TB. A retrospective comparison of patients with TB and control subjects was used to measure the expression of YY1 and CCL4 using tissue microarrays. Our results showed that YY1 regulates the transcription of CCL4; moreover, YY1, CCL4 and TGF-β were overexpressed in the lung tissues of mice with TB during the late stages of the disease and the tissues of TB patients. The expression of CCL4 and TGF-β correlated with YY1 expression. In conclusion, YY1 regulates CCL4 transcription; moreover, YY1 is overexpressed in experimental and human TB and is positively correlated with CCL4 and TGF-β expression. Therefore, treatments that decrease YY1 expression may be a new therapeutic strategy against TB. Copyright © 2015 Elsevier Ltd. All rights reserved.

NADPH:Quinone Oxidoreductase 1 Regulates Host Susceptibility to Ozone via Isoprostane Generation*

PubMed Central

Kummarapurugu, Apparao B.; Fischer, Bernard M.; Zheng, Shuo; Milne, Ginger L.; Ghio, Andrew J.; Potts-Kant, Erin N.; Foster, W. Michael; Soderblom, Erik J.; Dubois, Laura G.; Moseley, M. Arthur; Thompson, J. Will; Voynow, Judith A.

2013-01-01

NADPH:quinone oxidoreductase 1 (NQO1) is recognized as a major susceptibility gene for ozone-induced pulmonary toxicity. In the absence of NQO1 as can occur by genetic mutation, the human airway is protected from harmful effects of ozone. We recently reported that NQO1-null mice are protected from airway hyperresponsiveness and pulmonary inflammation following ozone exposure. However, NQO1 regenerates intracellular antioxidants and therefore should protect the individual from oxidative stress. To explain this paradox, we tested whether in the absence of NQO1 ozone exposure results in increased generation of A2-isoprostane, a cyclopentenone isoprostane that blunts inflammation. Using GC-MS, we found that NQO1-null mice had greater lung tissue levels of D2- and E2-isoprostanes, the precursors of J2- and A2-isoprostanes, both at base line and following ozone exposure compared with congenic wild-type mice. We confirmed in primary cultures of normal human bronchial epithelial cells that A2-isoprostane inhibited ozone-induced NF-κB activation and IL-8 regulation. Furthermore, we determined that A2-isoprostane covalently modified the active Cys179 domain in inhibitory κB kinase in the presence of ozone in vitro, thus establishing the biochemical basis for A2-isoprostane inhibition of NF-κB. Our results demonstrate that host factors may regulate pulmonary susceptibility to ozone by regulating the generation of A2-isoprostanes in the lung. These observations provide the biochemical basis for the epidemiologic observation that NQO1 regulates pulmonary susceptibility to ozone. PMID:23275341

Effects of exercise training on pulmonary vessel muscularization and right ventricular function in an animal model of COPD.

PubMed

Hassel, Erlend; Berre, Anne Marie; Skjulsvik, Anne Jarstein; Steinshamn, Sigurd

2014-09-28

Right ventricular dysfunction in COPD is common, even in the absence of pulmonary hypertension. The aim of the present study was to examine the effects of high intensity interval training (HIIT) on right ventricular (RV) function, as well as pulmonary blood vessel remodeling in a mouse model of COPD. 42 female A/JOlaHsd mice were randomized to exposure to either cigarette smoke or air for 6 hours/day, 5 days/week for 14 weeks. Mice from both groups were further randomized to sedentariness or HIIT for 4 weeks. Cardiac function was evaluated by echocardiography and muscularization of pulmonary vessel walls by immunohistochemistry. Smoke exposure induced RV systolic dysfunction demonstrated by reduced tricuspid annular plane systolic excursion. HIIT in smoke-exposed mice reversed RV dysfunction. There were no significant effects on the left ventricle of neither smoke exposure nor HIIT. Muscularization of the pulmonary vessels was reduced after exercise intervention, but no significant effects on muscularization were observed from smoke exposure. RV function was reduced in mice exposed to cigarette smoke. No Increase in pulmonary vessel muscularization was observed in these mice, implying that other mechanisms caused the RV dysfunction. HIIT attenuated the RV dysfunction in the smoke exposed mice. Reduced muscularization of the pulmonary vessels due to HIIT suggests that exercise training not only affects the heart muscle, but also has important effects on the pulmonary vasculature.

Relationship of respiratory symptoms and pulmonary function to tar, nicotine, and carbon monoxide yield of cigarettes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Krzyzanowski, M.; Sherrill, D.L.; Paoletti, P.

The data from consecutive surveys of the Tucson Epidemiologic Study (1981-1988) were used to evaluate the relationship in cigarette smokers of respiratory symptoms and pulmonary function to tar, nicotine, and carbon monoxide (CO) yields of the cigarette. There were 690 subjects who reported smoking regularly in at least one survey, over age 15. After adjustment for intensity and duration of smoking and for depth of inhalation, the risk of chronic phlegm, cough, and dyspnea were not related to the tar and nicotine yields. In 414 subjects with pulmonary function tested in at least one of the three surveys the spirometricmore » indices used were significantly related to the daily dose of tar, nicotine, and CO (product of the cigarette yield and daily number of cigarettes smoked). The effects were more pronounced for past than for current doses. However, the differentiation of pulmonary function due to various yields of cigarettes was small in comparison to the difference in pulmonary function between smokers and nonsmokers.« less

IDENTIFICATION AND CHARACTERIZATION OF DISEASE USING PULMONARY FUNCTION TESTS

EPA Science Inventory

Abstract
Pulmonary function testing is used routinely in human medicine to objectively define functional deficits in individuals with respiratory disease. Despite the fact that respiratory disease is a common problem in veterinary medicine, evaluation of the small animal pa...

Lentivirus-ABCG1 instillation reduces lipid accumulation and improves lung compliance in GM-CSF knock-out mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Malur, Anagha; Huizar, Isham; Wells, Greg

2011-11-18

Highlights: Black-Right-Pointing-Pointer Lentivirus-ABCG1 reduces lipid accumulation in lungs of GM-CSF knock-out mice. Black-Right-Pointing-Pointer Up-regulation of ABCG1 improves lung function. Black-Right-Pointing-Pointer Upregulation of ABCG1 improves surfactant metabolism. -- Abstract: We have shown decreased expression of the nuclear transcription factor, peroxisome proliferator-activated receptor-gamma (PPAR{gamma}) and the PPAR{gamma}-regulated ATP-binding cassette transporter G1 (ABCG1) in alveolar macrophages from patients with pulmonary alveolar proteinosis (PAP). PAP patients also exhibit neutralizing antibodies to granulocyte-macrophage colony stimulating factor (GM-CSF), an upregulator of PPAR{gamma}. In association with functional GM-CSF deficiency, PAP lung is characterized by surfactant-filled alveolar spaces and lipid-filled alveolar macrophages. Similar pathology characterizes GM-CSF knock-out (KO)more » mice. We reported previously that intratracheal instillation of a lentivirus (lenti)-PPAR{gamma} plasmid into GM-CSF KO animals elevated ABCG1 and reduced alveolar macrophage lipid accumulation. Here, we hypothesized that instillation of lenti-ABCG1 might be sufficient to decrease lipid accumulation and improve pulmonary function in GM-CSF KO mice. Animals received intratracheal instillation of lenti-ABCG1 or control lenti-enhanced Green Fluorescent Protein (eGFP) plasmids and alveolar macrophages were harvested 10 days later. Alveolar macrophage transduction efficiency was 79% as shown by lenti-eGFP fluorescence. Quantitative PCR analyses indicated a threefold (p = 0.0005) increase in ABCG1 expression with no change of PPAR{gamma} or ABCA1 in alveolar macrophages of lenti-ABCG1 treated mice. ABCG1 was unchanged in control lenti-eGFP and PBS-instilled groups. Oil Red O staining detected reduced intracellular neutral lipid in alveolar macrophages from lenti-ABCG1 treated mice. Extracellular cholesterol and phospholipids were also decreased as shown by analysis of bronchoalveolar lavage fluid. Lung compliance was diminished in untreated GMCSF KO mice but improved significantly after lenti-ABCG1 treatment. Data demonstrate that in vivo instillation of lenti-ABCG1 in GM-CSF KO mice is sufficient to restore pulmonary homeostasis by: (1) upregulating ABCG1; (2) reducing intra and extracellular lipids; and (3) improving lung function. Results suggest that the ABCG1 lipid transporter is the key downstream target of GM-CSF-induced PPAR{gamma} necessary for surfactant catabolism.« less

Incidence of Pneumothorax in Patients With Lymphangioleiomyomatosis Undergoing Pulmonary Function and Exercise Testing.

PubMed

Taveira-DaSilva, Angelo M; Julien-Williams, Patricia; Jones, Amanda M; Moss, Joel

2016-07-01

Because pneumothorax is frequent in lymphangioleiomyomatosis, patients have expressed concerns regarding the risk of pneumothorax associated with pulmonary function or exercise testing. Indeed, pneumothorax has been reported in patients with lung disease after both of these tests. The aim of this study was to determine the incidence of pneumothorax in patients with lymphangioleiomyomatosis during admissions to the National Institutes of Health Clinical Research Center between 1995 and 2015. Medical records were reviewed to identify patients who had a pneumothorax during their stay at the National Institutes of Health. A total of 691 patients underwent 4,523 pulmonary function tests and 1,900 exercise tests. Three patients developed pneumothorax after pulmonary function tests and/or exercise tests. The incidence of pneumothorax associated with lung function testing was 0.14 to 0.29 of 100 patients or 0.02 to 0.04 of 100 tests. The incidence of pneumothorax in patients undergoing exercise testing was 0.14 to 0.28 of 100 patients or 0.05 to 0.10 of 100 tests. The risk of pneumothorax associated with pulmonary function or exercise testing in patients with lymphangioleiomyomatosis is low. Published by Elsevier Inc.

Inhibition of pulmonary fibrosis by the chemokine IP-10/CXCL10.

PubMed

Tager, Andrew M; Kradin, Richard L; LaCamera, Peter; Bercury, Scott D; Campanella, Gabriele S V; Leary, Carol P; Polosukhin, Vasiliy; Zhao, Long-Hai; Sakamoto, Hideo; Blackwell, Timothy S; Luster, Andrew D

2004-10-01

Pulmonary fibrosis is an enigmatic and devastating disease with few treatment options, now thought to result from abnormal wound healing in the lung in response to injury. We have previously noted a role for the chemokine interferon gamma-inducible protein of 10 kD (IP-10)/CXC chemokine ligand 10 in the regulation of cutaneous wound healing, and consequently investigated whether IP-10 regulates pulmonary fibrosis. We found that IP-10 is highly expressed in a mouse model of pulmonary fibrosis induced by bleomycin. IP-10-deficient mice exhibited increased pulmonary fibrosis after administration of bleomycin, suggesting that IP-10 limits the development of fibrosis in this model. Substantial fibroblast chemoattractant and proliferative activities were generated in the lung after bleomycin exposure. IP-10 significantly inhibited fibroblast responses to the chemotactic, but not the proliferative activity generated, suggesting that IP-10 may attenuate fibroblast accumulation in bleomycin-induced pulmonary fibrosis by limiting fibroblast migration. Consistent with this inhibitory activity of IP-10 on fibroblast migration, fibroblast accumulation in the lung after bleomycin exposure was dramatically increased in IP-10-deficient mice compared with wild-type mice. Conversely, transgenic mice overexpressing IP-10 were protected from mortality after bleomycin exposure, and demonstrated decreased fibroblast accumulation in the lung after challenge compared with wild-type mice. Our findings suggest that interruption of fibroblast recruitment may represent a novel therapeutic strategy for pulmonary fibrosis, which could have applicability to a wide range of fibrotic illnesses.

INTERPRETATIONS AND LIMITATION OF PULMONARY FUNCTION TESTING IN SMALL LABORATORY ANIMALS

EPA Science Inventory

Pulmonary function tests are tools available to the researcher and clinician to evaluate the ability of the lung to perform its essential function of gas exchange. o meet this principal function, the lung needs to operate efficiently with minimal mechanical work as well as provid...

Activating transcription factor 4 underlies the pathogenesis of arsenic trioxide-mediated impairment of macrophage innate immune functions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Srivastava, Ritesh K.; Li, Changzhao

Chronic arsenic exposure to humans is considered immunosuppressive with augmented susceptibility to several infectious diseases. The exact molecular mechanisms, however, remain unknown. Earlier, we showed the involvement of unfolded protein response (UPR) signaling in arsenic-mediated impairment of macrophage functions. Here, we show that activating transcription factor 4 (ATF4), a UPR transcription factor, regulates arsenic trioxide (ATO)-mediated dysregulation of macrophage functions. In ATO-treated ATF4{sup +/+} wild-type mice, a significant down-regulation of CD11b expression was associated with the reduced phagocytic functions of peritoneal and lung macrophages. This severe immuno-toxicity phenotype was not observed in ATO-treated ATF4{sup +/−} heterozygous mice. To confirm thesemore » observations, we demonstrated in Raw 264.7 cells that ATF4 knock-down rescues ATO-mediated impairment of macrophage functions including cytokine production, bacterial engulfment and clearance of engulfed bacteria. Sustained activation of ATF4 by ATO in macrophages induces apoptosis, while diminution of ATF4 expression protects against ATO-induced apoptotic cell death. Raw 264.7 cells treated with ATO also manifest dysregulated Ca{sup ++} homeostasis. ATO induces Ca{sup ++}-dependent calpain-1 and caspase-12 expression which together regulated macrophage apoptosis. Additionally, apoptosis was also induced by mitochondria-regulated pathway. Restoring ATO-impaired Ca{sup ++} homeostasis in ER/mitochondria by treatments with the inhibitors of inositol 1,4,5-trisphosphate receptor (IP3R) and voltage-dependent anion channel (VDAC) attenuate innate immune functions of macrophages. These studies identify a novel role for ATF4 in underlying pathogenesis of macrophage dysregulation and immuno-toxicity of arsenic. - Highlights: • ATF4 regulates arsenic-mediated impairment in macrophage functions. • Arsenic-mediated alterations in pulmonary macrophage are diminished in ATF4{sup +/−} mice. • Changes in macrophage functions can be attenuated by Ca{sup ++} homeostasis regulators.« less

Dynamic chest radiography: flat-panel detector (FPD) based functional X-ray imaging.

PubMed

Tanaka, Rie

2016-07-01

Dynamic chest radiography is a flat-panel detector (FPD)-based functional X-ray imaging, which is performed as an additional examination in chest radiography. The large field of view (FOV) of FPDs permits real-time observation of the entire lungs and simultaneous right-and-left evaluation of diaphragm kinetics. Most importantly, dynamic chest radiography provides pulmonary ventilation and circulation findings as slight changes in pixel value even without the use of contrast media; the interpretation is challenging and crucial for a better understanding of pulmonary function. The basic concept was proposed in the 1980s; however, it was not realized until the 2010s because of technical limitations. Dynamic FPDs and advanced digital image processing played a key role for clinical application of dynamic chest radiography. Pulmonary ventilation and circulation can be quantified and visualized for the diagnosis of pulmonary diseases. Dynamic chest radiography can be deployed as a simple and rapid means of functional imaging in both routine and emergency medicine. Here, we focus on the evaluation of pulmonary ventilation and circulation. This review article describes the basic mechanism of imaging findings according to pulmonary/circulation physiology, followed by imaging procedures, analysis method, and diagnostic performance of dynamic chest radiography.

Chronic respiratory disfunction due to diffuse alveolar hemorrhage in patients with systemic lupus erythematosus and primary vasculitis.

PubMed

Pérez Aceves, Eva; Pérez Cristóbal, Mario; Espinola Reyna, Gerardo A; Ariza Andraca, Raul; Xibille Fridmann, Daniel; Barile Fabris, Leonor A

2013-01-01

Pulmonary hemorrhage (PH) occurs in 2-5% of SLE patients, and is associated with a high mortality rate (79-90%). Diagnostic criteria for this complication include: 1) Pulmonary infiltrates, with at least ¾ of lung tissue involved in a chest x ray, 2) Acute respiratory failure, 3) A decrease of 3g/dL or more in hemoglobin levels. PH might lead to organized pneumonia, collagen deposition, and pulmonary fibrosis which in time might cause changes in pulmonary function tests with either restrictive or obstructive patterns. To evaluate the existence of abnormalities in pulmonary function tests after a PH episode. We included patients with SLE and primary vasculitis that developed PH. During the acute episode, we measured SLEDAI in SLE patients, five factor score in microscopic polyangiitis (MPA) and Birmingham Vasculitis Activity Store (BVAS) in granulomatosis with polyangiitis (GPA) (Wegener). We determined the number of PH events, treatment, and ventilator assistance requirements and correlated its association with abnormal pulmonary function tests. We included 10 patients, 7 with SLE, 2 with MPA and 1 with GPA (Wegener). The mean activity measures were: SLEDAI 20.4 ± 7.5, FFS 2, and BVAS 36. Treatment consisted in methylprednisolone (MPD) in 3 patients, MPD plus cyclophosphamide (CY) in 6 patients, and MPD, CY, IV immunoglobulin, and plasmapheresis in one patient. Five patients required ventilatory support. We found abnormalities in pulmonary function tests in 8 patients, three had an obstructive pattern and five a restrictive pattern; 2 patients did not show any change. We did not find a significant association with any of the studied variables. PH might cause abnormalities in pulmonary function tests and prolonged immunosuppressive treatment could be required. Copyright © 2012 Elsevier España, S.L. All rights reserved.

Integrin-Mediated Transforming Growth Factor-β Activation Regulates Homeostasis of the Pulmonary Epithelial-Mesenchymal Trophic Unit

PubMed Central

Araya, Jun; Cambier, Stephanie; Morris, Alanna; Finkbeiner, Walter; Nishimura, Stephen L.

2006-01-01

Trophic interactions between pulmonary epithelial and mesenchymal cell types, known as the epithelial-mesenchymal trophic unit (EMTU), are crucial in lung development and lung disease. Transforming growth factor (TGF)-β is a key factor in mediating these interactions, but it is expressed in a latent form that requires activation to be functional. Using intact fetal tracheal tissue and primary cultures of fetal tracheal epithelial cells and fibroblasts, we demonstrate that a subset of integrins, αvβ6 and αvβ8, are responsible for almost all of the TGF-β activation in the EMTU. Both αvβ8 and αvβ6 contribute to fetal tracheal epithelial activation of TGF-β, whereas only αvβ8 contributes to fetal tracheal fibroblast activation of TGF-β. Interestingly, fetal tracheal epithelial αvβ8-mediated TGF-β activation can be enhanced by phorbol esters, likely because of the increased activity of MT1-MMP, an essential co-factor in αvβ8-mediated activation of TGF-β. Autocrine αvβ8-mediated TGF-β activation by fetal tracheal fibroblasts results in suppression of both transcription and secretion of hepatocyte growth factor, which is sufficient to affect phosphorylation of the airway epithelial hepatocyte growth factor receptor, c-Met, as well as airway epithelial proliferation in a co-culture model of the EMTU. These findings elucidate the function and complex regulation of integrin-mediated activation of TGF-β within the EMTU. PMID:16877343

Integrin-mediated transforming growth factor-beta activation regulates homeostasis of the pulmonary epithelial-mesenchymal trophic unit.

PubMed

Araya, Jun; Cambier, Stephanie; Morris, Alanna; Finkbeiner, Walter; Nishimura, Stephen L

2006-08-01

Trophic interactions between pulmonary epithelial and mesenchymal cell types, known as the epithelial-mesenchymal trophic unit (EMTU), are crucial in lung development and lung disease. Transforming growth factor (TGF)-beta is a key factor in mediating these interactions, but it is expressed in a latent form that requires activation to be functional. Using intact fetal tracheal tissue and primary cultures of fetal tracheal epithelial cells and fibroblasts, we demonstrate that a subset of integrins, alpha(v)beta(6) and alpha(v)beta(8), are responsible for almost all of the TGF-beta activation in the EMTU. Both alpha(v)beta(8) and alpha(v)beta(6) contribute to fetal tracheal epithelial activation of TGF-beta, whereas only alpha(v)beta(8) contributes to fetal tracheal fibroblast activation of TGF-beta. Interestingly, fetal tracheal epithelial alpha(v)beta(8)-mediated TGF-beta activation can be enhanced by phorbol esters, likely because of the increased activity of MT1-MMP, an essential co-factor in alpha(v)beta(8)-mediated activation of TGF-beta. Autocrine alpha(v)beta(8)-mediated TGF-beta activation by fetal tracheal fibroblasts results in suppression of both transcription and secretion of hepatocyte growth factor, which is sufficient to affect phosphorylation of the airway epithelial hepatocyte growth factor receptor, c-Met, as well as airway epithelial proliferation in a co-culture model of the EMTU. These findings elucidate the function and complex regulation of integrin-mediated activation of TGF-beta within the EMTU.

Integrative analysis of differentially expressed microRNAs of pulmonary alveolar macrophages from piglets during H1N1 swine influenza A virus infection

PubMed Central

Jiang, Pengfei; Zhou, Na; Chen, Xinyu; Zhao, Xing; Li, Dengyun; Wang, Fen; Bi, Lijun; Zhang, Deli

2015-01-01

H1N1 swine influenza A virus (H1N1 SwIV) is one key subtype of influenza viruses with pandemic potential. MicroRNAs (miRNAs) are endogenous small RNA molecules that regulate gene expression. MiRNAs relevant with H1N1 SwIV have rarely been reported. To understand the biological functions of miRNAs during H1N1 SwIV infection, this study profiled differentially expressed (DE) miRNAs in pulmonary alveolar macrophages from piglets during the H1N1 SwIV infection using a deep sequencing approach, which was validated by quantitative real-time PCR. Compared to control group, 70 and 16 DE miRNAs were respectively identified on post-infection day (PID) 4 and PID 7. 56 DE miRNAs were identified between PID 4 and PID 7. Our results suggest that most host miRNAs are down-regulated to defend the H1N1 SwIV infection during the acute phase of swine influenza whereas their expression levels gradually return to normal during the recovery phase to avoid the occurrence of too severe porcine lung damage. In addition, targets of DE miRNAs were also obtained, for which bioinformatics analyses were performed. Our results would be useful for investigating the functions and regulatory mechanisms of miRNAs in human influenza because pig serves as an excellent animal model to study the pathogenesis of human influenza. PMID:25639204

Regulation of pulmonary surfactant secretion in the developing lizard, Pogona vitticeps.

PubMed

Sullivan, Lucy C; Orgeig, Sandra; Daniels, Christopher B

2002-11-01

Pulmonary surfactant is a mixture of lipids and proteins that is secreted by alveolar type II cells in the lungs of all air-breathing vertebrates. Pulmonary surfactant functions to reduce the surface tension in the lungs and, therefore, reduce the work of breathing. In mammals, the embryonic maturation of the surfactant system is controlled by a host of factors, including glucocorticoids, thyroid hormones and autonomic neurotransmitters. We have used a co-culture system of embryonic type II cells and lung fibroblasts to investigate the ability of dexamethasone, tri-iodothyronine (T(3)), adrenaline and carbamylcholine (carbachol) to stimulate the cellular secretion of phosphatidylcholine in the bearded dragon (Pogona vitticeps) at day 55 (approx. 92%) of incubation and following hatching. Adrenaline stimulated surfactant secretion both before and after hatching, whereas carbachol stimulated secretion only at day 55. Glucocorticoids and triiodothyronine together stimulated secretion at day 55 but did not after hatching. Therefore, adrenaline, carbachol, dexamethasone and T(3), are all involved in the development of the surfactant system in the bearded dragon. However, the efficacy of the hormones is attenuated during the developmental process. These differences probably relate to the changes in the cellular environment during development and the specific biology of the bearded dragon.

Role of the inflammasome in chronic obstructive pulmonary disease (COPD)

PubMed Central

Colarusso, Chiara; Terlizzi, Michela; Molino, Antonio; Pinto, Aldo; Sorrentino, Rosalinda

2017-01-01

Inflammation is central to the development of chronic obstructive pulmonary disease (COPD), a pulmonary disorder characterized by chronic bronchitis, chronic airway obstruction, emphysema, associated to progressive and irreversible decline of lung function. Emerging genetic and pharmacological evidence suggests that IL-1-like cytokines are highly detected in the sputum and broncho-alveolar lavage (BAL) of COPD patients, implying the involvement of the multiprotein complex inflammasome. So far, scientific evidence has focused on nucleotide-binding oligomerization domain-like receptors protein 3 (NLRP3) inflammasome, a specialized inflammatory signaling platform that governs the maturation and secretion of IL-1-like cytokines through the regulation of caspase-1-dependent proteolytic processing. Some studies revealed that it is involved during airway inflammation typical of COPD. Based on the influence of cigarette smoke in various respiratory diseases, including COPD, in this view we report its effects in inflammatory and immune responses in COPD mouse models and in human subjects affected by COPD. In sharp contrast to what reported on experimental and clinical studies, randomized clinical trials show that indirect inflammasome inhibitors did not have any beneficial effect in moderate to severe COPD patients. PMID:29137224

Silencing the Snail-dependent RNA splice regulator ESRP1 drives malignant transformation of human pulmonary epithelial cells. | Office of Cancer Genomics

Cancer.gov

Epithelial-to-mesenchymal transition (EMT) is organized in cancer cells by a set of key transcription factors, but the significance of this process is still debated including in non-small cell lung cancer (NSCLC). Here we report increased expression of the EMT-inducing transcription factor Snail in premalignant pulmonary lesions, relative to histologically normal pulmonary epithelium. In immortalized human pulmonary epithelial cells and isogenic derivatives, we documented Snail-dependent anchorage-independent growth in vitro and primary tumor growth and metastatic behavior in vivo.

The effect of pollutional haze on pulmonary function

PubMed Central

Liu, Shao-Kun; Cai, Shan; Chen, Yan; Xiao, Bing; Chen, Ping

2016-01-01

Detrimental health effects of atmospheric exposure to ambient particulate matter (PM) have been investigated in numerous studies. Exposure to pollutional haze, the carrier of air pollutants such as PM and nitrogen dioxide (NO2) has been linked to lung and cardiovascular disease, resulting increases in both hospital admissions and mortality. This review focuses on the constituents of pollutional haze and its effects on pulmonary function. The article presents the available information and seeks to correlate pollutional haze and pulmonary function. PMID:26904252

Hyperthyroidism and pulmonary hypertension: an important association.

PubMed

Vallabhajosula, Sailaja; Radhi, Saba; Cevik, Cihan; Alalawi, Raed; Raj, Rishi; Nugent, Kenneth

2011-12-01

Pulmonary hypertension is a complex disorder with multiple etiologies. The World Health Organization Group 5 (unclear multifactorial mechanisms) includes patients with thyroid disorders. The authors reviewed the literature on the association between hyperthyroidism and pulmonary hypertension and identified 20 publications reporting 164 patients with treatment outcomes. The systolic pulmonary artery (PA) pressures in these patients ranged from 28 to 78 mm Hg. They were treated with antithyroid medications, radioactive iodine and surgery. The mean pretherapy PA systolic pressure was 39 mm Hg; the mean posttreatment pressure was 30 mm Hg. Pulmonary hypertension should be considered in hyperthyroid patients with dyspnea. All patients with pulmonary hypertension should be screened for hyperthyroidism, because the treatment of hyperthyroidism can reduce PA pressures, potentially avoid the side-effects and costs with current therapies for pulmonary hypertension and limit the consequences of untreated hyperthyroidism. However, the long-term outcome in these patients is uncertain, and this issue needs more study. Changes in the pulmonary circulation and molecular regulators of vascular remodeling likely explain this association.

Three-Dimensional Right Ventricular Strain Versus Volume Quantification in Heart Transplant Recipients in Relation to Pulmonary Artery Pressure.

PubMed

Sade, Leyla Elif; Kozan, Hatice; Eroglu, Serpil; Pirat, Bahar; Aydinalp, Alp; Sezgin, Atilla; Muderrisoglu, Haldun

2017-02-01

Residual pulmonary hypertension challenges the right ventricular function and worsens the prognosis in heart transplant recipients. The complex geometry of the right ventricle complicates estimation of its function with conventional transthoracic echocardiography. We evaluated right ventricular function in heart transplant recipients with the use of 3-dimensional echocardiography in relation to systolic pulmonary artery pressure. We performed 32 studies in 26 heart transplant patients, with 6 patients having 2 studies at different time points with different pressures and thus included. Right atrial volume, tricuspid annular plane systolic excursion, peak systolic annular velocity, fractional area change, and 2-dimensional speckle tracking longitudinal strain were obtained by 2-dimensional and tissue Doppler imaging. Three-dimensional right ventricular volumes, ejection fraction, and 3-dimensional right ventricular strain were obtained from the 3-dimensional data set by echocardiographers. Systolic pulmonary artery pressure was obtained during right heart catheterization. Overall mean systolic pulmonary artery pressure was 26 ± 7 mm Hg (range, 14-44 mmHg). Three-dimensional end-diastolic (r = 0.75; P < .001) and end-systolic volumes (r = 0.55; P = .001)correlated well with systolic pulmonary artery pressure. Right ventricular ejection fraction and right atrium volume also significantly correlated with systolic pulmonary artery pressure (r = 0.49 and P = .01 for both). However, right ventricular 2- and 3-dimensional strain, tricuspid annular plane systolic excursion, and tricuspid annular velocity did not. The effects of pulmonary hemodynamic burden on right ventricular function are better estimated by a 3-dimensional volume evaluation than with 3-dimensional longitudinal strain and other 2-dimensional and tissue Doppler measurements. These results suggest that the peculiar anatomy of the right ventricle necessitates 3-dimensional volume quantification in heart transplant recipients in relation to residual pulmonary hypertension.

[MRI methods for pulmonary ventilation and perfusion imaging].

PubMed

Sommer, G; Bauman, G

2016-02-01

Separate assessment of respiratory mechanics, gas exchange and pulmonary circulation is essential for the diagnosis and therapy of pulmonary diseases. Due to the global character of the information obtained clinical lung function tests are often not sufficiently specific in the differential diagnosis or have a limited sensitivity in the detection of early pathological changes. The standard procedures of pulmonary imaging are computed tomography (CT) for depiction of the morphology as well as perfusion/ventilation scintigraphy and single photon emission computed tomography (SPECT) for functional assessment. Magnetic resonance imaging (MRI) with hyperpolarized gases, O2-enhanced MRI, MRI with fluorinated gases and Fourier decomposition MRI (FD-MRI) are available for assessment of pulmonary ventilation. For assessment of pulmonary perfusion dynamic contrast-enhanced MRI (DCE-MRI), arterial spin labeling (ASL) and FD-MRI can be used. Imaging provides a more precise insight into the pathophysiology of pulmonary function on a regional level. The advantages of MRI are a lack of ionizing radiation, which allows a protective acquisition of dynamic data as well as the high number of available contrasts and therefore accessible lung function parameters. Sufficient clinical data exist only for certain applications of DCE-MRI. For the other techniques, only feasibility studies and case series of different sizes are available. The clinical applicability of hyperpolarized gases is limited for technical reasons. The clinical application of the techniques described, except for DCE-MRI, should be restricted to scientific studies.

Cardiovascular function in pulmonary emphysema.

PubMed

Visca, Dina; Aiello, Marina; Chetta, Alfredo

2013-01-01

Chronic obstructive pulmonary disease (COPD) and chronic cardiovascular disease, such as coronary artery disease, congestive heart failure, and cardiac arrhythmias, have a strong influence on each other, and systemic inflammation has been considered as the main linkage between them. On the other hand, airflow limitation may markedly affect lung mechanics in terms of static and dynamic hyperinflation, especially in pulmonary emphysema, and they can in turn influence cardiac performance as well. Skeletal mass depletion, which is a common feature in COPD especially in pulmonary emphysema patients, may have also a role in cardiovascular function of these patients, irrespective of lung damage. We reviewed the emerging evidence that highlights the role of lung mechanics and muscle mass impairment on ventricular volumes, stroke volume, and stroke work at rest and on exercise in the presence of pulmonary emphysema. Patients with emphysema may differ among COPD population even in terms of cardiovascular function.

Advanced Techniques in Pulmonary Function Test Analysis Interpretation and Diagnosis

PubMed Central

Gildea, T.J.; Bell, C. William

1980-01-01

The Pulmonary Functions Analysis and Diagnostic System is an advanced clinical processing system developed for use at the Pulmonary Division, Department of Medicine at the University of Nebraska Medical Center. The system generates comparative results and diagnostic impressions for a variety of routine and specialized pulmonary functions test data. Routine evaluation deals with static lung volumes, breathing mechanics, diffusing capacity, and blood gases while specialized tests include lung compliance studies, small airways dysfunction studies and dead space to tidal volume ratios. Output includes tabular results of normal vs. observed values, clinical impressions and commentary and, where indicated, a diagnostic impression. A number of pulmonary physiological and state variables are entered or sampled (A to D) with periodic status reports generated for the test supervisor. Among the various physiological variables sampled are respiratory frequency, minute ventilation, oxygen consumption, carbon dioxide production, and arterial oxygen saturation.

Recovery of pulmonary functions, exercise capacity, and quality of life after pulmonary rehabilitation in survivors of ARDS due to severe influenza A (H1N1) pneumonitis.

PubMed

Hsieh, Meng-Jer; Lee, Wei-Chun; Cho, Hsiu-Ying; Wu, Meng-Fang; Hu, Han-Chung; Kao, Kuo-Chin; Chen, Ning-Hung; Tsai, Ying-Huang; Huang, Chung-Chi

2018-04-20

Acute respiratory distress syndrome (ARDS) due to severe influenza A H1N1 pneumonitis would result in impaired pulmonary functions and health-related quality of life (HRQoL) after hospital discharge. The recovery of pulmonary functions, exercise capacity, and HRQoL in the survivors of ARDS due to 2009 pandemic influenza A H1N1 pneumonitis (H1N1-ARDS) was evaluated in a tertiary teaching hospital in northern Taiwan between May 2010 and June 2011. Data of spirometry, total lung capacity (TLC), diffusing capacity of carbon monoxide (DL CO ), and 6-minute walk distance (6MWD) in the patients survived from H1N1-ARDS were collected 1, 3, and 6 months post-hospital discharge. HRQoL was evaluated with St. George respiratory questionnaire (SGRQ). Nine survivors of H1N1-ARDS in the study period were included. All these patients received 2 months' pulmonary rehabilitation program. Pulmonary functions and exercise capacity included TLC, forced vital capacity (FVC), forced expiratory volume in the first second (FEV 1 ), DL CO , and 6MWD improved from 1 to 3 months post-hospital discharge. Only TLC had further significant improvement from 3 to 6 months. HRQoL represented as the total score of SGRQ had no significant improvement in the first 3 months but improved significantly from 3 to 6 months post-discharge. The impaired pulmonary functions and exercise capacity in the survivors of H1N1-ARDS improved soon at 3 months after hospital discharge. Their quality of life had keeping improved at 6 months even though there was no further improvement of their pulmonary functions and exercise capacity. © 2018 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.

An integrated programme after pulmonary rehabilitation in patients with chronic obstructive pulmonary disease: effect on emotional and functional dimensions of quality of life.

PubMed

Moullec, G; Ninot, G

2010-02-01

To assess whether a maintenance integrated health care programme is effective in improving functional and emotional dimensions of quality of life in patients with chronic obstructive pulmonary disease (COPD) after a first pulmonary rehabilitation. Prospective controlled trial. Three rehabilitation centres and three patient self-help associations within a health care network in France. Forty patients with moderate to severe COPD. After a first four-week inpatient pulmonary rehabilitation programme, patients took part in a maintenance integrated health care programme or usual care for 12 months. The primary outcomes were the change in functional and emotional dimensions of quality of life measured by the St George's Respiratory Questionnaire (SGRQ), the brief World Health Organization Quality of Life questionnaire (Brief-WHOQOL) and six specific questions using a 10-cm visual analogue scale. Secondary outcomes were change in exercise tolerance measured by six-minute walking test and cycle exercise. At one year, the maintenance intervention (n = 11) produced improvements in functional and emotional dimensions scores of quality of life and exercise tolerance. Patients in the usual aftercare group (n = 16) exhibited maintenance of functional dimension scores of quality of life, but a clinically relevant decline in emotional scores of quality of life and in six-minute walking distance one year after the pulmonary rehabilitation. Patient self-help association seems to be an innovative and efficient organizational structure to support patients with COPD after pulmonary rehabilitation in real-life settings. A distinction between emotional and functional dimensions of quality of life may improve the design and evaluation of integrated health care programmes in patients with COPD.

Melatonin Decreases Pulmonary Vascular Remodeling and Oxygen Sensitivity in Pulmonary Hypertensive Newborn Lambs

PubMed Central

Astorga, Cristian R.; González-Candia, Alejandro; Candia, Alejandro A.; Figueroa, Esteban G.; Cañas, Daniel; Ebensperger, Germán; Reyes, Roberto V.; Llanos, Aníbal J.; Herrera, Emilio A.

2018-01-01

Background: Chronic hypoxia and oxidative stress during gestation lead to pulmonary hypertension of the neonate (PHN), a condition characterized by abnormal pulmonary arterial reactivity and remodeling. Melatonin has strong antioxidant properties and improves pulmonary vascular function. Here, we aimed to study the effects of melatonin on the function and structure of pulmonary arteries from PHN lambs. Methods: Twelve lambs (Ovis aries) gestated and born at highlands (3,600 m) were instrumented with systemic and pulmonary catheters. Six of them were assigned to the control group (CN, oral vehicle) and 6 were treated with melatonin (MN, 1 mg.kg−1.d−1) during 10 days. At the end of treatment, we performed a graded oxygenation protocol to assess cardiopulmonary responses to inspired oxygen variations. Further, we obtained lung and pulmonary trunk samples for histology, molecular biology, and immunohistochemistry determinations. Results: Melatonin reduced the in vivo pulmonary pressor response to oxygenation changes. In addition, melatonin decreased cellular density of the media and diminished the proliferation marker KI67 in resistance vessels and pulmonary trunk (p < 0.05). This was associated with a decreased in the remodeling markers α-actin (CN 1.28 ± 0.18 vs. MN 0.77 ± 0.04, p < 0.05) and smoothelin-B (CN 2.13 ± 0.31 vs. MN 0.88 ± 0.27, p < 0.05). Further, melatonin increased vascular density by 134% and vascular luminal surface by 173% (p < 0.05). Finally, melatonin decreased nitrotyrosine, an oxidative stress marker, in small pulmonary vessels (CN 5.12 ± 0.84 vs. MN 1.14 ± 0.34, p < 0.05). Conclusion: Postnatal administration of melatonin blunts the cardiopulmonary response to hypoxia, reduces the pathological vascular remodeling, and increases angiogenesis in pulmonary hypertensive neonatal lambs.These effects improve the pulmonary vascular structure and function in the neonatal period under chronic hypoxia. PMID:29559926

Parenchymal preserving anatomic resections result in less pulmonary function loss in patients with Stage I non-small cell lung cancer.

PubMed

Macke, Ryan A; Schuchert, Matthew J; Odell, David D; Wilson, David O; Luketich, James D; Landreneau, Rodney J

2015-04-01

A suggested benefit of sublobar resection for stage I non-small cell lung cancer (NSCLC) compared to lobectomy is a relative preservation of pulmonary function. Very little objective data exist, however, supporting this supposition. We sought to evaluate the relative impact of both anatomic segmental and lobar resection on pulmonary function in patients with resected clinical stage I NSCLC. The records of 159 disease-free patients who underwent anatomic segmentectomy (n = 89) and lobectomy (n = 70) for the treatment of stage I NSCLC with pre- and postoperative pulmonary function tests performed between 6 to 36 months after resection were retrospectively reviewed. Changes in forced expiratory volume in one second (FEV1) and diffusion capacity of carbon monoxide (DLCO) were analyzed based upon the number of anatomic pulmonary segments removed: 1-2 segments (n = 77) or 3-5 segments (n = 82). Preoperative pulmonary function was worse in the lesser resection cohort (1-2 segments) compared to the greater resection group (3-5 segments) (FEV1(%predicted): 79% vs. 85%, p = 0.038; DLCO(%predicted): 63% vs. 73%, p = 0.010). A greater decline in FEV1 was noted in patients undergoing resection of 3-5 segments (FEV1 (observed): 0.1 L vs. 0.3 L, p = 0.003; and FEV1 (% predicted): 4.3% vs. 8.2%, p = 0.055). Changes in DLCO followed this same trend (DLCO(observed): 1.3 vs. 2.4 mL/min/mmHg, p = 0.015; and DLCO(% predicted): 3.6% vs. 5.9%, p = 0.280). Parenchymal-sparing resections resulted in better preservation of pulmonary function at a median of one year, suggesting a long-term functional benefit with small anatomic segmental resections (1-2 segments). Prospective studies to evaluate measurable functional changes, as well as quality of life, between segmentectomy and lobectomy with a larger patient cohort appear justified.

Deficiency of Kruppel-like factor KLF4 in mammary tumor cells inhibits tumor growth and pulmonary metastasis and is accompanied by compromised recruitment of myeloid-derived suppressor cells

PubMed Central

Yu, Fang; Shi, Ying; Wang, Junfeng; Li, Juan; Fan, Daping; Ai, Walden

2013-01-01

Increasing evidence indicates that myeloid-derived suppressor cells (MDSCs) negatively regulate immune responses during tumor progression, inflammation and infection. However, the underlying molecular mechanisms of their development and mobilization remain to be fully delineated. Kruppel-like factor KLF4 is a transcription factor that has an oncogenic function in breast cancer development, but its function in tumor microenvironment, a critical component for tumorigenesis, has not been examined. By using a spontaneously metastatic 4T1 breast cancer mouse model and an immunodeficient NOD/SCID mouse model, we demonstrated that KLF4 knockdown delayed tumor development and inhibited pulmonary metastasis, which was accompanied by decreased accumulation of MDSCs in bone marrow, spleens and primary tumors. Mechanistically, we found that KLF4 knockdown resulted in a significant decrease of circulating GM-CSF, an important cytokine for MDSC biology. Consistently, recombinant GM-CSF restored the frequency of MDSCs in purified bone marrow cells incubated with conditioned medium from KLF4 deficient cells. In addition, we identified CXCL5 as a critical mediator to enhance the expression and function of GM-CSF. Reduced CXCL5 expression by KLF4 knockdown in primary tumors and breast cancer cells was correlated with a decreased GM-CSF expression in our mouse models. Finally, we found that CXCL5/CXCR2 axis facilitated MDSC migration and that anti-GM-CSF antibodies neutralized CXCL5-induced accumulation of MDSCs. Taken together, our data suggest that KLF4 modulates maintenance of MDSCs in bone marrow by inducing GM-CSF production via CXCL5 and regulates recruitment of MDSCs into the primary tumors through the CXCL5/CXCR2 axis, both of which contribute to KLF4-mediated mammary tumor development. PMID:23737434

Computational Modeling of Airway and Pulmonary Vascular Structure and Function: Development of a “Lung Physiome”

PubMed Central

Tawhai, M. H.; Clark, A. R.; Donovan, G. M.; Burrowes, K. S.

2011-01-01

Computational models of lung structure and function necessarily span multiple spatial and temporal scales, i.e., dynamic molecular interactions give rise to whole organ function, and the link between these scales cannot be fully understood if only molecular or organ-level function is considered. Here, we review progress in constructing multiscale finite element models of lung structure and function that are aimed at providing a computational framework for bridging the spatial scales from molecular to whole organ. These include structural models of the intact lung, embedded models of the pulmonary airways that couple to model lung tissue, and models of the pulmonary vasculature that account for distinct structural differences at the extra- and intra-acinar levels. Biophysically based functional models for tissue deformation, pulmonary blood flow, and airway bronchoconstriction are also described. The development of these advanced multiscale models has led to a better understanding of complex physiological mechanisms that govern regional lung perfusion and emergent heterogeneity during bronchoconstriction. PMID:22011236

A Critical Role for the Anti-apoptotic Protein ARC (Apoptosis Repressor with CARD) in Hypoxia-Induced Pulmonary Hypertension

PubMed Central

Zaiman, Ari L; Damico, Rachel; Thoms-Chesley, Alan; Files, D Clark; Kesari, Priya; Johnston, Laura; Swaim, Mara; Mozammel, Shehzin; Myers, Alan C; Halushka, Marc; El-Haddad, Hasim; Shimoda, Larissa A; Peng, Chang-Fu; Hassoun, Paul M; Champion, Hunter C; Kitsis, Richard N; Crow, Michael T

2015-01-01

Background Pulmonary hypertension (PH) is a lethal syndrome associated with the pathogenic remodeling of the pulmonary vasculature and the emergence of apoptosis-resistant cells. ARC (Apoptosis Repressor with Caspase Recruitment Domain) is an inhibitor of multiple forms of cell death known to be abundantly expressed in striated muscle. We show for the first time that ARC is expressed in arterial smooth muscle cells of the pulmonary vasculature and is markedly up-regulated in several experimental models of PH. In this study, we test the hypothesis that ARC expression is essential for the development of chronic hypoxia-induced PH. Methods and Results Experiments in which cells or mice were rendered ARC-deficient revealed that ARC not only protected pulmonary arterial smooth muscle cells from hypoxia-induced death, but also facilitated growth factor-induced proliferation and hypertrophy and hypoxia-induced down-regulation of selective voltage-gated potassium channels, the latter a hallmark of the syndrome in humans. Moreover, ARC-deficient mice exhibited diminished vascular remodeling, increased apoptosis, and decreased proliferation in response to chronic hypoxia, resulting in marked protection from PH in vivo. Patients with PH have significantly increased ARC expression not only in remodeled vessels but also in the lumen-occluding lesions associated with severe disease. Conclusions These data show that ARC, previously unlinked to pulmonary hypertension, is a critical determinant of vascular remodeling in this syndrome. PMID:22082675

The Mid-Term Changes of Pulmonary Function Tests After Phrenic Nerve Transfer.

PubMed

Yavari, Masoud; Hassanpour, Seyed Esmail; Khodayari, Mohammad

2016-03-01

In the restoration of elbow flexion, the phrenic nerve has proven to be a good donor, but considering the role of the phrenic nerve in respiratory function, we cannot disregard the potential dangers of this method. In the current study, we reviewed the results of pulmonary function tests (PFT) in four patients who underwent phrenic nerve transfer. We reviewed the results of serial spirometry tests, which were performed before and after phrenic nerve transfer surgery. All patients regained Biceps power to M3 strength or above. None of our patients experienced pulmonary problems or respiratory complaints, but a significant reduction of spirometric parameters occurred after surgery. This study highlights the close link between the role of the phrenic nerve and pulmonary function, such that the use of this nerve as a transfer donor leads to spirometric impairments.

[Study on the correlation between the severity of chronic rhinosinusitis and bronchial asthma and pulmonary function].

PubMed

Liu, Yonggang

2015-07-01

To explore the correlation between the severity of patients with rhinitis-nasosinusitis and the bronchial asthma and the pulmonary function. Sixty-four cases of patients with rhinitis-nasosinusitis and 53 cases of patients with chronic sinusitis from June 2012 to September 2013 were randomly selected, and the patients were divided into group of rhinitis-nasosinusitis with nasal polyps and group of chronic sinusitis according to disease species, and analyzed the correlation between the severity of the deseases and the changes of the pulmonary function respectively for the patients of two groups by using Spearman method. The incidence of asthma for patients with different levels of sinusitis and nasal polyps seemed no significant difference (P > 0.05); the incidence of allergic rhinitis also seemed no significant difference (P > 0.05); the incidence of asthma for patients with different lesion range of sinusitis and nasal polyps seemed no significant difference (P > 0.05); the incidence of allergic rhinitis also seemed no significant different (P < 0.05). The conditions of the patients with different levels of sinusitis and nasal polyps were directly related to the reduction of pulmonary function (r = 2.431, P < 0.05); The conditions of the patients with different lesion range of sinusitis were directly related to the reduction of pulmonary function (r = 2.641, P < 0.05). There was some correlation between the severity of patients with rhinitis-nasosinusitis and the bronchial asthma and the condition of pulmonary function of patients.

Amount of smoking, pulmonary function, and bone mineral density in middle-aged Korean men: KNHANES 2008-2011.

PubMed

Lee, Ji Hyun; Hong, A Ram; Kim, Jung Hee; Kim, Kyoung Min; Koo, Bo Kyung; Shin, Chan Soo; Kim, Sang Wan

2018-01-01

Smoking induces bone loss; however, data on the relationship between smoking history and bone mineral density (BMD) are lacking. Age and pulmonary function can affect BMD. We investigated the relationships among pack-years (PYs) of smoking, pulmonary function, and BMD in middle-aged Korean men (50-64 years old). This cross-sectional study used data from the Korean National Health and Nutrition Examination Survey, 2008-2011. All participants underwent BMD measurements using dual energy X-ray absorptiometry and pulmonary function tests using standardized spirometry. In total, 388 never-smokers and 1088 ever-smokers were analyzed. The number of PYs of smoking was negatively correlated with total hip BMD (r = -0.088; P = 0.004) after adjusting for age, height, and weight. Ever-smokers were classified into 3 groups according to PYs of smoking. The highest tertile (n = 482) exhibited significantly lower total hip bone mass than the lowest tertile (n = 214) after adjusting for confounding factors (age, height, weight, forced expiratory volume in 1 s (FEV 1 ), alcohol consumption, physical activity, and vitamin D levels) that could affect bone metabolism (P = 0.003). In conclusion, smoking for >30 PYs was significantly associated with low hip BMD after adjusting for pulmonary function in middle-aged Korean men. Long-term smoking may be a risk factor for bone loss in middle-aged men independent of age, height, weight, and pulmonary function.

Role for miR-204 in human pulmonary arterial hypertension

PubMed Central

Courboulin, Audrey; Paulin, Roxane; Giguère, Nellie J.; Saksouk, Nehmé; Perreault, Tanya; Meloche, Jolyane; Paquet, Eric R.; Biardel, Sabrina; Provencher, Steeve; Côté, Jacques; Simard, Martin J.

2011-01-01

Pulmonary arterial hypertension (PAH) is characterized by enhanced proliferation and reduced apoptosis of pulmonary artery smooth muscle cells (PASMCs). Because microRNAs have been recently implicated in the regulation of cell proliferation and apoptosis, we hypothesized that these regulatory molecules might be implicated in the etiology of PAH. In this study, we show that miR-204 expression in PASMCs is down-regulated in both human and rodent PAH. miR-204 down-regulation correlates with PAH severity and accounts for the proliferative and antiapoptotic phenotypes of PAH-PASMCs. STAT3 activation suppresses miR-204 expression, and miR-204 directly targets SHP2 expression, thereby SHP2 up-regulation, by miR-204 down-regulation, activates the Src kinase and nuclear factor of activated T cells (NFAT). STAT3 also directly induces NFATc2 expression. NFAT and SHP2 were needed to sustain PAH-PASMC proliferation and resistance to apoptosis. Finally, delivery of synthetic miR-204 to the lungs of animals with PAH significantly reduced disease severity. This study uncovers a new regulatory pathway involving miR-204 that is critical to the etiology of PAH and indicates that reestablishing miR-204 expression should be explored as a potential new therapy for this disease. PMID:21321078

[A rare form of obstructive pulmonary disease].

PubMed

van Loenhout, C J; den Bakker, M A; van Wijsenbeek, M S; Hoek, R A S; van Hal, P Th W

2016-01-01

Lymphangioleiomyomatosis (LAM) is characterised by progressive dyspnoea, spontaneous pneumothorax and cystic pulmonary destruction. The disease may show similarities with emphysema clinically, radiologically and on lung function tests. A 44-year-old woman was referred for lung transplantation because of a 6-year history of dyspnoea and severe obstructive pulmonary function disorder with decreased diffusion capacity. Both her relatively young age and the fact that she had never smoked made us doubt the diagnosis 'COPD'. The pulmonary cysts seen on high-resolution CT (HRCT) suggested LAM. This was confirmed when we revised a pulmonary biopsy that had previously been performed. CT investigation should be carried out in patients with severe obstructive pulmonary disease without a risk profile appropriate for COPD. Diffuse, homogenous cysts on CT scan can indicate LAM, particularly in women. Conflict of interest and financial support: none declared.

In smokers, Sonic hedgehog modulates pulmonary endothelial function through vascular endothelial growth factor.

PubMed

Henno, Priscilla; Grassin-Delyle, Stanislas; Belle, Emeline; Brollo, Marion; Naline, Emmanuel; Sage, Edouard; Devillier, Philippe; Israël-Biet, Dominique

2017-05-23

Tobacco-induced pulmonary vascular disease is partly driven by endothelial dysfunction. The Sonic hedgehog (SHH) pathway is involved in vascular physiology. We sought to establish whether the SHH pathway has a role in pulmonary endothelial dysfunction in smokers. The ex vivo endothelium-dependent relaxation of pulmonary artery rings in response to acetylcholine (Ach) was compared in 34 current or ex-smokers and 8 never-smokers. The results were expressed as a percentage of the contraction with phenylephrine. We tested the effects of SHH inhibitors (GANT61 and cyclopamine), an SHH activator (SAG) and recombinant VEGF on the Ach-induced relaxation. The level of VEGF protein in the pulmonary artery ring was measured in an ELISA. SHH pathway gene expression was quantified in reverse transcriptase-quantitative polymerase chain reactions. Ach-induced relaxation was much less intense in smokers than in never-smokers (respectively 24 ± 6% and 50 ± 7% with 10 -4 M Ach; p = 0.028). All SHH pathway genes were expressed in pulmonary artery rings from smokers. SHH inhibition by GANT61 reduced Ach-induced relaxation and VEGF gene expression in the pulmonary artery ring. Recombinant VEGF restored the ring's endothelial function. VEGF gene and protein expression levels in the pulmonary artery rings were positively correlated with the degree of Ach-induced relaxation and negatively correlated with the number of pack-years. SHH pathway genes and proteins are expressed in pulmonary artery rings from smokers, where they modulate endothelial function through VEGF.

Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation.

PubMed

Davies, Jane C; Wainwright, Claire E; Canny, Gerard J; Chilvers, Mark A; Howenstine, Michelle S; Munck, Anne; Mainz, Jochen G; Rodriguez, Sally; Li, Haihong; Yen, Karl; Ordoñez, Claudia L; Ahrens, Richard

2013-06-01

Ivacaftor (VX-770), a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, has been shown to improve lung function, pulmonary exacerbation rate, respiratory symptoms, and weight gain compared with placebo in patients with cystic fibrosis aged 12 years or older with a G551D-CFTR mutation. This randomized, double-blind, placebo-controlled trial evaluated ivacaftor in patients with cystic fibrosis aged 6-11 years with a G551D-CFTR mutation on at least one allele. Patients were randomly assigned to receive ivacaftor administered orally at 150 mg (n = 26) or placebo (n = 26) every 12 hours for 48 weeks in addition to existing prescribed cystic fibrosis therapies. Despite near-normal mean baseline values in FEV1, patients receiving ivacaftor had a significant increase in percent predicted FEV1 from baseline through Week 24 versus placebo group (treatment effect, 12.5 percentage points; P < 0.001). Effects on pulmonary function were evident by 2 weeks, and a significant treatment effect was maintained through Week 48. Patients treated with ivacaftor gained, on average, 2.8 kg more than those receiving placebo at Week 48 (P < 0.001). The change from baseline through Week 48 in the concentration of sweat chloride, a measure of CFTR activity, with ivacaftor was -53.5 mmol/L (P < 0.001) versus placebo. The incidence of adverse events was similar in the two groups. In patients who are younger and healthier than those in previously studied populations, ivacaftor demonstrated a significant improvement in pulmonary function, weight, and CFTR activity compared with placebo. Clinical trial registered with www.clinicaltrials.gov (NCT00909727).

Biodistribution and Efficacy of Targeted Pulmonary Delivery of a Protein Kinase C-δ Inhibitory Peptide: Impact on Indirect Lung Injury

PubMed Central

Mondrinos, Mark J.; Knight, Linda C.; Kennedy, Paul A.; Wu, Jichuan; Kauffman, Matthew; Baker, Sandy T.; Wolfson, Marla R.

2015-01-01

Sepsis and sepsis-induced lung injury remain a leading cause of death in intensive care units. We identified protein kinase C-δ (PKCδ) as a critical regulator of the acute inflammatory response and demonstrated that PKCδ inhibition was lung-protective in a rodent sepsis model, suggesting that targeting PKCδ is a potential strategy for preserving pulmonary function in the setting of indirect lung injury. In this study, whole-body organ biodistribution and pulmonary cellular distribution of a transactivator of transcription (TAT)–conjugated PKCδ inhibitory peptide (PKCδ-TAT) was determined following intratracheal (IT) delivery in control and septic [cecal ligation and puncture (CLP)] rats to ascertain the impact of disease pathology on biodistribution and efficacy. There was negligible lung uptake of radiolabeled peptide upon intravenous delivery [<1% initial dose (ID)], whereas IT administration resulted in lung retention of >65% ID with minimal uptake in liver or kidney (<2% ID). IT delivery of a fluorescent-tagged (tetramethylrhodamine-PKCδ-TAT) peptide demonstrated uniform spatial distribution and cellular uptake throughout the peripheral lung. IT delivery of PKCδ-TAT at the time of CLP surgery significantly reduced PKCδ activation (tyrosine phosphorylation, nuclear translocation and cleavage) and acute lung inflammation, resulting in improved lung function and gas exchange. Importantly, peptide efficacy was similar when delivered at 4 hours post-CLP, demonstrating therapeutic relevance. Conversely, spatial lung distribution and efficacy were significantly impaired at 8 hours post-CLP, which corresponded to marked histopathological progression of lung injury. These studies establish a functional connection between peptide spatial distribution, inflammatory histopathology in the lung, and efficacy of this anti-inflammatory peptide. PMID:26243739

Efficacy and Safety of Ivacaftor in Patients Aged 6 to 11 Years with Cystic Fibrosis with a G551D Mutation

PubMed Central

Wainwright, Claire E.; Canny, Gerard J.; Chilvers, Mark A.; Howenstine, Michelle S.; Munck, Anne; Mainz, Jochen G.; Rodriguez, Sally; Li, Haihong; Yen, Karl; Ordoñez, Claudia L.; Ahrens, Richard

2013-01-01

Rationale: Ivacaftor (VX-770), a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, has been shown to improve lung function, pulmonary exacerbation rate, respiratory symptoms, and weight gain compared with placebo in patients with cystic fibrosis aged 12 years or older with a G551D-CFTR mutation. Objectives: This randomized, double-blind, placebo-controlled trial evaluated ivacaftor in patients with cystic fibrosis aged 6–11 years with a G551D-CFTR mutation on at least one allele. Methods: Patients were randomly assigned to receive ivacaftor administered orally at 150 mg (n = 26) or placebo (n = 26) every 12 hours for 48 weeks in addition to existing prescribed cystic fibrosis therapies. Measurements and Main Results: Despite near-normal mean baseline values in FEV1, patients receiving ivacaftor had a significant increase in percent predicted FEV1 from baseline through Week 24 versus placebo group (treatment effect, 12.5 percentage points; P < 0.001). Effects on pulmonary function were evident by 2 weeks, and a significant treatment effect was maintained through Week 48. Patients treated with ivacaftor gained, on average, 2.8 kg more than those receiving placebo at Week 48 (P < 0.001). The change from baseline through Week 48 in the concentration of sweat chloride, a measure of CFTR activity, with ivacaftor was −53.5 mmol/L (P < 0.001) versus placebo. The incidence of adverse events was similar in the two groups. Conclusions: In patients who are younger and healthier than those in previously studied populations, ivacaftor demonstrated a significant improvement in pulmonary function, weight, and CFTR activity compared with placebo. Clinical trial registered with www.clinicaltrials.gov (NCT00909727). PMID:23590265

The effect of perioperative beta-blockade on the pulmonary function of patients undergoing major arterial surgery.

PubMed

Kieran, S M; Cahill, R A; Browne, I; Sheehan, S J; Mehigan, D; Barry, M C

2006-09-01

Concern about the potential detrimental side-effects of beta-blockade on pulmonary function often dissuades against their perioperative use in patients undergoing major arterial surgery (especially in those with chronic obstructive pulmonary disease (COPD)). In this study we aimed to establish prospectively the clinical relevance of these concerns. After ethics committee approval and individual informed consent, the pulmonary function of twenty patients (mean age 68.7 years (range 43-82), 11 males) scheduled to undergo non-emergency major vascular surgery was studied by recording symptoms and spirometry before and after institution of effective beta-blockade. Fifteen patients (75%) had significant smoking histories (mean pack years/patient=50), while 12 (60%) had COPD. All patients tolerated effective beta-blockade satisfactorily without developing either subjective deterioration in symptoms or significant change on spirometry. The mean change in FEV1 following adequate beta-blockade was 0.05+/-0.24 liters (95% CI -0.06 to +1.61), p=0.35, giving a mean percentage change of 3.18%+/-11.66 (95% CI -2.26 to 8.62). Previously held concerns about worsening pulmonary function through the short-term use of beta-blockers should not dissuade their perioperative usage in patients with peripheral vascular disease. Furthermore, the accuracy of pulmonary function tests in preoperative assessment and risk stratification also appears unaffected by this therapy.

Pulmonary function and health-related quality of life 1-year follow up after cardiac surgery.

PubMed

Westerdahl, Elisabeth; Jonsson, Marcus; Emtner, Margareta

2016-07-08

Pulmonary function is severely reduced in the early period after cardiac surgery, and impairments have been described up to 4-6 months after surgery. Evaluation of pulmonary function in a longer perspective is lacking. In this prospective study pulmonary function and health-related quality of life were investigated 1 year after cardiac surgery. Pulmonary function measurements, health-related quality of life (SF-36), dyspnoea, subjective breathing and coughing ability and pain were evaluated before and 1 year after surgery in 150 patients undergoing coronary artery bypass grafting, valve surgery or combined surgery. One year after surgery the forced vital capacity and forced expiratory volume in 1 s were significantly decreased (by 4-5 %) compared to preoperative values (p < 0.05). Saturation of peripheral oxygen was unchanged 1 year postoperatively compared to baseline. A significantly improved health-related quality of life was found 1 year after surgery, with improvements in all eight aspects of SF-36 (p < 0.001). Sternotomy-related pain was low 1 year postoperatively at rest (median 0 [min-max; 0-7]), while taking a deep breath (0 [0-4]) and while coughing (0 [0-8]). A more pronounced decrease in pulmonary function was associated with dyspnoea limitations and impaired subjective breathing and coughing ability. One year after cardiac surgery static and dynamic lung function measurements were slightly decreased, while health-related quality of life was improved in comparison to preoperative values. Measured levels of pain were low and saturation of peripheral oxygen was same as preoperatively.

Lung function declines in patients with pulmonary sarcoidosis and increased respiratory epithelial permeability to sup 99m Tc-DTPA

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chinet, T.; Dusser, D.; Labrune, S.

1990-02-01

Respiratory epithelial clearance of {sup 99m}Tc-DTPA (RC-Tc-DTPA) and pulmonary function tests (PFT) were determined at intervals of 6 or 12 months in 37 untreated, nonsmoking patients with sarcoidosis over a period of 6 to 36 months. PFT included the measurements of total lung capacity (TLC), vital capacity (VC), FEV1, and diffusing capacity for carbon monoxide. No difference was found between the respiratory clearance of {sup 113m}In-DTPA (2.25 +/- 1.00%/min) and RC-Tc-DTPA (2.29 +/- 1.11%/min) in eight patients with pulmonary sarcoidosis. Pulmonary function decreased 15% or more in at least 2 function tests during 11 follow-up periods, but it remained stablemore » during 47 follow-up periods. In patients whose lung function deteriorated, RC-Tc-DTPA increased to 3.51 +/- 1.55%/min; in contrast, in patients whose lung function remained stable, regardless of the initial values, RC-Tc-DTPA was normal (1.00 +/- 0.50%/min; p less than 0.001). In eight patients who were treated with corticosteroids, RC-Tc-DTPA decreased from 3.48 +/- 1.31%/min to 1.56 +/- 0.64%/min (p less than 0.001), and PFT improved. We conclude that in nonsmokers with pulmonary sarcoidosis, increased RC-Tc-DTPA is not related to dissociation of 99mTc from DTPA, RC-Tc-DTPA is increased when pulmonary function decreases, and, when increased, RC-Tc-DTPA decreases with corticosteroid therapy.« less

Differential roles of NADPH oxidases in vascular physiology and pathophysiology

PubMed Central

Amanso, Angelica M.; Griendling, Kathy K.

2012-01-01

Reactive oxygen species (ROS) are produced by all vascular cells and regulate the major physiological functions of the vasculature. Production and removal of ROS are tightly controlled and occur in discrete subcellular locations, allowing for specific, compartmentalized signaling. Among the many sources of ROS in the vessel wall, NADPH oxidases are implicated in physiological functions such as control of vasomotor tone, regulation of extracellular matrix and phenotypic modulation of vascular smooth muscle cells. They are involved in the response to injury, whether as an oxygen sensor during hypoxia, as a regulator of protein processing, as an angiogenic stimulus, or as a mechanism of wound healing. These enzymes have also been linked to processes leading to disease development, including migration, proliferation, hypertrophy, apoptosis and autophagy. As a result, NADPH oxidases participate in atherogenesis, systemic and pulmonary hypertension and diabetic vascular disease. The role of ROS in each of these processes and diseases is complex, and a more full understanding of the sources, targets, cell-specific responses and counterbalancing mechanisms is critical for the rational development of future therapeutics. PMID:22202108

Selective reversible inhibition of autophagy in hypoxic breast cancer cells promotes pulmonary metastasis

PubMed Central

Dower, Christopher M.; Bhat, Neema; Wang, Edward W.; Wang, Hong-Gang

2016-01-01

Autophagy influences how cancer cells respond to nutrient deprivation and hypoxic stress, two hallmarks of the tumor microenvironment (TME). In this study, we explored the impact of autophagy on the pathophysiology of breast cancer cells, using a novel hypoxia-dependent, reversible dominant negative strategy to regulate autophagy at the cellular level within the TME. Suppression of autophagy via hypoxia-induced expression of the kinase-dead unc-51 like autophagy activating kinase (ULK1) mutant K46N increased lung metastases in MDA-MB-231 xenograft mouse models. Consistent with this effect, expressing a dominant-negative mutant of ULK1 or ATG4b or a ULK1-targeting shRNA facilitated cell migration in vitro. Functional proteomic and transcriptome analysis revealed that loss of hypoxia-regulated autophagy promotes metastasis via induction of the fibronectin integrin signaling axis. Indeed, loss of ULK1 function increased fibronectin deposition in the hypoxic TME. Together, our results indicated that hypoxia-regulated autophagy suppresses metastasis in breast cancer by preventing tumor fibrosis. These results also suggest cautions in the development of autophagy-based strategies for cancer treatment. PMID:28115361

Trajectories of change in cognitive function in people with chronic obstructive pulmonary disease.

PubMed

Park, Soo Kyung

2018-04-01

To describe changes in cognitive function, as measured by the trail making test; to identify distinct patterns of change in cognitive function; and to examine predictors of change in cognitive function in people with severe chronic obstructive pulmonary disease. How cognitive function changes in people with chronic obstructive pulmonary disease and what factors influence those changes over time is not well known, despite the fact that it declines rapidly in this population and significantly impacts functional decline in healthy older adults. A secondary analysis and longitudinal study with a follow-up period of 3 years. A data set from the National Emphysema Treatment Trial provided participant data. Patients with severe chronic obstructive pulmonary disease (n = 307) were recruited at a clinical site. Several demographic and clinical measures were assessed at baseline. Trail making test scores were measured at baseline, 1, 2 and 3 years. Cognitive function was stable for 3 years in people with chronic obstructive pulmonary disease. However, four distinct patterns of change in cognitive function were identified. Age, education, 6-min walk distance and cognitive impairment scores at baseline on the trail making test Part B were significant predictors of worsening cognitive function and below-average cognitive function over 3 years. These findings suggest that increasing exercise capacity improves cognitive function and delays deterioration of cognitive function in people with COPD. Understanding the trajectories of change in cognitive function and predictors of change in cognitive function over 3 years may enable health care providers to identify patients at greatest risk of developing mental deterioration and those who might benefit from interventions to improve cognitive function. Health care providers should periodically assess and frequently screen people with COPD for cognitive function. © 2018 John Wiley & Sons Ltd.

Pulmonary Impairment in Tuberculosis Survivors: The Korean National Health and Nutrition Examination Survey 2008-2012.

PubMed

Jung, Jae-Woo; Choi, Jae-Chol; Shin, Jong-Wook; Kim, Jae-Yeol; Choi, Byoung-Whui; Park, In-Won

2015-01-01

Pulmonary tuberculosis (TB) can affect lung function, but studies regarding long-term follow-up in patients with no sequelae on chest X-ray (CXR) have not been performed. We evaluated lung functional impairment and persistent respiratory symptoms in those with prior pulmonary TB and those with prior pulmonary TB with no residual sequelae on CXR, and determined risk factors for airflow obstruction. We used data from adults aged ≥ 40 years from the annual Korean National Health and Nutrition Examination Surveys conducted between 2008 and 2012. P values for comparisons were adjusted for age, sex, and smoking status. In total of 14,967 adults, 822 subjects (5.5%) had diagnosed and treated pulmonary TB (mean 29.0 years ago). The FVC% (84.9 vs. 92.6), FEV1% (83.4 vs. 92.4), and FEV1/FVC% (73.4 vs. 77.9) were significantly decreased in subjects with prior pulmonary TB compared to those without (p < 0.001, each). In 12,885 subjects with no sequalae on CXR, those with prior pulmonary TB (296, 2.3%) had significantly lower FEV1% (90.9 vs. 93.4, p = 0.001) and FEV1/FVC% (76.6 vs. 78.4, p < 0.001) than those without. Subjects with prior pulmonary TB as well as subjects with no sequalae on CXR were more likely to experience cough and physical activity limitations due to pulmonary symptoms than those without prior pulmonary TB (p < 0.001, each). In total subjects, prior pulmonary TB (OR, 2.314; 95% CI, 1.922-2.785), along with age, male, asthma, and smoking mount was risk factor for airflow obstruction. In subjects with prior pulmonary tuberculosis, inactive TB lesion on chest x-ray (OR, 2.300; 95% CI, 1.606-3.294) were risk factors of airflow obstruction. In addition to subjects with inactive TB lesion on CXR, subjects with no sequelae on CXR can show impaired pulmonary function and respiratory symptoms. Prior TB is a risk factor for airflow obstruction and that the risk is more important when they have inactive lesions on chest X-ray. Hence, the patients with treated TB should need to have regular follow-up of lung function and stop smoking for early detection and prevention of the chronic airway disease.

Pulmonary Function, Muscle Strength and Mortality in Old Age

PubMed Central

Buchman, A. S.; Boyle, P. A.; Wilson, R.S.; Gu, Liping; Bienias, Julia L.; Bennett, D. A.

2009-01-01

Numerous reports have linked extremity muscle strength with mortality but the mechanism underlying this association is not known. We used data from 960 older persons without dementia participating in the Rush Memory and Aging Project to test two sequential hypotheses: first, that extremity muscle strength is a surrogate for respiratory muscle strength, and second, that the association of respiratory muscle strength with mortality is mediated by pulmonary function. In a series of proportional hazards models, we first demonstrated that the association of extremity muscle strength with mortality was no longer significant after including a term for respiratory muscle strength, controlling for age, sex, education, and body mass index. Next, the association of respiratory muscle strength with mortality was attenuated by more than 50% and no longer significant after including a term for pulmonary function. The findings were unchanged after controlling for cognitive function, parkinsonian signs, physical frailty, balance, physical activity, possible COPD, use of pulmonary medications, vascular risk factors including smoking, chronic vascular diseases, musculoskeletal joint pain, and history of falls. Overall, these findings suggest that pulmonary function may partially account for the association of muscle strength and mortality. PMID:18755207

Pulmonary Nontuberculous Mycobacterial Disease

PubMed Central

Kim, Richard D.; Greenberg, David E.; Ehrmantraut, Mary E.; Guide, Shireen V.; Ding, Li; Shea, Yvonne; Brown, Margaret R.; Chernick, Milica; Steagall, Wendy K.; Glasgow, Connie G.; Lin, JingPing; Jolley, Clara; Sorbara, Lynn; Raffeld, Mark; Hill, Suvimol; Avila, Nilo; Sachdev, Vandana; Barnhart, Lisa A.; Anderson, Victoria L.; Claypool, Reginald; Hilligoss, Dianne M.; Garofalo, Mary; Fitzgerald, Alan; Anaya-O'Brien, Sandra; Darnell, Dirk; DeCastro, Rosamma; Menning, Heather M.; Ricklefs, Stacy M.; Porcella, Stephen F.; Olivier, Kenneth N.; Moss, Joel; Holland, Steven M.

2008-01-01

Rationale: Pulmonary nontuberculous mycobacterial (PNTM) disease is increasing, but predisposing features have been elusive. Objectives: To prospectively determine the morphotype, immunophenotype, and cystic fibrosis transmembrane conductance regulator genotype in a large cohort with PNTM. Methods: We prospectively enrolled 63 patients with PNTM infection, each of whom had computerized tomography, echocardiogram, pulmonary function, and flow cytometry of peripheral blood. In vitro cytokine production in response to mitogen, LPS, and cytokines was performed. Anthropometric measurements were compared with National Health and Nutrition Examination Survey (NHANES) age- and ethnicity-matched female control subjects extracted from the NHANES 2001–2002 dataset. Measurements and Main Results: Patients were 59.9 (±9.8 yr [SD]) old, and 5.4 (±7.9 yr) from diagnosis to enrollment. Patients were 95% female, 91% white, and 68% lifetime nonsmokers. A total of 46 were infected with Mycobacterium avium complex, M. xenopi, or M. kansasii; 17 were infected with rapidly growing mycobacteria. Female patients were significantly taller (164.7 vs. 161.0 cm; P < 0.001) and thinner (body mass index, 21.1 vs. 28.2; P < 0.001) than matched NHANES control subjects, and thinner (body mass index, 21.1 vs. 26.8; P = 0.002) than patients with disseminated nontuberculous mycobacterial infection. A total of 51% of patients had scoliosis, 11% pectus excavatum, and 9% mitral valve prolapse, all significantly more than reference populations. Stimulated cytokine production was similar to that of healthy control subjects, including the IFN-γ/IL-12 pathway. CD4+, CD8+, B, and natural killer cell numbers were normal. A total of 36% of patients had mutations in the cystic fibrosis transmembrane conductance regulator gene. Conclusions: Patients with PNTM infection are taller and leaner than control subjects, with high rates of scoliosis, pectus excavatum, mitral valve prolapse, and cystic fibrosis transmembrane conductance regulator mutations, but without recognized immune defects. PMID:18703788

Role of Hypoxia-Induced Brain Derived Neurotrophic Factor in Human Pulmonary Artery Smooth Muscle

PubMed Central

Hartman, William; Helan, Martin; Smelter, Dan; Sathish, Venkatachalem; Thompson, Michael; Pabelick, Christina M.; Johnson, Bruce; Prakash, Y. S.

2015-01-01

Background Hypoxia effects on pulmonary artery structure and function are key to diseases such as pulmonary hypertension. Recent studies suggest that growth factors called neurotrophins, particularly brain-derived neurotrophic factor (BDNF), can influence lung structure and function, and their role in the pulmonary artery warrants further investigation. In this study, we examined the effect of hypoxia on BDNF in humans, and the influence of hypoxia-enhanced BDNF expression and signaling in human pulmonary artery smooth muscle cells (PASMCs). Methods and Results 48h of 1% hypoxia enhanced BDNF and TrkB expression, as well as release of BDNF. In arteries of patients with pulmonary hypertension, BDNF expression and release was higher at baseline. In isolated PASMCs, hypoxia-induced BDNF increased intracellular Ca2+ responses to serotonin: an effect altered by HIF1α inhibition or by neutralization of extracellular BDNF via chimeric TrkB-Fc. Enhanced BDNF/TrkB signaling increased PASMC survival and proliferation, and decreased apoptosis following hypoxia. Conclusions Enhanced expression and signaling of the BDNF-TrkB system in PASMCs is a potential mechanism by which hypoxia can promote changes in pulmonary artery structure and function. Accordingly, the BDNF-TrkB system could be a key player in the pathogenesis of hypoxia-induced pulmonary vascular diseases, and thus a potential target for therapy. PMID:26192455

Gene expression of cyclin-dependent kinase inhibitors and effect of heparin on their expression in mice with hypoxia-induced pulmonary hypertension

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yu Lunyin; Quinn, Deborah A.; Garg, Hari G.

The balance between cell proliferation and cell quiescence is regulated delicately by a variety of mediators, in which cyclin-dependent kinases (CDK) and CDK inhibitors (CDKI) play a very important role. Heparin which inhibits pulmonary artery smooth muscle cell (PASMC) proliferation increases the levels of two CDKIs, p21 and p27, although only p27 is important in inhibition of PASMC growth in vitro and in vivo. In the present study we investigated the expression profile of all the cell cycle regulating genes, including all seven CDKIs (p21, p27, p57, p15, p16, p18, and p19), in the lungs of mice with hypoxia-induced pulmonarymore » hypertension. A cell cycle pathway specific gene microarray was used to profile the 96 genes involved in cell cycle regulation. We also observed the effect of heparin on gene expression. We found that (a) hypoxic exposure for two weeks significantly inhibited p27 expression and stimulated p18 activity, showing a 98% decrease in p27 and 81% increase in p18; (b) other CDKIs, p21, p57, p15, p16, and p19 were not affected significantly in response to hypoxia; (c) heparin treatment restored p27 expression, but did not influence p18; (d) ERK1/2 and p38 were mediators in heparin upregulation of p27. This study provides an expression profile of cell cycle regulating genes under hypoxia in mice with hypoxia-induced pulmonary hypertension and strengthens the previous finding that p27 is the only CDKI involved in heparin regulation of PASMC proliferation and hypoxia-induced pulmonary hypertension.« less

[Pulmonary function in patients with infiltrative pulmonary tuberculosis].

PubMed

Nefedov, V B; Popova, L A; Shergina, E A

2007-01-01

Vital capacity (VC), forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), FEV1/VC%, PEF, MEF25, MEF50, MEF75, TLC, TGV, pulmonary residual volume (PRV), R(aw), R(in),, R(ex), DLCO-SB, DLCO-SS, PaO2, and PaCO2 were determined in 103 patients with infiltrative pulmonary tuberculosis. Pulmonary dysfunction was detected in 83.5% of the patients. Changes were found in lung volumes and capacities in 63.1%, impaired bronchial patency and pulmonary gas exchange dysfunction were in 60.2 and 41.7%, respectively. The changes in pulmonary volumes and capacities appeared as increased PRV, decreased VC and FVC, and decreased and increased TGV and TLC; impaired bronchial patency presented as decreased PEF, MEF25, MEF50, MEF75, FEV1/VC% and increased R(aw) R(in), and R(ex); pulmonary gas exchange dysfunction manifested itself as reduced DLCO-SB, DLCO-SS, and PaO2 and decreased and increased PaCO2. The magnitude of the observed functional changes was generally slight. Significant disorders were observed rarely and very pronounced ones were exceptional.

[Pulmonary function in patients with disseminated pulmonary tuberculosis].

PubMed

Nefedov, V B; Shergina, E A; Popova, L A

2007-01-01

Vital capacity (VC), forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), FEV1/VC%, PEF, MEF25%, MEF50%, MEF75%, TLS, TGV, pulmonary residual volume (PRV), Raw, Rin, Rex, DLCO-SB, DLCO-SS, PaO2, and PaCO2 were determined in 29 patients with disseminated pulmonary tuberculosis. Pulmonary dysfunction was detected in 93.1% of the patients. Changes were found in lung volumes and capacities in 65.5%, impaired bronchial patency and pulmonary gas exchange dysfunction were in 79.3 and 37.9%, respectively. The changes in pulmonary volumes and capacities appeared as increased PRV, decreased VC, FVC, and TLS, decreased and increased TGV; impaired bronchial patency presented as decreased PEF, MEF25%, MEF50%, MEF75%, and FEV1/VC% and increased Raw, Rin, and Rex; pulmonary gas exchange dysfunction manifested itself as reduced DLCO-SS and PaO2 and decreased and increased PaCO2. The observed functional changes varied from slight to significant and pronounced with a preponderance of small disorders, a lower detection rate of significant disorders, and rare detection of very pronounced ones.

Recommendations for a Standardized Pulmonary Function Report. An Official American Thoracic Society Technical Statement.

PubMed

Culver, Bruce H; Graham, Brian L; Coates, Allan L; Wanger, Jack; Berry, Cristine E; Clarke, Patricia K; Hallstrand, Teal S; Hankinson, John L; Kaminsky, David A; MacIntyre, Neil R; McCormack, Meredith C; Rosenfeld, Margaret; Stanojevic, Sanja; Weiner, Daniel J

2017-12-01

The American Thoracic Society committee on Proficiency Standards for Pulmonary Function Laboratories has recognized the need for a standardized reporting format for pulmonary function tests. Although prior documents have offered guidance on the reporting of test data, there is considerable variability in how these results are presented to end users, leading to potential confusion and miscommunication. A project task force, consisting of the committee as a whole, was approved to develop a new Technical Standard on reporting pulmonary function test results. Three working groups addressed the presentation format, the reference data supporting interpretation of results, and a system for grading quality of test efforts. Each group reviewed relevant literature and wrote drafts that were merged into the final document. This document presents a reporting format in test-specific units for spirometry, lung volumes, and diffusing capacity that can be assembled into a report appropriate for a laboratory's practice. Recommended reference sources are updated with data for spirometry and diffusing capacity published since prior documents. A grading system is presented to encourage uniformity in the important function of test quality assessment. The committee believes that wide adoption of these formats and their underlying principles by equipment manufacturers and pulmonary function laboratories can improve the interpretation, communication, and understanding of test results.

Functional classification of pulmonary hypertension in children: Report from the PVRI pediatric taskforce, Panama 2011.

PubMed

Lammers, Astrid E; Adatia, Ian; Cerro, Maria Jesus Del; Diaz, Gabriel; Freudenthal, Alexandra Heath; Freudenthal, Franz; Harikrishnan, S; Ivy, Dunbar; Lopes, Antonio A; Raj, J Usha; Sandoval, Julio; Stenmark, Kurt; Haworth, Sheila G

2011-08-02

The members of the Pediatric Task Force of the Pulmonary Vascular Research Institute (PVRI) were aware of the need to develop a functional classification of pulmonary hypertension in children. The proposed classification follows the same pattern and uses the same criteria as the Dana Point pulmonary hypertension specific classification for adults. Modifications were necessary for children, since age, physical growth and maturation influences the way in which the functional effects of a disease are expressed. It is essential to encapsulate a child's clinical status, to make it possible to review progress with time as he/she grows up, as consistently and as objectively as possible. Particularly in younger children we sought to include objective indicators such as thriving, need for supplemental feeds and the record of school or nursery attendance. This helps monitor the clinical course of events and response to treatment over the years. It also facilitates the development of treatment algorithms for children. We present a consensus paper on a functional classification system for children with pulmonary hypertension, discussed at the Annual Meeting of the PVRI in Panama City, February 2011.

Secondary Pulmonary Hypertension and Right-Sided Heart Failure at Presentation in Grave's Disease.

PubMed

Ganeshpure, Swapnil Panjabrao; Vaidya, Gaurang Nandkishor; Gattani, Vipul

2012-01-01

A young female presented with evidence of right-sided heart failure and was subsequently found to have significant pulmonary artery hypertension (PAH). Because of her normal left ventricular function and pulmonary capillary wedge pressure, the most probable site of etiology seemed to be the pulmonary vasculature. All the common possible secondary causes of PAH were ruled out, but during the investigations, she was found to have elevated thyroid function tests compatible with the diagnosis of Grave's disease. The treatment of Grave's disease, initially by medications and subsequently by radioiodine therapy, was associated with a significant reduction in the pulmonary artery systolic pressure. The purpose of this case report is to highlight one of the unusual and underdiagnosed presentations of Grave's disease.

Right ventricle performances with echocardiography and 99mTc myocardial perfusion imaging in pulmonary arterial hypertension patients.

PubMed

Liu, Jie; Fei, Lei; Huang, Guang-Qing; Shang, Xiao-Ke; Liu, Mei; Pei, Zhi-Jun; Zhang, Yong-Xue

2018-05-01

Right heart catheterization is commonly used to measure right ventricle hemodynamic parameters and is the gold standard for pulmonary arterial hypertension diagnosis; however, it is not suitable for patients' long-term follow-up. Non-invasive echocardiography and nuclear medicine have been applied to measure right ventricle anatomy and function, but the guidelines for the usefulness of clinical parameters remain to be established. The goal of this study is to identify reliable clinical parameters of right ventricle function in pulmonary arterial hypertension patients and analyze the relationship of these clinical parameters with the disease severity of pulmonary arterial hypertension. In this study, 23 normal subjects and 23 pulmonary arterial hypertension patients were recruited from January 2015 to March 2016. Pulmonary arterial hypertension patients were classified into moderate and severe pulmonary arterial hypertension groups according to their mean pulmonary arterial pressure levels. All the subjects were subjected to physical examination, chest X-ray, 12-lead electrocardiogram, right heart catheterization, two-dimensional echocardiography, and technetium 99m ( 99m Tc) myocardial perfusion imaging. Compared to normal subjects, the right heart catheterization indexes including right ventricle systolic pressure, right ventricle end diastolic pressure, pulmonary artery systolic pressure, pulmonary artery diastolic pressure, pulmonary vascular resistance, and right ventricle end systolic pressure increased in pulmonary arterial hypertension patients and were correlated with mean pulmonary arterial pressure levels. Echocardiography parameters, including tricuspid regurgitation peak velocity, tricuspid regurgitation pressure gradient, tricuspid annular plane systolic excursion and fractional area, right ventricle-myocardial performance index, were significantly associated with the mean pulmonary arterial pressure levels in pulmonary arterial hypertension patients. Furthermore, myocardial perfusion imaging was not observed in the normal subjects but in pulmonary arterial hypertension patients, especially severe pulmonary arterial hypertension subgroup, and showed potential diagnostic properties for pulmonary arterial hypertension. In conclusion, mean pulmonary arterial pressure levels are correlated with several right heart catheterization and echocardiography markers in pulmonary arterial hypertension patients; echocardiography and 99m Tc myocardial perfusion can be used to evaluate right ventricle performance in pulmonary arterial hypertension patients. Impact statement In this study, we analyzed the clinical parameters for evaluating RV function, including right ventricle catheterization (RHC), echocardiography, and technetium 99m ( 99m Tc) myocardial perfusion imaging (MPI) in normal Asian subjects and PAH patients ( n = 23 for each group). Our results demonstrated that six RHC indexes, four echocardiography indexes and MPI index were significantly altered in PAH patients and correlated with the levels of mean pulmonary arterial pressure. Importantly, we evaluated the diagnostic performance of MPI and found that MPI has a strong diagnostic accuracy in PAH patients. The findings from this study will be of interest to clinical investigators who make diagnosis and therapeutic strategies for PAH patients.

Fibronectin Matrix Remodeling in the Regulation of the Inflammatory Response within the Lung: An Early Step in Lung Cancer Progression

DTIC Science & Technology

2011-09-01

such as that which occurs in chronic obstructive pulmonary disease (COPD) and emphysema , is associated with increased risk of lung cancer. These...effect of the fibronectin III-1c peptide on the expression of inflammatory genes by human lung fibroblasts, lung cancer cells, and pulmonary ...CXCR2 in bleomycin-induced pulmonary inflammation and fibrosis. Am J Respir Cell Mol Biol. 2009; 40:410-21. 7. Barnes PJ. New therapies for chronic

Pulmonary function in children with development coordination disorder.

PubMed

Wu, Sheng K; Cairney, John; Lin, Hsiao-Hui; Li, Yao-Chuen; Song, Tai-Fen

2011-01-01

The purpose of this study was to compare pulmonary function in children with developmental coordination disorder (DCD) with children who are typically developing (TD), and also analyze possible gender differences in pulmonary function between these groups. The Movement ABC test was used to identify the movement coordination ability of children. Two hundred and fifty participants (90 children with DCD and 160 TD children) aged 9-10 years old completed this study. Using the KoKo spirometry, forced vital capacity (FVC) and forced expiratory volume in 1s (FEV(1.0)) were used to measure pulmonary function. The 800-m run was also conducted to assess cardiopulmonary fitness of children in the field. There was a significant difference in pulmonary function between TD children and those with DCD. The values of FVC and FEV(1.0) in TD children were significantly higher than in children with DCD. A significant, but low correlation (r = -0.220, p < .001) was found between total score on the MABC and FVC; similarly, a positive but low correlation (r = 0.252, p < .001) was found between total score on the MABC and the completion time of 800-m run. However, no significant correlation between FVC and the time of 800-m run was found (p > .05). Significant correlations between total score on the MABC and the completion time of the 800-m run (r = 0.352, p < .05) and between FVC and the time of 800-m run (r = -0.285, p < .05) were observed in girls with DCD but not boys with this condition. Based on the results of this study, pulmonary function in children with DCD was significantly lower than that of TD children. The field test, 800-m run, may not be a good indicator to distinguish aerobic ability between children with DCD and those who are TD. It is possible that poor pulmonary function in children with DCD is due to reduced physical activity in this population. Copyright © 2010 Elsevier Ltd. All rights reserved.

Monitoring pulmonary function with superimposed pulmonary gas exchange curves from standard analyzers.

PubMed

Zar, Harvey A; Noe, Frances E; Szalados, James E; Goodrich, Michael D; Busby, Michael G

2002-01-01

A repetitive graphic display of the single breath pulmonary function can indicate changes in cardiac and pulmonary physiology brought on by clinical events. Parallel advances in computer technology and monitoring make real-time, single breath pulmonary function clinically practicable. We describe a system built from a commercially available airway gas monitor and off the shelf computer and data-acquisition hardware. Analog data for gas flow rate, O2, and CO2 concentrations are introduced into a computer through an analog-to-digital conversion board. Oxygen uptake (VO2) and carbon dioxide output (VCO2) are calculated for each breath. Inspired minus expired concentrations for O2 and CO2 are displayed simultaneously with the expired gas flow rate curve for each breath. Dead-space and alveolar ventilation are calculated for each breath and readily appreciated from the display. Graphs illustrating the function of the system are presented for the following clinical scenarios; upper airway obstruction, bronchospasm, bronchopleural fistula, pulmonary perfusion changes and inadequate oxygen delivery. This paper describes a real-time, single breath pulmonary monitoring system that displays three parameters graphed against time: expired flow rate, oxygen uptake and carbon dioxide production. This system allows for early and rapid recognition of treatable conditions that may lead to adverse events without any additional patient measurements or invasive procedures. Monitoring systems similar to the one described in this paper may lead to a higher level of patient safety without any additional patient risk.

Lung Function in Pregnancy in Langerhans Cell Histiocytosis.

PubMed

Radzikowska, Elżbieta; Wiatr, Elżbieta; Franczuk, Monika; Bestry, Iwona; Roszkowski-Śliż, Kazimierz

2018-01-01

Pulmonary Langerhans cell histiocytosis (LCH) is a rare disease, affecting usually young people. The course of the disease is variable. In some pulmonary LCH patients a severe lung destruction and progression in spite of chemotherapy is observed, but in others just a cessation of smoking induces a regression of the disease. In the present study we seek to determine the influence of pregnancy on pulmonary function in LCH patients, an unchartered area of research. We addressed the issue by investigating eight pregnant women out of the 45 women hospitalized with the diagnosis of pulmonary LCH in the period from 2000 to 2015. For five of the eight pregnant women it was the second gestation. The median follow-up period was 120 months (range 72-175 months). Ten healthy children were born by a C-section. Two spontaneous miscarriages in the seventh week of gestation, and one tubal ectopic pregnancy were recorded. We found that pregnancy did not significantly influence pulmonary function assessed by the following indices: forced expiratory volume in 1 s (FEV1), lung vital capacity (VC), total lung capacity (TLC), residual volume (RV), diffusing capacity of the lungs for carbon monoxide (DLCO), and the distance and arterial oxygen saturation in 6-min walk test. Only one patient in the third trimester of pregnancy experienced bilateral pneumothorax, with persistent air leak. In all patients, delivery and postpartum period were uneventful. We conclude that pregnancy in pulmonary LCH patients is safe and not associated with deterioration of pulmonary function or blood oxygenation.

Influenza A virus-dependent remodeling of pulmonary clock function in a mouse model of COPD

PubMed Central

Sundar, Isaac K.; Ahmad, Tanveer; Yao, Hongwei; Hwang, Jae-woong; Gerloff, Janice; Lawrence, B. Paige; Sellix, Michael T.; Rahman, Irfan

2015-01-01

Daily oscillations of pulmonary function depend on the rhythmic activity of the circadian timing system. Environmental tobacco/cigarette smoke (CS) disrupts circadian clock leading to enhanced inflammatory responses. Infection with influenza A virus (IAV) increases hospitalization rates and death in susceptible individuals, including patients with Chronic Obstructive Pulmonary Disease (COPD). We hypothesized that molecular clock disruption is enhanced by IAV infection, altering cellular and lung function, leading to severity in airway disease phenotypes. C57BL/6J mice exposed to chronic CS, BMAL1 knockout (KO) mice and wild-type littermates were infected with IAV. Following infection, we measured diurnal rhythms of clock gene expression in the lung, locomotor activity, pulmonary function, inflammatory, pro-fibrotic and emphysematous responses. Chronic CS exposure combined with IAV infection altered the timing of clock gene expression and reduced locomotor activity in parallel with increased lung inflammation, disrupted rhythms of pulmonary function, and emphysema. BMAL1 KO mice infected with IAV showed pronounced detriments in behavior and survival, and increased lung inflammatory and pro-fibrotic responses. This suggests that remodeling of lung clock function following IAV infection alters clock-dependent gene expression and normal rhythms of lung function, enhanced emphysematous and injurious responses. This may have implications for the pathobiology of respiratory virus-induced airway disease severity and exacerbations. PMID:25923474

Regulators and effectors of bone morphogenetic protein signalling in the cardiovascular system.

PubMed

Luo, Jiang-Yun; Zhang, Yang; Wang, Li; Huang, Yu

2015-07-15

Bone morphogenetic proteins (BMPs) play key roles in the regulation of cell proliferation, differentiation and apoptosis in various tissues and organs, including the cardiovascular system. BMPs signal through both Smad-dependent and -independent cascades to exert a wide spectrum of biological activities. Cardiovascular disorders such as abnormal angiogenesis, atherosclerosis, pulmonary hypertension and cardiac hypertrophy have been linked to aberrant BMP signalling. To correct the dysregulated BMP signalling in cardiovascular pathogenesis, it is essential to get a better understanding of how the regulators and effectors of BMP signalling control cardiovascular function and how the dysregulated BMP signalling contributes to cardiovascular dysfunction. We hence highlight several key regulators of BMP signalling such as extracellular regulators of ligands, mechanical forces, microRNAs and small molecule drugs as well as typical BMP effectors like direct downstream target genes, mitogen-activated protein kinases, reactive oxygen species and microRNAs. The insights into these molecular processes will help target both the regulators and important effectors to reverse BMP-associated cardiovascular pathogenesis. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

COPD and exercise: does it make a difference?

PubMed Central

Burtin, Chris; De Boever, Patrick; Langer, Daniël; Vogiatzis, Ioannis; Wouters, Emiel F.M.; Franssen, Frits M.E.

2016-01-01

Key points Physiological changes are observed following a structured exercise training programme in patients with COPD, without changes in resting lung function. Exercise training is the cornerstone of a comprehensive pulmonary rehabilitation programme in patients with COPD. Most comorbidities in patients referred for pulmonary rehabilitation remain undiagnosed and untreated. After careful screening, it is safe for COPD patients with comorbidities to obtain significant and clinically relevant improvements in functional exercise capacity and health status after an exercise-based pulmonary rehabilitation programme. Educational aims To inform readers of the positive effects of exercise-based pulmonary rehabilitation in patients with COPD, even with comorbid conditions. To inform readers of the importance of physical activity in patients with COPD. Exercise training is widely regarded as the cornerstone of pulmonary rehabilitation in patients with chronic obstructive pulmonary disease (COPD). Indeed, exercise training has been identified as the best available means of improving muscle function and exercise tolerance in patients with COPD. So, exercise training truly makes a difference in the life of patients with COPD. In this review, an overview is provided on the history of exercise training (as standalone intervention or as part of a comprehensive pulmonary rehabilitation programme), exercise training in comorbid patients with COPD, and the impact of physical activity counselling in a clean air environment. PMID:27408645

Pre-operative optimisation of lung function

PubMed Central

Azhar, Naheed

2015-01-01

The anaesthetic management of patients with pre-existing pulmonary disease is a challenging task. It is associated with increased morbidity in the form of post-operative pulmonary complications. Pre-operative optimisation of lung function helps in reducing these complications. Patients are advised to stop smoking for a period of 4–6 weeks. This reduces airway reactivity, improves mucociliary function and decreases carboxy-haemoglobin. The widely used incentive spirometry may be useful only when combined with other respiratory muscle exercises. Volume-based inspiratory devices have the best results. Pharmacotherapy of asthma and chronic obstructive pulmonary disease must be optimised before considering the patient for elective surgery. Beta 2 agonists, inhaled corticosteroids and systemic corticosteroids, are the main drugs used for this and several drugs play an adjunctive role in medical therapy. A graded approach has been suggested to manage these patients for elective surgery with an aim to achieve optimal pulmonary function. PMID:26556913

Pulmonary function evaluation during and following Skylab space flights

NASA Technical Reports Server (NTRS)

Sawin, C. F.; Nicogossian, A. E.; Schachter, A. P.; Rummel, J. A.; Michel, E. L.

1974-01-01

Previous experience during the Apollo postflight exercise testing indicated no major changes in pulmonary function. Although pulmonary function has been studied in detail following exposure to hypoxic and hyperoxic environments, few studies have dealt with normoxic environments at reduced total pressure as encountered during the Skylab missions. Forced vital capacity was measured during the preflight and postflight periods of the Skylab 2 mission. Initial in-flight measurements of vital capacity were obtained during the last two weeks of the second manned mission (Skylab 3). Comprehensive pulmonary function screening was accomplished during the Skylab 4 mission. The primary measurements made during Skylab 4 testing included residual volume determination, closing volume, vital capacity, and forced vital capacity and its derivatives. In addition, comprehensive in-flight vital capacity measurements were made during the Skylab 4 mission. Vital capacity was decreased slightly during flight in all Skylab 4 crewmen. No major preflight to postflight changes were observed in the other parameters.

Pulmonary function abnormalities in never-smoking flight attendants exposed to secondhand tobacco smoke in the aircraft cabin.

PubMed

Arjomandi, Mehrdad; Haight, Thaddeus; Redberg, Rita; Gold, Warren M

2009-06-01

To determine whether the flight attendants who were exposed to secondhand tobacco smoke in the aircraft cabin have abnormal pulmonary function. We administered questionnaires and performed pulmonary function testing in 61 never-smoking female flight attendants who worked in active air crews before the smoking ban on commercial aircraft (preban). Although the preban flight attendants had normal FVC, FEV1, and FEV1/FVC ratio, they had significantly decreased flow at mid- and low-lung volumes, curvilinear flow-volume curves, and evidence of air trapping. Furthermore, the flight attendants had significantly decreased diffusing capacity (77.5% +/- 11.2% predicted normal) with 51% having a diffusing capacity below their 95% normal prediction limit. This cohort of healthy never-smoking flight attendants who were exposed to secondhand tobacco smoke in the aircraft cabin showed pulmonary function abnormalities suggestive of airway obstruction and impaired diffusion.

The Critical Role of Pulmonary Arterial Compliance in Pulmonary Hypertension

PubMed Central

Prins, Kurt W.; Pritzker, Marc R.; Scandurra, John; Volmers, Karl; Weir, E. Kenneth

2016-01-01

The normal pulmonary circulation is a low-pressure, high-compliance system. Pulmonary arterial compliance decreases in the presence of pulmonary hypertension because of increased extracellular matrix/collagen deposition in the pulmonary arteries. Loss of pulmonary arterial compliance has been consistently shown to be a predictor of increased mortality in patients with pulmonary hypertension, even more so than pulmonary vascular resistance in some studies. Decreased pulmonary arterial compliance causes premature reflection of waves from the distal pulmonary vasculature, leading to increased pulsatile right ventricular afterload and eventually right ventricular failure. Evidence suggests that decreased pulmonary arterial compliance is a cause rather than a consequence of distal small vessel proliferative vasculopathy. Pulmonary arterial compliance decreases early in the disease process even when pulmonary artery pressure and pulmonary vascular resistance are normal, potentially enabling early diagnosis of pulmonary vascular disease, especially in high-risk populations. With the recognition of the prognostic importance of pulmonary arterial compliance, its impact on right ventricular function, and its contributory role in the development and progression of distal small-vessel proliferative vasculopathy, pulmonary arterial compliance is an attractive target for the treatment of pulmonary hypertension. PMID:26848601

Unique spatial and cellular expression patterns of Hoxa5, Hoxb4 and Hoxb6 proteins in normal developing murine lung are modified in pulmonary hypoplasia

PubMed Central

Volpe, MaryAnn Vitoria; Wang, Karen Ting Wai; Nielsen, Heber Carl; Chinoy, Mala Romeshchandra

2009-01-01

Background Hox transcription factors modulate signaling pathways controlling organ morphogenesis and maintain cell fate and differentiation in adults. Retinoid signaling, key in regulating Hox expression, is altered in pulmonary hypoplasia. Information on pattern-specific expression of Hox proteins in normal lung development and in pulmonary hypoplasia is minimal. Our objective was to determine how pulmonary hypoplasia alters temporal, spatial and cellular expression of Hoxa5, Hoxb4 and Hoxb6 proteins compared to normal lung development. Methods Temporal, spatial and cellular Hoxa5, Hoxb4 and Hoxb6 expression was studied in normal (untreated) and nitrofen-induced hypoplastic (NT-PH) lungs from gestational day 13.5, 16, 19 fetuses and neonates using western blot and immunohistochemistry. Results Modification of protein levels and spatial and cellular Hox expression patterns in NT-PH lungs was consistent with delayed lung development. Distinct protein isoforms were detected for each Hox protein. Expression levels of the Hoxa5 and Hoxb6 isoforms changed with development and further in NT-PH lungs. Compared to normal lungs, Gd19 and neonatal NT-PH lungs had decreased Hoxb6 and increased Hoxa5 and Hoxb4. Hoxa5 cellular localization changed from mesenchyme to epithelia earlier in normal lungs. Hoxb4 was expressed in mesenchyme and epithelial cells throughout development. Hoxb6 remained mainly in mesenchymal cells around distal airways. Conclusions Unique spatial and cellular expression of Hoxa5, Hoxb4 and Hoxb6 participates in branching morphogenesis and terminal sac formation. Altered Hox protein temporal and cellular balance of expression either contributes to pulmonary hypoplasia or functions as a compensatory mechanism attempting to correct abnormal lung development and maturation in this condition. PMID:18553509

Selective activation of angiotensin AT2 receptors attenuates progression of pulmonary hypertension and inhibits cardiopulmonary fibrosis.

PubMed

Bruce, E; Shenoy, V; Rathinasabapathy, A; Espejo, A; Horowitz, A; Oswalt, A; Francis, J; Nair, A; Unger, T; Raizada, M K; Steckelings, U M; Sumners, C; Katovich, M J

2015-05-01

Pulmonary hypertension (PH) is a devastating disease characterized by increased pulmonary arterial pressure, which progressively leads to right-heart failure and death. A dys-regulated renin angiotensin system (RAS) has been implicated in the development and progression of PH. However, the role of the angiotensin AT2 receptor in PH has not been fully elucidated. We have taken advantage of a recently identified non-peptide AT2 receptor agonist, Compound 21 (C21), to investigate its effects on the well-established monocrotaline (MCT) rat model of PH. A single s.c. injection of MCT (50 mg·kg(-1) ) was used to induce PH in 8-week-old male Sprague Dawley rats. After 2 weeks of MCT administration, a subset of animals began receiving either 0.03 mg·kg(-1) C21, 3 mg·kg(-1) PD-123319 or 0.5 mg·kg(-1) A779 for an additional 2 weeks, after which right ventricular haemodynamic parameters were measured and tissues were collected for gene expression and histological analyses. Initiation of C21 treatment significantly attenuated much of the pathophysiology associated with MCT-induced PH. Most notably, C21 reversed pulmonary fibrosis and prevented right ventricular fibrosis. These beneficial effects were associated with improvement in right heart function, decreased pulmonary vessel wall thickness, reduced pro-inflammatory cytokines and favourable modulation of the lung RAS. Conversely, co-administration of the AT2 receptor antagonist, PD-123319, or the Mas antagonist, A779, abolished the protective actions of C21. Taken together, our results suggest that the AT2 receptor agonist, C21, may hold promise for patients with PH. © 2014 The British Pharmacological Society.

Novel therapeutic approaches for pulmonary fibrosis

PubMed Central

Datta, Arnab; Scotton, Chris J; Chambers, Rachel C

2011-01-01

Pulmonary fibrosis represents the end stage of a number of heterogeneous conditions and is, to a greater or lesser degree, the hallmark of the interstitial lung diseases. It is characterized by the excessive deposition of extracellular matrix proteins within the pulmonary interstitium leading to the obliteration of functional alveolar units and in many cases, respiratory failure. While a small number of interstitial lung diseases have known aetiologies, most are idiopathic in nature, and of these, idiopathic pulmonary fibrosis is the most common and carries with it an appalling prognosis – median survival from the time of diagnosis is less than 3 years. This reflects the lack of any effective therapy to modify the course of the disease, which in turn is indicative of our incomplete understanding of the pathogenesis of this condition. Current prevailing hypotheses focus on dysregulated epithelial–mesenchymal interactions promoting a cycle of continued epithelial cell injury and fibroblast activation leading to progressive fibrosis. However, it is likely that multiple abnormalities in a myriad of biological pathways affecting inflammation and wound repair – including matrix regulation, epithelial reconstitution, the coagulation cascade, neovascularization and antioxidant pathways – modulate this defective crosstalk and promote fibrogenesis. This review aims to offer a pathogenetic rationale behind current therapies, briefly outlining previous and ongoing clinical trials, but will focus on recent and exciting advancements in our understanding of the pathogenesis of idiopathic pulmonary fibrosis, which may ultimately lead to the development of novel and effective therapeutic interventions for this devastating condition. LINKED ARTICLES This article is part of a themed issue on Respiratory Pharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.163.issue-1 PMID:21265830

Protective effect of exogenous hydrogen sulfide on pulmonary artery endothelial cells by suppressing endoplasmic reticulum stress in a rat model of chronic obstructive pulmonary disease.

PubMed

Ding, Hai-Bo; Liu, Kai-Xiong; Huang, Jie-Feng; Wu, Da-Wen; Chen, Jun-Ying; Chen, Qing-Shi

2018-06-13

Chronic obstructive pulmonary disease (COPD) is a multicomponent disorder characterized by inflammation, representing a significant leading cause of chronic morbidity and mortality. Reports have implicated hydrogen sulfide (H 2 S) in both the pathology and treatment of COPD. The present study aimed to explore the effects involved with exogenous H 2 S on endoplasmic reticulum stress (ERS) and pulmonary artery endothelial cells (PAECs) in a rat model of COPD. Rat models of COPD were successfully established by means of passive smoke exposure and intratracheal injection with lipopolysaccharide (LPS). Pulmonary function tests were performed and histopathological changes were observed. The expression of ERS markers, glucose-regulated protein-78 (GRP78), and C/EBP homologous protein (CHOP) and caspase-12, associated with ERS-induced apoptosis, were determined by western blot and immunohistochemistry methods. TUNEL assay was applied to determine the apoptosis index (AI) in PAECs. Treatment with NaHS was followed by the exhibition of markedly increased forced expiratory volume over 0.3 s (FEV0.3)/forced vital capacity (FVC) and dynamic lung compliance as well as integral optical density (IOD), with decreased RI among COPD rats. Western blot analysis, immunohistochemistry and TUNEL assay results revealed there to be reduced expressions of GRP78, CHOP and caspase-12 in the lung tissues and AI of PAECs, post NaHS treatment. The key findings of the current study highlight ERS in COPD rats, as well as well as reduced apoptosis in PAECs in connection with exogenous H 2 S by suppressing ERS. Copyright © 2018. Published by Elsevier Masson SAS.

The use of spirometry to evaluate pulmonary function in olive ridley sea turtles (Lepidochelys olivacea) with positive buoyancy disorders.

PubMed

Schmitt, Todd L; Munns, Suzanne; Adams, Lance; Hicks, James

2013-09-01

This study utilized computed spirometry to compare the pulmonary function of two stranded olive ridley sea turtles (Lepidochelys olivacea) presenting with a positive buoyancy disorder with two healthy captive olive ridley sea turtles held in a large public aquarium. Pulmonary function test (PFT) measurements demonstrated that the metabolic cost of breathing was much greater for animals admitted with positive buoyancy than for the normal sea turtles. Positively buoyant turtles had higher tidal volumes and significantly lower breathing-frequency patterns with significantly higher expiration rates, typical of gasp-type breathing. The resulting higher energetic cost of breathing in the diseased turtles may have a significant impact on their long-term survival. The findings represent a method for clinical respiratory function analysis for an individual animal to assist with diagnosis, therapy, and prognosis. This is the first study, to our knowledge, to evaluate objectively sea turtles presenting with positive buoyancy and respiratory disease using pulmonary function tests.

On the Evolution of the Pulmonary Alveolar Lipofibroblast

PubMed Central

Torday, John S.; Rehan, Virender K.

2015-01-01

The pulmonary alveolar lipofibroblast was first reported in 1970. Since then its development, structure, function and molecular characteristics have been determined. Its capacity to actively absorb, store and ‘traffic’ neutral lipid for protection of the alveolus against oxidant injury, and for the active supply of substrate for lung surfactant phospholipid production have offered the opportunity to identify a number of specialized functions of these strategically placed cells. Namely, Parathyroid Hormone-related Protein (PTHrP) signaling, expression of Adipocyte Differentiation Related Protein, leptin, peroxisome proliferator activator receptor gamma, and the prostaglandin E2 receptor EP2-which are all stretch-regulated, explaining how and why surfactant production is ‘on-demand’ in service to ventilation-perfusion matching. Because of the central role of the lipofibroblast in vertebrate lung physiologic evolution, it is a Rosetta Stone for understanding how and why the lung evolved in adaptation to terrestrial life, beginning with the duplication of the PTHrP Receptor some 300 mya. Moreover, such detailed knowledge of the workings of the lipofibroblast have provided insight to the etiology and effective treatment of Bronchopulmonary Dysplasia based on physiologic principles rather than on pharmacology. PMID:26706109

Mitochondrial dysfunction in alveolar and white matter developmental failure in premature infants

PubMed Central

Ten, Vadim S.

2017-01-01

At birth, some organs in premature infants are not developed enough to meet challenges of the extra-uterine life. Although growth and maturation continues after premature birth, postnatal organ development may become sluggish or even arrested, leading to organ dysfunction. There is no clear mechanistic concept of this postnatal organ developmental failure in premature neonates. This review introduces a concept-forming hypothesis: Mitochondrial bioenergetic dysfunction is a fundamental mechanism of organs maturation failure in premature infants. Data collected in support of this hypothesis are relevant to two major diseases of prematurity: white matter injury and broncho-pulmonary dysplasia. In these diseases, totally different clinical manifestations are defined by the same biological process, developmental failure of the main functional units—alveoli in the lungs and axonal myelination in the brain. Although molecular pathways regulating alveolar and white matter maturation differ, proper bioenergetic support of growth and maturation remains critical biological requirement for any actively developing organ. Literature analysis suggests that successful postnatal pulmonary and white matter development highly depends on mitochondrial function which can be inhibited by sublethal postnatal stress. In premature infants, sublethal stress results mostly in organ maturation failure without excessive cellular demise. PMID:27901512

Mitochondrial dysfunction in alveolar and white matter developmental failure in premature infants.

PubMed

Ten, Vadim S

2017-02-01

At birth, some organs in premature infants are not developed enough to meet challenges of the extra-uterine life. Although growth and maturation continues after premature birth, postnatal organ development may become sluggish or even arrested, leading to organ dysfunction. There is no clear mechanistic concept of this postnatal organ developmental failure in premature neonates. This review introduces a concept-forming hypothesis: Mitochondrial bioenergetic dysfunction is a fundamental mechanism of organs maturation failure in premature infants. Data collected in support of this hypothesis are relevant to two major diseases of prematurity: white matter injury and broncho-pulmonary dysplasia. In these diseases, totally different clinical manifestations are defined by the same biological process, developmental failure of the main functional units-alveoli in the lungs and axonal myelination in the brain. Although molecular pathways regulating alveolar and white matter maturation differ, proper bioenergetic support of growth and maturation remains critical biological requirement for any actively developing organ. Literature analysis suggests that successful postnatal pulmonary and white matter development highly depends on mitochondrial function which can be inhibited by sublethal postnatal stress. In premature infants, sublethal stress results mostly in organ maturation failure without excessive cellular demise.

Ambient polycyclic aromatic hydrocarbons and pulmonary function in children

PubMed Central

Padula, Amy M.; Balmes, John R.; Eisen, Ellen A.; Mann, Jennifer; Noth, Elizabeth M.; Lurmann, Frederick W.; Pratt, Boriana; Tager, Ira B.; Nadeau, Kari; Hammond, S. Katharine

2014-01-01

Few studies have examined the relationship between ambient polycyclic aromatic hydrocarbons (PAHs) and pulmonary function in children. Major sources include vehicular emissions, home heating, wildland fires, agricultural burning, and power plants. PAHs are an important component of fine particulate matter that has been linked to respiratory health. This cross-sectional study examines the relationship between estimated individual exposures to the sum of PAHs with 4, 5, or 6 rings (PAH456) and pulmonary function tests (forced expiratory volume in one second (FEV1) and forced expiratory flow between 25% and 75% of vital capacity) in asthmatic and non-asthmatic children. We applied land-use regression to estimate individual exposures to ambient PAHs for averaging periods ranging from 1 week to 1 year. We used linear regression to estimate the relationship between exposure to PAH456 with pre- and postbronchodilator pulmonary function tests in children in Fresno, California (N =297). Among non-asthmatics, there was a statistically significant association between PAH456 during the previous 3 months, 6 months, and 1 year and postbronchodilator FEV1. The magnitude of the association increased with the length of the averaging period ranging from 60 to 110 ml decrease in FEV1 for each 1 ng/m3 increase in PAH456. There were no associations with PAH456 observed among asthmatic children. We identified an association between annual PAHs and chronic pulmonary function in children without asthma. Additional studies are needed to further explore the association between exposure to PAHs and pulmonary function, especially with regard to differential effects between asthmatic and non-asthmatic children. PMID:24938508

Modulation of Lung Function by Increased Nitric Oxide Production

PubMed Central

Yadav, Ram Lochan; Yadav, Prakash Kumar

2017-01-01

Introduction Cigarette smoking reduces endogenous Nitric Oxide (NO) production by reducing Nitric Oxide Synthase (NOS) activity, which is one of the probable reason for increased rate of pulmonary diseases in smokers. Nitric oxide/oxygen blends are used in critical care to promote capillary and pulmonary dilation to treat several pulmonary vascular diseases. Among several supplements, the highest NOS activation has been proved for garlic with its unique mechanism of action. Aim To investigate the effect of dietary supplementation of NO producing garlic on pulmonary function of smokers. Materials and Methods The study was conducted on 40 healthy non-smoker (Group A) and 40 chronic smoker (Group B) males with matched age, height and weight. The pulmonary function tests- Forced Vital Capacity (FVC), Forced Expiratory Volume in one second (FEV1), FEV1/FVC ratio and Peak Expiratory Flow Rate (PEFR) were performed in non-smokers (Group A), smokers (Group B) and smokers after supplementation of approximately 4 gm of raw garlic (2 garlic cloves) per day for three months (Group C). Endogenous NO production was studied in smokers before and after garlic supplementation and in non-smokers without supplementation. The data obtained were compared between the groups using unpaired student’s t-test. The p-value considered significant at <0.05. Results Our results showed that FVC, FEV1, FEV1/FVC ratio and PEFR were reduced significantly along with a significant decreased NOS activity among smokers (Group B) when compared with non-smokers (Group A). Garlic supplementation significantly improved the pulmonary function tests in Group C in comparison to Group B by increasing NOS activity. Conclusion Dietary supplementation of garlic, which might be by increasing NOS activity, has significantly improved pulmonary functions in smokers. PMID:28764150

ASSOCIATION OF ANXIETY AND DEPRESSION WITH PULMONARY-SPECIFIC SYMPTOMS IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE*

PubMed Central

Doyle, Todd; Palmer, Scott; Johnson, Julie; Babyak, Michael A.; Smith, Patrick; Mabe, Stephanie; Welty-Wolf, Karen; Martinu, Tereza; Blumenthal, James A.

2014-01-01

Objectives To examine the association of anxiety and depression with pulmonary-specific symptoms of Chronic Obstructive Pulmonary Disease (COPD), and to determine the extent to which disease severity and functional capacity modify this association. Method Patients (N = 162) enrolled in the INSPIRE-II study, an ongoing randomized, clinical trial of COPD patients and their caregivers who received either telephone-based coping skills training or education and symptom monitoring. Patients completed a psychosocial test battery including: Brief Fatigue Inventory, St. George’s Respiratory Questionnaire, UCSD Shortness of Breath Questionnaire, State-Trait Anxiety Inventory, and Beck Depression Inventory. Measures of disease severity and functional capacity (i.e., FEV1 and six-minute walk test) were also obtained. Results After covariate adjustment, higher anxiety and depression levels were associated with greater fatigue levels (ps < .001, ΔR2 = 0.16 and 0.29, respectively), shortness of breath (ps < .001, ΔR2 = 0.12 and 0.10), and frequency of COPD symptoms (ps < .001, ΔR2 = 0.11 and 0.13). In addition, functional capacity was a moderator of anxiety and pulmonary-specific COPD symptoms. The association between anxiety and shortness of breath (p = 0.009) and frequency of COPD symptoms (p = 0.02) was greater among patients with lower functional capacity. Conclusions Anxiety and depression were associated with higher levels of fatigue, shortness of breath, and frequency of COPD symptoms. It is important for clinicians to be aware of the presence of anxiety and depression in COPD patients, which appears to correlate with pulmonary-specific COPD symptoms, especially in patients with lower functional capacity. Prospective design studies are needed to elucidate the causal relationships between anxiety and depression and pulmonary-specific symptoms in COPD patients. PMID:23977821

The effect of chronic infection with Aspergillus fumigatus on lung function and hospitalization in patients with cystic fibrosis.

PubMed

Amin, Reshma; Dupuis, Annie; Aaron, Shawn D; Ratjen, Felix

2010-01-01

The relevance of Aspergillus fumigatus in patients with cystic fibrosis (CF) not affected by allergic bronchopulmonary aspergillosis is unclear. Our aim was to determine the effect of persistent infection with A fumigatus on pulmonary exacerbations and lung function in children with CF. This was a retrospective cohort study of patients with CF followed at The Hospital for Sick Children from 1999 to 2006. Persistent A fumigatus infection was defined as the presence of two or more positive sputum or bronchoalveolar cultures for A fumigatus in a given year. The primary outcome measure was the annual number of hospitalizations for pulmonary exacerbations. Two hundred thirty patients with CF were included in the analysis. The FEV(1) of patients persistently infected with A fumigatus was 3.61% (P< or =.0001) lower during the study period compared with uninfected patients. There was a significant interaction between A fumigatus and Pseudomonas aeruginosa on lung function (P=.0006). Patients not infected with either organism had the highest pulmonary function. Persistent A fumigatus infection (relative risk [RR]=1.94, P=.0002) and CF-related diabetes (RR=1.64, P=.028) were associated with an increased risk of pulmonary exacerbations requiring hospitalization, whereas there was no increased risk of pulmonary exacerbations among patients with allergic bronchopulmonary aspergillosis (RR=1.02, P=.94). When adjusted for baseline pulmonary function, none of these variables were associated with a significantly increased risk of pulmonary exacerbations, with only chronic A fumigatus infection trending toward significance (RR=1.40, P=.065). Persistent A fumigatus infection is an independent risk factor for hospital admissions in patients with CF.

Differential co-expression analysis of a microarray gene expression profiles of pulmonary adenocarcinoma.

PubMed

Fu, Shijie; Pan, Xufeng; Fang, Wentao

2014-08-01

Lung cancer severely reduces the quality of life worldwide and causes high socioeconomic burdens. However, key genes leading to the generation of pulmonary adenocarcinoma remain elusive despite intensive research efforts. The present study aimed to identify the potential associations between transcription factors (TFs) and differentially co‑expressed genes (DCGs) in the regulation of transcription in pulmonary adenocarcinoma. Gene expression profiles of pulmonary adenocarcinoma were downloaded from the Gene Expression Omnibus, and gene expression was analyzed using a computational method. A total of 37,094 differentially co‑expressed links (DCLs) and 251 DCGs were identified, which were significantly enriched in 10 pathways. The construction of the regulatory network and the analysis of the regulatory impact factors revealed eight crucial TFs in the regulatory network. These TFs regulated the expression of DCGs by promoting or inhibiting their expression. In addition, certain TFs and target genes associated with DCGs did not appear in the DCLs, which indicated that those TFs could be synergistic with other factors. This is likely to provide novel insights for research into pulmonary adenocarcinoma. In conclusion, the present study may enhance the understanding of disease mechanisms and lead to an improved diagnosis of lung cancer. However, further studies are required to confirm these observations.

Changes in Speckle Tracking Echocardiography Measures of Ventricular Function after Percutaneous Implantation of the Edwards SAPIEN Transcatheter Heart Valve in the Pulmonary Position

PubMed Central

Chowdhury, Shahryar M.; Hijazi, Ziyad M.; Rhodes, John F.; Kar, Saibal; Makkar, Raj; Mullen, Michael; Cao, Qi-Ling; Mandinov, Lazar; Buckley, Jason; Pietris, Nicholas P.; Shirali, Girish S.

2015-01-01

Background Patients with free pulmonary regurgitation or mixed pulmonary stenosis and regurgitation and severely dilated right ventricles (RV) show little improvement in ventricular function after pulmonary valve replacement when assessed by traditional echocardiographic markers. We evaluated changes in right and left ventricular (LV) function using speckle tracking echocardiography in patients after SAPIEN transcatheter pulmonary valve (TPV) placement. Methods Echocardiograms were evaluated at baseline, discharge, 1 and 6 months after TPV placement in 24 patients from 4 centers. Speckle tracking measures of function included peak longitudinal strain, strain rate, and early diastolic strain rate. RV fractional area change, tricuspid annular plane systolic excursion, and left ventricular LV ejection fraction were assessed. Routine Doppler and tissue Doppler velocities were measured. Results At baseline, all patients demonstrated moderate to severe pulmonary regurgitation; this improved following TPV placement. No significant changes were detected in conventional measures of RV or LV function at 6 months. RV longitudinal strain (−16.9% vs. −19.6%, P < 0.01), strain rate (−0.87 s−1 vs. −1.16 s−1, P = 0.01), and LV longitudinal strain (−16.2% vs. −18.2%, P = 0.01) improved between baseline and 6 month follow-up. RV early diastolic strain rate, LV longitudinal strain rate and early diastolic strain rate showed no change. Conclusion Improvements in RV longitudinal strain, strain rate, and LV longitudinal strain are seen at 6 months post-TPV. Diastolic function does not appear to change at 6 months. Speckle tracking echocardiography may be more sensitive than traditional measures in detecting changes in systolic function after TPV implantation. (Echocardiography 2015;32:461–469) PMID:25047063

Isolated Human Pulmonary Artery Structure and Function Pre- and Post-Cardiopulmonary Bypass Surgery.

PubMed

Dora, Kim A; Stanley, Christopher P; Al Jaaly, Emad; Fiorentino, Francesca; Ascione, Raimondo; Reeves, Barnaby C; Angelini, Gianni D

2016-02-23

Pulmonary dysfunction is a known complication after cardiac surgery using cardiopulmonary bypass, ranging from subclinical functional changes to prolonged postoperative ventilation, acute lung injury, and acute respiratory distress syndrome. Whether human pulmonary arterial function is compromised is unknown. The aim of the present study was to compare the structure and function of isolated and cannulated human pulmonary arteries obtained from lung biopsies after the chest was opened (pre-cardiopulmonary bypass) to those obtained at the end of cardiopulmonary bypass (post-cardiopulmonary bypass) from patients undergoing coronary artery bypass graft surgery. Pre- and post-cardiopulmonary bypass lung biopsies were received from 12 patients undergoing elective surgery. Intralobular small arteries were dissected, cannulated, pressurized, and imaged using confocal microscopy. Functionally, the thromboxane mimetic U46619 produced concentration-dependent vasoconstriction in 100% and 75% of pre- and post-cardiopulmonary bypass arteries, respectively. The endothelium-dependent agonist bradykinin stimulated vasodilation in 45% and 33% of arteries pre- and post-cardiopulmonary bypass, respectively. Structurally, in most arteries smooth muscle cells aligned circumferentially; live cell viability revealed that although 100% of smooth muscle and 90% of endothelial cells from pre-cardiopulmonary bypass biopsies had intact membranes and were considered viable, only 60% and 58%, respectively, were viable from post-cardiopulmonary bypass biopsies. We successfully investigated isolated pulmonary artery structure and function in fresh lung biopsies from patients undergoing heart surgery. Pulmonary artery contractile tone and endothelium-dependent dilation were significantly reduced in post-cardiopulmonary bypass biopsies. The decreased functional responses were associated with reduced cell viability. URL: http://www.isrctn.com/ISRCTN34428459. Unique identifier: ISRCTN 34428459. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

The alpha-tocopherol form of vitamin E reverses age-associated susceptibility to Streptococcus pneumoniae lung infection by modulating pulmonary neutrophil recruitment

USDA-ARS?s Scientific Manuscript database

Streptococcus pneumonia infections are an important cause of morbidity and mortality in older patients. Uncontrolled neutrophil-driven pulmonary inflammation exacerbates this disease. To test whether the alpha-tocopherol (alpha-Toc) form of vitamin E, a regulator of immunity, can modulate neutrophil...

Pulmonary tolerance in man to continuous oxygen exposure at 3.0, 2.5, 2.0, and 1.5 ATA in Predictive Studies V

NASA Technical Reports Server (NTRS)

Clark, J. M.; Gelfand, R.; Flores, N. D.; Lambertsen, C. J.; Pisarello, J. B.

1987-01-01

Oxygen effects on pulmonary function were measured in normal, resting men who breathed oxygen continuously at 3.0, 2.5, 2.0, and 1.5 ATA to predefined limits of CNS, cardiac, or pulmonary tolerance. Rates of pulmonary symptom intensification and decrease in vital capacity (VC) increased progressively with elevation of inspired oxygen pressure. Although VC decrements occurred concurrently with symptoms, the lung volume changes became prominent when symptoms were still mild. The observed effects were consistent with the interpretation that small airway function is impaired more selectively by oxygen exposure at 3.0 and 2.5 ATA than by exposure at 2.0 and 1.5 ATA. Despite similar VC changes after oxygen exposure at 2.0 ATA for nearly 10 hr and exposure at 1.5 ATA for almost 18 hr, the 2.0 ATA exposure caused greater impairment of pulmonary function and required a longer recovery period.

Influenza Vaccination Coverage Rate according to the Pulmonary Function of Korean Adults Aged 40 Years and Over: Analysis of the Fifth Korean National Health and Nutrition Examination Survey

PubMed Central

2016-01-01

Influenza vaccination is an effective strategy to reduce morbidity and mortality, particularly for those who have decreased lung functions. This study was to identify the factors that affect vaccination coverage according to the results of pulmonary function tests depending on the age. In this cross-sectional study, data were obtained from 3,224 adults over the age of 40 who participated in the fifth National Health and Nutrition Examination Survey and underwent pulmonary function testing in 2012. To identify the factors that affect vaccination rate, logistic regression analysis was conducted after dividing the subjects into two groups based on the age of 65. Influenza vaccination coverage of the entire subjects was 45.2%, and 76.8% for those aged 65 and over. The group with abnormal pulmonary function had a higher vaccination rate than the normal group, but any pulmonary dysfunction or history of COPD did not affect the vaccination coverage in the multivariate analysis. The subjects who were 40-64 years-old had higher vaccination coverage when they were less educated or with restricted activity level, received health screenings, and had chronic diseases. Those aged 65 and over had significantly higher vaccination coverage only when they received regular health screenings. Any pulmonary dysfunction or having COPD showed no significant correlation with the vaccination coverage in the Korean adult population. PMID:27134491

Protocatechuic aldehyde ameliorates experimental pulmonary fibrosis by modulating HMGB1/RAGE pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Liang, E-mail: countryspring@sina.com; Ji, Yunxia, E-mail: 413499057@qq.com; Kang, Zechun, E-mail: davidjiangwl@163.com

An abnormal high mobility group box 1 (HMGB1) activation and a decrease in receptor for advanced glycation end-product (RAGE) play a key role in the pathogenesis of pulmonary fibrosis. Protocatechuic aldehyde (PA) is a naturally occurring compound, which is extracted from the degradation of phenolic acids. However, whether PA has anti-fibrotic functions is unknown. In this study, the effects of PA on the transforming growth factor-β1 (TGF-β1)-mediated epithelial–mesenchymal transition (EMT) in A549 cells, on the apoptosis of human type I alveolar epithelial cells (AT I), on the proliferation of human lung fibroblasts (HLF-1) in vitro, and on bleomycin (BLM)-induced pulmonarymore » fibrosis in vivo were investigated. PA treatment resulted in a reduction of EMT in A549 cells with a decrease in vimentin and HMGB, an increase of E-cadherin and RAGE, a reduction of HLF-1 proliferation with a decrease of fibroblast growth factor 2 (FGF-2) and platelet-derived growth factor (PDGF). Apoptosis of AT I was attenuated with an increase of RAGE. PA ameliorated BLM-induced pulmonary fibrosis in rats with a reduction of histopathological scores and collagen deposition, and a lower FGF-2, PDGF, α-smooth muscle actin (α-SMA) and HMGB1 expression, whereas higher RAGE was found in BLM-instilled lungs. Through the decrease of HGMB1 and the regulation of RAGE, PA reversed the EMT, inhibited HLF-1 proliferation as well as reduced apoptosis in AT I, and prevented pulmonary fibrosis in vivo. Collectively, our results demonstrate that PA prevents experimental pulmonary fibrosis by modulating HMGB1/RAGE pathway. - Highlights: • PA prevents EMT, reduces the apoptosis of AT1 in vitro. • PA decreases proliferation of HLF-1, reduces PDGF and FGF expression in vitro. • PA prevents experimental pulmonary fibrosis by modulating the HMGB1/RAGE pathway.« less

Differences in the effects of Asian dust on pulmonary function between adult patients with asthma and those with asthma–chronic obstructive pulmonary disease overlap syndrome

PubMed Central

Watanabe, Masanari; Noma, Hisashi; Kurai, Jun; Sano, Hiroyuki; Ueda, Yasuto; Mikami, Masaaki; Yamamoto, Hiroyuki; Tokuyasu, Hirokazu; Kato, Kazuhiro; Konishi, Tatsuya; Tatsukawa, Toshiyuki; Shimizu, Eiji; Kitano, Hiroya

2016-01-01

Background Asian dust (AD) exposure exacerbates pulmonary dysfunction in patients with asthma. Asthma–chronic obstructive pulmonary disease overlap syndrome (ACOS), characterized by coexisting symptoms of asthma and chronic obstructive pulmonary disease, is considered a separate disease entity. Previously, we investigated the effects of AD on pulmonary function in adult patients with asthma. Here, we present the findings of our further research on the differences in the effects of AD exposure on pulmonary function between patients with asthma alone and those with ACOS. Methods Between March and May 2012, we conducted a panel study wherein we monitored daily peak expiratory flow (PEF) values in 231 adult patients with asthma. These patients were divided into 190 patients with asthma alone and 41 patients with ACOS in this study. Daily AD particle levels were measured using light detection and ranging systems. Two heavy AD days (April 23 and 24) were determined according to the Japan Meteorological Agency definition. A linear mixed model was used to estimate the association between PEF and AD exposure. Results Increments in the interquartile range of AD particles (0.018 km−1) led to PEF changes of −0.50 L/min (95% confidence interval, −0.98 to −0.02) in patients with asthma alone and −0.11 L/min (−0.11 to 0.85) in patients with ACOS. The PEF changes after exposure to heavy AD were −2.21 L/min (−4.28 to −0.15) in patients with asthma alone and −2.76 L/min (−6.86 to 1.35) in patients with ACOS. In patients with asthma alone, the highest decrease in PEF values was observed on the heavy AD day, with a subsequent gradual increase over time. Conclusion Our results suggest that the effects of AD exposure on pulmonary function differ between patients with asthma alone and ACOS, with the former exhibiting a greater likelihood of decreased pulmonary function after AD exposure. PMID:26869784

[Analysis of factors related to pulmonary hypertensive crisis in patients with idiopathic pulmonary arterial hypertension].

PubMed

Zhang, Chen; Li, Qiangqiang; Zhu, Yan; Gu, Hong

2014-06-10

To explore the risk and protective factors for pulmonary hypertensive crisis (PHC) in patients with idiopathic pulmonary arterial hypertension (IPAH). A retrospective study was performed for 65 patients with a diagnosis of IPAH between January 2010 and December 2013. According to clinical manifestations, they were divided into two groups of susceptibility and non-susceptibility to PHC. Clinical and hemodynamic parameters were analyzed in univariate and multivariate manners. Among them, there were 32 males and 33 females with a mean age of (14.4 ± 12.3) (10/12-47.3) years. Twenty-three patients had typical manifestations of PHC and 18 of them were induced by exercises.Univariate analysis revealed that the proportion of patients with World Health Organization (WHO) functional class III-IV in PHC-susceptible group was significantly higher than PHC-nonsusceptible group (60.9% vs 23.8%, P = 0.003) while the percentage of patent foramen ovale in PHC-susceptible group was significantly lower than PHC-nonsusceptible group (8.7% vs 45.2%, P = 0.003).In patients with WHO functional classI-II, hemodynamic variables including the decline of pulmonary arterial pressure and positive rate in vasoreactivity testing in PHC-susceptible group were significantly higher than PHC-nonsusceptible group.In patients with WHO functional class III-IV, baseline pulmonary arterial pressure and mean right atrial pressure in PHC-susceptible group were significantly higher than those in PHC-nonsusceptible group. Multivariate Logistic regression analysis revealed that, for those with WHO functional class III-IV (OR = 23.45, 95%CI: 2.85-193.09) and the decline of systolic pulmonary arterial pressure in vasoreactivity testing (OR = 1.12, 95%CI: 1.04-1.22) were independent risk factors for PHC in IPAH patients while patent foramen ovale (OR = 0.01, 95%CI: 0.00-0.52) was a protective factor. PHC in IPAH patients is correlated with WHO functional class, pulmonary vascular reactivity, baseline pulmonary arterial pressure and patent foramen ovale. And exercise is the most common stimulus to PHC.

Lung function requirements in flying duty the problem of bronchial hyperresponsiveness in military aircrew.

PubMed

Hartmann, C M; Steinhoff-Lankes, D; Maya-Pelzer, P

1999-09-09

Uncompromised lung function is essential for fitness to fly. Under hypobaric conditions there is an increased risk of hypoxemia. G-forces, positive pressure breathing and anti-G maneuvers cause physical stress to the lung tissue and altered pulmonary blood flow. Breathing with pure oxygen, dry cabin air and ozone can cause airway irritation. Chemically and physically by irritating agents may be present. Emergencies such as smoke in the cockpit or inhalation of tear gas can rapidly compromise the pulmonary system in susceptible persons. Sudden incapacitation may occur. Trapped gases may cause overinflation and lung rupture in rapid decompression. Applicants for military duty have to pass basic lung function tests routinely. Preselection of aircrew candidates tends to be even stricter. Asthma and obstructive lung disease are disqualifying. Trained aircrew with late onset of pulmonary problems can be waived under certain restrictions in many cases. Some national regulations exclude even applicants with allergies. Due to aeromedical experience we should always be aware of the latent unspecific bronchial hyperresponsiveness (BHR). BHR is one of the characteristics of asthma bronchiale. If BHR exists there is an increased risk of later development of asthma bronchiale, especially together with perennial allergies such as against house dust mite. Under certain conditions BHR can become symptomatic and aeromedically relevant. In some cases we saw an exacerbation under medication, mostly under beta-receptor-blockers. In one case even under betablocker-containing eye drops. In the Gulf War 1991 a number of allied military personnel had to be withdrawn because of bronchospastic symptoms. This can be explained among others by medication with physostigmine. Physostigmine is a systemically active cholinergic drug which is prophylactically used under threat of chemically warfare agents. In individuals with latent BHR physostigmine will lower the threshold for bronchial reactions considerably and even cause manifest bronchospasm. We recommend an unspecific bronchial challenge test in the selection of personnel for duties where uncompromised lung function under all environmental conditions is essential.

Secondary Pulmonary Hypertension and Right-Sided Heart Failure at Presentation in Grave's Disease

PubMed Central

Ganeshpure, Swapnil Panjabrao; Vaidya, Gaurang Nandkishor; Gattani, Vipul

2012-01-01

A young female presented with evidence of right-sided heart failure and was subsequently found to have significant pulmonary artery hypertension (PAH). Because of her normal left ventricular function and pulmonary capillary wedge pressure, the most probable site of etiology seemed to be the pulmonary vasculature. All the common possible secondary causes of PAH were ruled out, but during the investigations, she was found to have elevated thyroid function tests compatible with the diagnosis of Grave's disease. The treatment of Grave's disease, initially by medications and subsequently by radioiodine therapy, was associated with a significant reduction in the pulmonary artery systolic pressure. The purpose of this case report is to highlight one of the unusual and underdiagnosed presentations of Grave's disease. PMID:23198182

Imaging-based assessment of dyspnea in cigarette smokers

NASA Astrophysics Data System (ADS)

Galvin, Jeffrey R.; Chang, Paul J.; Schwartz, David A.; Hunninghake, Gary W.; Helmers, Richard; Mori, Masaki

1994-05-01

Patients with pulmonary fibrosis frequently smoke cigarettes. The cause of dyspnea in these patients is often complex because of the coexistence of multiple disease processes. We investigated 10 cigarette smokers with pulmonary fibrosis who were referred for evaluation of new onset or worsening dyspnea. Chest radiographs and pulmonary function tests were obtained in addition to high-resolution computed tomography (HRCT). In those patients with HRCT evidence of both diseases, spirometry and lung volumes were most often normal. Although plain films provided a reasonable assessment of fibrosis, they underestimated the severity of emphysema. Quantitation of both emphysema and fibrosis by HRCT was reproducible and correlated with key pulmonary function tests. Our findings indicate that the HRCT scan is a useful diagnostic test in patients with pulmonary fibrosis who are also cigarette smokers.

Linking microbiota and respiratory disease.

PubMed

Hauptmann, Matthias; Schaible, Ulrich E

2016-11-01

An increasing body of evidence indicates the relevance of microbiota for pulmonary health and disease. Independent investigations recently demonstrated that the lung harbors a resident microbiota. Therefore, it is intriguing that a lung microbiota can shape pulmonary immunity and epithelial barrier functions. Here, we discuss the ways how the composition of the microbial community in the lung may influence pulmonary health and vice versa, factors that determine community composition. Prominent microbiota at other body sites such as the intestinal one may also contribute to pulmonary health and disease. However, it is difficult to discriminate between influences of lung vs. gut microbiota due to systemic mutuality between both communities. With focuses on asthma and respiratory infections, we discuss how microbiota of lung and gut can determine pulmonary immunity and barrier functions. © 2016 Federation of European Biochemical Societies.

New Concepts in the Invasive and Non Invasive Evaluation of Remodelling of the Right Ventricle and Pulmonary Vasculature in Pulmonary Arterial Hypertension

PubMed Central

Domingo, Enric; Aguilar, Rio; López-Meseguer, Manuel; Teixidó, Gisela; Vazquez, Manuel; Roman, Antonio

2009-01-01

Pulmonary arterial hypertension (PAH) is a rare fatal disease defined as a sustained elevation of pulmonary arterial pressure to more than 25 mmHg at rest, with a mean pulmonary-capillary wedge pressure and left ventricular enddiastolic pressure of less than 15 mmHg at rest. Histopathology of PAH is founded on structural modifications on the vascular wall of small pulmonary arteries characterized by thickening of all its layers. These changes, named as vascular remodelling, include vascular proliferation, fibrosis, and vessel obstruction. In clinical practice the diagnosis of PAH relies on measurements of pulmonary vascular pressure and cardiac output, and calculation of pulmonary vascular resistances. Direct evaluation of pulmonary vascular structure is not routinely performed in pulmonary hypertension since current imaging techniques are limited and since little is known about the relationship between structural changes and functional characteristics of the pulmonary vasculature. Intravascular ultrasound studies in patients with pulmonary hypertension have shown a thicker middle layer, increased wall-thickness ratio and diminished pulsatility than in control patients. Optical Coherence Tomography, a new high resolution imaging modality that has proven its superiority over intravascular ultrasound (IVUS) for the detection and characterization of coronary atherosclerotic plaque composition, may potentially be a useful technique for the in vivo study of the pulmonary arterial wall. In addition current progress in Echo Doppler technique will quantify right ventricular function with parameters independent of loading conditions and not requiring volumetric approximations of the complex geometry of the right ventricle. This would allow the in vivo study of right ventricular and pulmonary artery remodelling in PAH. PMID:19452037

Percutaneous Pulmonary Valve Placement

PubMed Central

Prieto, Lourdes R.

2015-01-01

Patients with congenital heart disease and pulmonary valve disease need multiple procedures over their lifetimes to replace their pulmonary valves. Chronic pulmonary stenosis, regurgitation, or both have untoward effects on ventricular function and on the clinical status of these patients. To date, all right ventricle–pulmonary artery conduits have had relatively short lifespans. Percutaneous pulmonary valve implantation, although relatively new, will probably reduce the number of operative procedures that these patients will have to undergo over a lifetime. Refinement and further development of this procedure holds promise for the extension of this technology to other patient populations. PMID:26175629

Integrative analyses of miRNA and proteomics identify potential biological pathways associated with onset of pulmonary fibrosis in the bleomycin rat model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fukunaga, Satoki; Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., 3-1-98 Kasugade-Naka, Konohana-ku, Osaka 554-8558; Kakehashi, Anna

To determine miRNAs and their predicted target proteins regulatory networks which are potentially involved in onset of pulmonary fibrosis in the bleomycin rat model, we conducted integrative miRNA microarray and iTRAQ-coupled LC-MS/MS proteomic analyses, and evaluated the significance of altered biological functions and pathways. We observed that alterations of miRNAs and proteins are associated with the early phase of bleomycin-induced pulmonary fibrosis, and identified potential target pairs by using ingenuity pathway analysis. Using the data set of these alterations, it was demonstrated that those miRNAs, in association with their predicted target proteins, are potentially involved in canonical pathways reflective ofmore » initial epithelial injury and fibrogenic processes, and biofunctions related to induction of cellular development, movement, growth, and proliferation. Prediction of activated functions suggested that lung cells acquire proliferative, migratory, and invasive capabilities, and resistance to cell death especially in the very early phase of bleomycin-induced pulmonary fibrosis. The present study will provide new insights for understanding the molecular pathogenesis of idiopathic pulmonary fibrosis. - Highlights: • We analyzed bleomycin-induced pulmonary fibrosis in the rat. • Integrative analyses of miRNA microarray and proteomics were conducted. • We determined the alterations of miRNAs and their potential target proteins. • The alterations may control biological functions and pathways in pulmonary fibrosis. • Our result may provide new insights of pulmonary fibrosis.« less

[Percutaneous closure of ductus arteriosus and muscular ventricular defect with amplatzer occluder in a patient with severe pulmonary hypertension].

PubMed

García-Montes, José Antonio; Zabal Cerdeira, Carlos; Calderón-Colmenero, Juan; Espínola, Nilda; Fernández de la Reguera, Guillermo; Buendía Hernández, Alfonso

2005-01-01

Surgical treatment of multiple muscular ventricular septal defects with associated lesions and severe pulmonary hypertension has a high morbility and mortality. Closure of these defects by the Amplatzer muscular VSD occluder is an alternative to surgery, avoiding the need of cardiopulmonary bypass. We present the case of a 38 year-old woman with signs of heart failure in NYHA functional class IV, with two muscular ventricular septal defects, patent ductus arteriosus and severe pulmonary hypertension, that were treated with three Amplatzer muscular VSD occluders, with significant reduction of pulmonary pressure and functional class improvement.

Recent lung imaging studies. [Effectiveness for diagnosis of chronic obstructive pulmonary disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Taplin, G.V.; Chopra, S.K.

1976-01-01

Radionuclide lung imaging procedures have been available for 11 years but only the perfusion examination has been used extensively and mainly for the diagnosis of pulmonary embolism (P.E.). Its ability to reveal localized ischemia makes it a valuable test of regional lung function as well as a useful diagnostic aid in P.E. Although it had been recognized for several years that chronic obstructive pulmonary disease (COPD) can cause lung perfusion defects which may simulate pulmonary embolism, relatively little use has been made of either the radioxenon or the radioaerosol inhalation lung imaging procedures until the last few years as amore » means of distinguishing P.E. from COPD. In this review emphasis is placed on our recent experience with both of these inhalation procedures in comparison with pulmonary function tests and roentgenography for the early detection of COPD in population studies. Equal emphasis is given to simultaneous aerosol ventilation-perfusion (V/P) imaging for a functional diagnosis of P.E. Two new developments in regional lung diffusion imaging, performed after the inhalation of radioactive gases and/or rapidly absorbed radioaerosols are described. The experimental basis for their potential clinical application in pulmonary embolism detection is presented.« less

Use of responder threshold criteria to evaluate the response to treatment in the phase III CHEST-1 study.

PubMed

D'Armini, Andrea M; Ghofrani, Hossein-Ardeschir; Kim, Nick H; Mayer, Eckhard; Morsolini, Marco; Pulido-Zamudio, Tomás; Simonneau, Gerald; Wilkins, Martin R; Curram, John; Davie, Neil; Hoeper, Marius M

2015-03-01

In the Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase - Stimulator Trial 1 (CHEST-1) study, riociguat improved 6-minute walking distance (6MWD) vs placebo in patients with inoperable chronic thromboembolic pulmonary hypertension or persistent/recurrent pulmonary hypertension after pulmonary endarterectomy. In this study, the proportion of patients who achieved responder thresholds that correlate with improved outcome in patients with pulmonary arterial hypertension was determined at baseline and at the end of CHEST-1. Patients received placebo or riociguat individually adjusted up to 2.5 mg 3 times a day for 16 weeks. Response criteria were defined as follows: 6MWD increase ≥40 m, 6MWD ≥380 m, cardiac index ≥2.5 liters/min/m(2), pulmonary vascular resistance <500 dyn∙sec∙cm(-5), mixed venous oxygen saturation ≥65%, World Health Organization functional class I/II, N-terminal pro-brain natriuretic peptide <1,800 pg/ml, and right atrial pressure <8 mm Hg. Riociguat increased the proportion of patients with 6MWD ≥380 m, World Health Organization functional class I/II, and pulmonary vascular resistance <500 dyn∙sec∙cm(-5) from 37%, 34%, and 25% at baseline to 58%, 57%, and 50% at Week 16, whereas there was little change in placebo-treated patients (6MWD ≥380 m, 43% vs 44%; World Health Organization functional class I/II, 29% vs 38%; pulmonary vascular resistance <500 dyn∙sec∙cm(-5), 27% vs 26%). Similar changes were observed for thresholds for cardiac index, mixed venous oxygen saturation, N-terminal pro-brain natriuretic peptide, and right atrial pressure. In this exploratory analysis, riociguat increased the proportion of patients with inoperable chronic thromboembolic pulmonary hypertension or persistent/recurrent pulmonary hypertension after pulmonary endarterectomy achieving criteria defining a positive response to therapy. Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Clinical characteristics of obesity-hypoventilation syndrome in Japan: a multi-center study.

PubMed

Akashiba, Tsuneto; Akahoshi, Toshiki; Kawahara, Seiji; Uematsu, Akihito; Katsura, Kazuhito; Sakurai, Shigeru; Murata, Akira; Sakakibara, Hiroki; Chin, Kazuo; Hida, Wataru; Nakamura, Hiroshi

2006-01-01

To clarify the prevalence and clinical characteristics of obesity-hypoventilation syndrome (OHS) in a large number of patients with moderate to severe obstructive sleep apnea syndrome (OSAS). Subjects comprised 611 patients with OSAS registered from 7 sleep centers and clinics and analyzed according to the definitions of the Respiratory Failure Research Group of the Japanese Ministry of Health and Welfare. Baseline characteristics, polysomnographic data during sleep, laboratory blood examinations, excessive daytime sleepiness, pulmonary functions, and arterial blood gases were compared between OHS and non-OHS patients. Determinants of daytime hypercapnia were also examined in OHS patients. OHS was identified in 55 of the 611 patients with OSAS (9%). OHS patients were younger, heavier, and more somnolent than non-OHS patients and displayed more severe OSAS, liver dysfunctions, higher total cholesterol, and impaired pulmonary function. However, these differences were resolved except for pulmonary function after correction for obesity. Daytime hypercapnia was associated with impaired pulmonary function. Percent vital capacity (%VC) was most closely correlated with PaCO2 in OHS. OHS patients display numerous abnormalities due to obesity compared with non-OHS patients. Impaired pulmonary function, particularly %VC, may play an important role in the development of daytime hypercapnia independent of obesity in OHS patients.

Pulmonary Screening in Subjects after the Fontan Procedure.

PubMed

Liptzin, Deborah R; Di Maria, Michael V; Younoszai, Adel; Narkewicz, Michael R; Kelly, Sarah L; Wolfe, Kelly R; Veress, Livia A

2018-05-07

To review the pulmonary findings of the first 51 patients who presented to our interdisciplinary single-ventricle clinic after undergoing the Fontan procedure. We performed an Institutional Review Board-approved retrospective review of 51 patients evaluated following the Fontan procedure. Evaluation included history, physical examination, pulmonary function testing, and 6-minute walk. Descriptive statistics were used to describe the population and testing data. Sixty-one percent of the patients had a pulmonary concern raised during the visit. Three patients had plastic bronchitis. Abnormal lung function testing was present in 46% of patients. Two-thirds (66%) of the patients had significant desaturation during the 6-minute walk test. Patients who underwent a fenestrated Fontan procedure and those who underwent unfenestrated Fontan were compared in terms of saturation and 6-minute walk test results. Sleep concerns were present in 45% of the patients. Pulmonary morbidities are common in patients after Fontan surgery and include plastic bronchitis, abnormal lung function, desaturations with walking, and sleep concerns. Abnormal lung function and obstructive sleep apnea may stress the Fontan circuit and may have implications for cognitive and emotional functioning. A pulmonologist involved in the care of patients after Fontan surgery can assist in screening for comorbidities and recommend interventions. Copyright © 2018 Elsevier Inc. All rights reserved.

Infection, inflammation, and lung function decline in infants with cystic fibrosis.

PubMed

Pillarisetti, Naveen; Williamson, Elizabeth; Linnane, Barry; Skoric, Billy; Robertson, Colin F; Robinson, Phil; Massie, John; Hall, Graham L; Sly, Peter; Stick, Stephen; Ranganathan, Sarath

2011-07-01

Better understanding of evolution of lung function in infants with cystic fibrosis (CF) and its association with pulmonary inflammation and infection is crucial in informing both early intervention studies aimed at limiting lung damage and the role of lung function as outcomes in such studies. To describe longitudinal change in lung function in infants with CF and its association with pulmonary infection and inflammation. Infants diagnosed after newborn screening or clinical presentation were recruited prospectively. FVC, forced expiratory volume in 0.5 seconds (FEV(0.5)), and forced expiratory flows at 75% of exhaled vital capacity (FEF(75)) were measured using the raised-volume technique, and z-scores were calculated from published reference equations. Pulmonary infection and inflammation were measured in bronchoalveolar lavage within 48 hours of lung function testing. Thirty-seven infants had at least two successful repeat lung function measurements. Mean (SD) z-scores for FVC were -0.8 (1.0), -0.9 (1.1), and -1.7 (1.2) when measured at the first visit, 1-year visit, or 2-year visit, respectively. Mean (SD) z-scores for FEV(0.5) were -1.4 (1.2), -2.4 (1.1), and -4.3 (1.6), respectively. In those infants in whom free neutrophil elastase was detected, FVC z-scores were 0.81 lower (P=0.003), and FEV(0.5) z-scores 0.96 lower (P=0.001), respectively. Significantly greater decline in FEV(0.5) z-scores occurred in those infected with Staphylococcus aureus (P=0.018) or Pseudomonas aeruginosa (P=0.021). In infants with CF, pulmonary inflammation is associated with lower lung function, whereas pulmonary infection is associated with a greater rate of decline in lung function. Strategies targeting pulmonary inflammation and infection are required to prevent early decline in lung function in infants with CF.

Pulmonary function, respiratory symptoms, and dust exposures among workers engaged in early manufacturing processes of tea: a cohort study.

PubMed

Shieh, Tzong-Shiun; Chung, Jui-Jung; Wang, Chung-Jing; Tsai, Perng-Jy; Kuo, Yau-Chang; Guo, How-Ran

2012-02-13

To evaluate pulmonary function and respiratory symptoms in workers engaged in the early manufacturing processes of tea and to identify the associated factors, we conducted a study in a tea production area in Taiwan. We recruited tea workers who engaged in the early manufacturing process in the Mountain Ali area in Taiwan and a comparison group of local office workers who were matched for age, gender, and smoking habits. We performed questionnaire interviews, pulmonary function tests, skin prick tests, and measurement of specific IgE for tea on the participants and assessed tea dust exposures in the tea factories. The 91 participating tea workers had higher prevalence of respiratory symptoms than the comparison group (32 participants). Among tea workers, ball-rolling workers had the highest prevalence of symptoms and the highest exposures of inhalable dusts. At baseline, tea workers had similar pulmonary functions as the comparison group, but compared to the other tea workers ball-rolling workers had a lower ratio of the 1-second forced expiratory volume to forced vital capacity (FEV1/FVC) and a lower maximal mid-expiratory flow rate expressed as% of the predicted value--MMF (%pred). A total of 58 tea workers participated in the on-site investigation and the cross-shift lung function measurements. We found ball-rolling yielded the highest inhalable dust level, panning yielded the highest respirable dust level, and withering yielded the lowest levels of both dusts. Ball-rolling also yielded the highest coarse fraction (defined as inhalable dusts minus respirable dusts), which represented exposures from nose to tracheobronchial tract. During the shift, we observed significant declines in pulmonary function, especially in ball-rolling workers. Multiple regressions showed that age, height, work tasks, coarse fraction, and number of months working in tea manufacturing each year were independent predictors of certain pulmonary function parameters in tea workers. Tea workers engaged in early manufacturing processes of tea have higher prevalence of respiratory symptoms and pulmonary function impairment, which might be related to tea dust exposures, especially the coarse fraction.

[Normal lung volumes in patients with idiopathic pulmonary fibrosis and emphysema].

PubMed

Casas, Juan Pablo; Abbona, Horacio; Robles, Adriana; López, Ana María

2008-01-01

Pulmonary function tests in idiopathic pulmonary fibrosis characteristically show a restrictive pattern, resulting from reduction of pulmonary compliance due to diffuse fibrosis. Conversely, an obstructive pattern with hyperinflation results in emphysema by loss of elastic recoil, expiratory collapse of the peripheral airways and air trapping. Previous reports suggest that when both diseases coexist, pulmonary volumes are compensated and a smaller than expected reduction or even normal lung volumes can be found. We report 4 male patients of 64, 60, 73 and 70 years, all with heavy cigarette smoking history and progressive breathlessness. Three of them had severe limitation in their quality of life. All four showed advanced lung interstitial involvement, at high resolution CT scan, fibrotic changes predominantly in the subpleural areas of lower lung fields and concomitant emphysema in the upper lobes. Emphysema and pulmonary fibrosis was confirmed by open lung biopsy in one patient. The four patients showed normal spirometry and lung volumes with severe compromise of gas exchange and poor exercise tolerance evaluated by 6 minute walk test. Severe pulmonary arterial hypertension was also confirmed in three patients. Normal lung volumes does not exclude diagnosis of idiopathic pulmonary fibrosis in patients with concomitant emphysema. The relatively preserved lung volumes may underestimate the severity of idiopathic pulmonary fibrosis and attenuate its effects on lung function parameters.

Haemophilus influenzae genome evolution during persistence in the human airways in chronic obstructive pulmonary disease.

PubMed

Pettigrew, Melinda M; Ahearn, Christian P; Gent, Janneane F; Kong, Yong; Gallo, Mary C; Munro, James B; D'Mello, Adonis; Sethi, Sanjay; Tettelin, Hervé; Murphy, Timothy F

2018-04-03

Nontypeable Haemophilus influenzae (NTHi) exclusively colonize and infect humans and are critical to the pathogenesis of chronic obstructive pulmonary disease (COPD). In vitro and animal models do not accurately capture the complex environments encountered by NTHi during human infection. We conducted whole-genome sequencing of 269 longitudinally collected cleared and persistent NTHi from a 15-y prospective study of adults with COPD. Genome sequences were used to elucidate the phylogeny of NTHi isolates, identify genomic changes that occur with persistence in the human airways, and evaluate the effect of selective pressure on 12 candidate vaccine antigens. Strains persisted in individuals with COPD for as long as 1,422 d. Slipped-strand mispairing, mediated by changes in simple sequence repeats in multiple genes during persistence, regulates expression of critical virulence functions, including adherence, nutrient uptake, and modification of surface molecules, and is a major mechanism for survival in the hostile environment of the human airways. A subset of strains underwent a large 400-kb inversion during persistence. NTHi does not undergo significant gene gain or loss during persistence, in contrast to other persistent respiratory tract pathogens. Amino acid sequence changes occurred in 8 of 12 candidate vaccine antigens during persistence, an observation with important implications for vaccine development. These results indicate that NTHi alters its genome during persistence by regulation of critical virulence functions primarily by slipped-strand mispairing, advancing our understanding of how a bacterial pathogen that plays a critical role in COPD adapts to survival in the human respiratory tract.

Endothelial function in pigs transgenic for human complement regulating factor.

PubMed

Warnecke, Gregor; Severson, Sandra R; Ugurlu, Mustafa M; Taner, Cemal B; Logan, John S; Diamond, Lisa E; Miller, Virginia M; McGregor, Christopher G A

2002-04-15

Expression of human complement regulating factor (hCRF) in porcine organs prevents hyperacute rejection of these organs after xenotransplantation to nonhuman primates. Experiments were designed to characterize endothelial and smooth muscle function of arteries from pigs transgenic for hCD46. Arterial blood from outbred pigs transgenic for hCD46 expression and nontransgenic animals of the same lineage was analyzed for angiotensin-converting enzyme (ACE), C-type natriuretic peptide (CNP), and nitric oxide. Aortic endothelial cells were prepared for measurement of mRNA or activity for nitric oxide synthase (NOS). Rings cut from femoral and pulmonary arteries were suspended in organ chambers for measurement of isometric tension. CNP was significantly greater, ACE was similar, and nitric oxide was significantly less in plasma from transgenic compared with nontransgenic pigs. Neither mRNA nor activity of NOS differed between the groups. Endothelium-dependent relaxations to bradykinin and acetylcholine but not the calcium ionophore were shifted significantly to the left in femoral and pulmonary arteries from hCD46 transgenic pigs compared with nontransgenic pigs. The ACE-inhibitor captopril augmented relaxations similarly in both groups, but NG-monomethyl-L-arginine (L-NMMA) did not inhibit relaxations in rings from transgenic pigs. Data suggest that expression of hCD46 on endothelium of pigs selectively augments endothelium-dependent relaxations to bradykinin by increased release of endothelium-derived factors other than nitric oxide. There does not seem to be any change in activity of ACE or NOS with expression of the human protein. Increased relaxations to bradykinin may be beneficial in lowering vascular resistance when transgenic organs are used for xenotransplantation.

mCLCA3 Modulates IL-17 and CXCL-1 Induction and Leukocyte Recruitment in Murine Staphylococcus aureus Pneumonia

PubMed Central

Dietert, Kristina; Reppe, Katrin; Mundhenk, Lars; Witzenrath, Martin; Gruber, Achim D.

2014-01-01

The human hCLCA1 and its murine ortholog mCLCA3 (calcium-activated chloride channel regulators) are exclusively expressed in mucus cells and linked to inflammatory airway diseases with increased mucus production, such as asthma, cystic fibrosis and chronic obstructive pulmonary disease. Both proteins have a known impact on the mucus cell metaplasia trait in these diseases. However, growing evidence points towards an additional role in innate immune responses. In the current study, we analyzed Staphylococcus aureus pneumonia, an established model to study pulmonary innate immunity, in mCLCA3-deficient and wild-type mice, focusing on the cellular and cytokine-driven innate inflammatory response. We compared clinical signs, bacterial clearance, leukocyte immigration and cytokine responses in the bronchoalveolar compartment, as well as pulmonary vascular permeability, histopathology, mucus cell number and mRNA expression levels of selected genes (mClca1 to 7, Muc5ac, Muc5b, Muc2, Cxcl-1, Cxcl-2, Il-17). Deficiency of mCLCA3 resulted in decreased neutrophilic infiltration into the bronchoalveolar space during bacterial infection. Only the cytokines IL-17 and the murine CXCL-8 homolog CXCL-1 were decreased on mRNA and protein levels during bacterial infection in mCLCA3-deficient mice compared to wild-type controls. However, no differences in clinical outcome, histopathology or mucus cell metaplasia were observed. We did not find evidence for regulation of any other CLCA homolog that would putatively compensate for the lack of mCLCA3. In conclusion, mCLCA3 appears to modulate leukocyte response via IL-17 and murine CXCL-8 homologs in acute Staphylococcus aureus pneumonia which is well in line with the proposed function of hCLCA1 as a signaling molecule acting on alveolar macrophages. PMID:25033194

Wilms' tumor 1 (Wt1) regulates pleural mesothelial cell plasticity and transition into myofibroblasts in idiopathic pulmonary fibrosis

PubMed Central

Karki, Suman; Surolia, Ranu; Hock, Thomas David; Guroji, Purusotham; Zolak, Jason S.; Duggal, Ryan; Ye, Tong; Thannickal, Victor J.; Antony, Veena B.

2014-01-01

Pleural mesothelial cells (PMCs), which are derived from the mesoderm, exhibit an extraordinary capacity to undergo phenotypic changes during development and disease. PMC transformation and trafficking has a newly defined role in idiopathic pulmonary fibrosis (IPF); however, the contribution of Wilms' tumor 1 (Wt1)-positive PMCs to the generation of pathognomonic myofibroblasts remains unclear. PMCs were obtained from IPF lung explants and healthy donor lungs that were not used for transplantation. Short hairpin Wt1-knockdown PMCs (sh Wt1) were generated with Wt1 shRNA, and morphologic and functional assays were performed in vitro. Loss of Wt1 abrogated the PMC phenotype and showed evidence of mesothelial-to-mesenchymal transition (MMT), with a reduced expression of E-cadherin and an increase in the profibrotic markers α-smooth muscle actin (α-SMA) and fibronectin, along with increased migration and contractility, compared with that of the control. Migration of PMCs in response to active transforming growth factor (TGF)-β1 was assessed by live-cell imaging with 2-photon microscopy and 3D imaging, of Wt1-EGFP transgenic mice. Lineage-tracing experiments to map the fate of Wt1+ PMCs in mouse lung in response to TGF-β1 were also performed by using a Cre-loxP system. Our results, for the first time, demonstrate that Wt1 is necessary for the morphologic integrity of pleural membrane and that loss of Wt1 contributes to IPF via MMT of PMCs into a myofibroblast phenotype.—Karki, S., Surolia, R., Hock, T. D., Guroji, P., Zolak, J. S., Duggal, R., Ye, T., Thannickal, V., J., Antony, V. B. Wilms' tumor 1 (Wt1) regulates pleural mesothelial cell plasticity and transition into myofibroblasts in idiopathic pulmonary fibrosis. PMID:24265486

A Case of Pulmonary Hypertension Due to Fistulas Between Multiple Systemic Arteries and the Right Pulmonary Artery in an Adult Discovered for Occulted Dyspnoea.

PubMed

Li, Ji-Feng; Zhai, Zhen-Guo; Kuang, Tu-Guang; Liu, Min; Ma, Zhan-Hong; Li, Yi-Dan; Yang, Yuan-Hua

2017-08-01

Pulmonary hypertension (PH) can be caused by a fistula between the systemic and pulmonary arteries. Here, we report a case of PH due to multiple fistulas between systemic arteries and the right pulmonary artery where the ventilation/perfusion scan showed no perfusion in the right lung. A 32-year-old male patient was hospitalised for community-acquired pneumonia. After treatment with antibiotics, the pneumonia was alleviated but dyspnoea persisted. Pulmonary hypertension was diagnosed using right heart catheterisation, which detected the mean pulmonary artery pressure as 37mmHg. The anomalies were confirmed by contrast-enhanced CT scan (CT pulmonary angiography), systemic arterial angiography and pulmonary angiography. Following embolisation of the largest fistula, the haemodynamics and oxygen dynamics did not improve, and even worsened to some extent. After supportive therapy including diuretics and oxygen, the patient's dyspnoea, WHO function class and right heart function by transthoracic echocardiography all improved during follow-up. Pulmonary hypertension can be present even when the right lung perfusion is lost. Closure of fistulas by embolisation, when those fistulas act as the proliferating vessels, may be harmful. Copyright © 2017 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.

Effects of home-based pulmonary rehabilitation with a metronome-guided walking pace in chronic obstructive pulmonary disease.

PubMed

Lee, Sung-soon; Kim, Changhwan; Jin, Young-Soo; Oh, Yeon-Mok; Lee, Sang-Do; Yang, Yun Jun; Park, Yong Bum

2013-05-01

Despite documented efficacy and recommendations, pulmonary rehabilitation (PR) in chronic obstructive pulmonary disease (COPD) has been underutilized. Home-based PR was proposed as an alternative, but there were limited data. The adequate exercise intensity was also a crucial issue. The aim of this study was to investigate the effects of home-based PR with a metronome-guided walking pace on functional exercise capacity and health-related quality of life (HRQOL) in COPD. The subjects participated in a 12-week home-based PR program. Exercise intensity was initially determined by cardiopulmonary exercise test, and was readjusted (the interval of metronome beeps was reset) according to submaximal endurance test. Six-minute walk test, pulmonary function test, cardiopulmonary exercise test, and St. George's Respiratory Questionnaire (SGRQ) were done before and after the 12-week program, and at 6 months after completion of rehabilitation. Thirty-three patients participated in the program. Six-minute walking distance was significantly increased (48.8 m; P = 0.017) and the SGRQ score was also improved (-15; P < 0.001) over the six-month follow-up period after rehabilitation. There were no significant differences in pulmonary function and peak exercise parameters. We developed an effective home-based PR program with a metronome-guided walking pace for COPD patients. This rehabilitation program may improve functional exercise capacity and HRQOL.

Use of milrinone to treat cardiac dysfunction in infants with pulmonary hypertension secondary to congenital diaphragmatic hernia: a review of six patients.

PubMed

Patel, Neil

2012-01-01

Pulmonary hypertension and secondary cardiac dysfunction are important contributors of morbidity and mortality in infants with congenital diaphragmatic hernia (CDH). Milrinone, a phosphodiesterase-3 inhibitor, may be useful in this setting for its combined actions as a pulmonary vasodilator and to improve systolic and diastolic function. This study aimed to assess the effects of milrinone on cardiac function and pulmonary artery pressure in infants with CDH. A retrospective review of echocardiograms performed on infants with CDH who received milrinone was performed. Tissue Doppler imaging velocities were used to assess systolic and diastolic function. Pulmonary artery pressure was assessed from the pattern and velocity of ductal shunting. Six infants with CDH and severe pulmonary hypertension were identified. Systolic and diastolic myocardial velocities were reduced in the right ventricle (RV) and interventricular septum (IVS) at baseline. In the 72 h after commencement of milrinone, there was a significant increase in early diastolic myocardial velocities in the RV, accompanied by increasing systolic velocities in the RV and IVS. Oxygenation index was significantly reduced, blood pressure unchanged, and ductal shunt velocity minimally altered over the same time period. Milrinone use was associated with an improvement in systolic and diastolic function in the RV, corresponding to an improvement in clinical status. Copyright © 2012 S. Karger AG, Basel.

The impact of bariatric surgery on pulmonary function: a meta-analysis.

PubMed

Alsumali, Adnan; Al-Hawag, Ali; Bairdain, Sigrid; Eguale, Tewodros

2018-02-01

Morbid obesity may affect several body systems and cause ill effects to the cardiovascular, hepatobiliary, endocrine, and mental health systems. However, the impact on the pulmonary system and pulmonary function has been debated in the literature. A systematic review and meta-analysis for studies that have evaluated the impact of bariatric surgery on pulmonary function were pooled for this analysis. PubMed, Cochrane, and Embase databases were evaluated through September 31, 2016. They were used as the primary search engine for studies evaluating the impact pre- and post-bariatric surgery on pulmonary function. Pooled effect estimates were calculated using random-effects model. Twenty-three studies with 1013 participants were included in the final meta-analysis. Only 8 studies had intervention and control groups with different time points, but 15 studies had matched groups with different time points. Overall, pulmonary function score was significantly improved after bariatric surgery, with a pooled standardized mean difference of .59 (95% confidence interval: .46-.73). Heterogeneity test was performed by using Cochran's Q test (I 2 = 46%; P heterogeneity = .10). Subgroup analysis and univariate meta-regression based on study quality, age, presurgery body mass index, postsurgery body mass index, study design, female patients only, study continent, asthmatic patients in the study, and the type of bariatric surgery confirmed no statistically significant difference among these groups (P value>.05 for all). A multivariate meta-regression model, which adjusted simultaneously for these same covariates, did not change the results (P value > .05 overall). Assessment of publication bias was done visually and by Begg's rank correlation test and indicated the absence of publication bias (asymmetric shape was observed and P = .34). This meta-analysis shows that bariatric surgery significantly improved overall pulmonary functions score for morbid obesity. Copyright © 2018 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.

Thoracic Epidural Anesthesia Reduces Right Ventricular Systolic Function With Maintained Ventricular-Pulmonary Coupling.

PubMed

Wink, Jeroen; de Wilde, Rob B P; Wouters, Patrick F; van Dorp, Eveline L A; Veering, Bernadette Th; Versteegh, Michel I M; Aarts, Leon P H J; Steendijk, Paul

2016-10-18

Blockade of cardiac sympathetic fibers by thoracic epidural anesthesia may affect right ventricular function and interfere with the coupling between right ventricular function and right ventricular afterload. Our main objectives were to study the effects of thoracic epidural anesthesia on right ventricular function and ventricular-pulmonary coupling. In 10 patients scheduled for lung resection, right ventricular function and its response to increased afterload, induced by temporary, unilateral clamping of the pulmonary artery, was tested before and after induction of thoracic epidural anesthesia using combined pressure-conductance catheters. Thoracic epidural anesthesia resulted in a significant decrease in right ventricular contractility (ΔESV 25 : +25.5 mL, P=0.0003; ΔEes: -0.025 mm Hg/mL, P=0.04). Stroke work, dP/dt MAX , and ejection fraction showed a similar decrease in systolic function (all P<0.05). A concomitant decrease in effective arterial elastance (ΔEa: -0.094 mm Hg/mL, P=0.004) yielded unchanged ventricular-pulmonary coupling. Cardiac output, systemic vascular resistance, and mean arterial blood pressure were unchanged. Clamping of the pulmonary artery significantly increased afterload (ΔEa: +0.226 mm Hg/mL, P<0.001). In response, right ventricular contractility increased (ΔESV 25 : -26.6 mL, P=0.0002; ΔEes: +0.034 mm Hg/mL, P=0.008), but ventricular-pulmonary coupling decreased (Δ(Ees/Ea) = -0.153, P<0.0001). None of the measured indices showed significant interactive effects, indicating that the effects of increased afterload were the same before and after thoracic epidural anesthesia. Thoracic epidural anesthesia impairs right ventricular contractility but does not inhibit the native positive inotropic response of the right ventricle to increased afterload. Right ventricular-pulmonary arterial coupling was decreased with increased afterload but not affected by the induction of thoracic epidural anesthesia. URL: http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2844. Unique identifier: NTR2844. © 2016 American Heart Association, Inc.

Pulmonary physiology during pulmonary embolism.

PubMed

Elliott, C G

1992-04-01

Acute pulmonary thromboembolism produces a number of pathophysiologic derangements of pulmonary function. Foremost among these alterations is increased pulmonary vascular resistance. For patients without preexistent cardiopulmonary disease, increased pulmonary vascular resistance is directly related to the degree of vascular obstruction demonstrated on the pulmonary arteriogram. Vasoconstriction, either reflexly or biochemically mediated, may contribute to increased pulmonary vascular resistance. Acute pulmonary thromboembolism also disturbs matching of ventilation and blood flow. Consequently, some lung units are overventilated relative to perfusion (increased dead space), while other lung units are underventilated relative to perfusion (venous admixture). True right-to-left shunting of mixed venous blood can occur through the lungs (intrapulmonary shunt) or across the atrial septum (intracardiac shunt). In addition, abnormalities of pulmonary gas exchange (carbon monoxide transfer), pulmonary compliance and airway resistance, and ventilatory control may accompany pulmonary embolism. Thrombolytic therapy can reverse the hemodynamic derangements of acute pulmonary thromboembolism more rapidly than anticoagulant therapy. Limited data suggest a sustained benefit of thrombolytic treatment on the pathophysiologic alterations of pulmonary vascular resistance and pulmonary gas exchange produced by acute pulmonary emboli.

A computer system for processing data from routine pulmonary function tests.

PubMed Central

Pack, A I; McCusker, R; Moran, F

1977-01-01

In larger pulmonary function laboratories there is a need for computerised techniques of data processing. A flexible computer system, which is used routinely, is described. The system processes data from a relatively large range of tests. Two types of output are produced--one for laboratory purposes, and one for return to the referring physician. The system adds an automatic interpretative report for each set of results. In developing the interpretative system it has been necessary to utilise a number of arbitrary definitions. The present terminology for reporting pulmonary function tests has limitations. The computer interpretation system affords the opportunity to take account of known interaction between measurements of function and different pathological states. Images PMID:329462

Pulmonary function and high-resolution computed tomography examinations among offshore drill floor workers.

PubMed

Kirkhus, Niels E; Skare, Øivind; Ulvestad, Bente; Aaløkken, Trond Mogens; Günther, Anne; Olsen, Raymond; Thomassen, Yngvar; Lund, May Brit; Ellingsen, Dag G

2018-04-01

The aim of this study was to assess short-term changes in pulmonary function in drill floor workers currently exposed to airborne contaminants generated as a result of drilling offshore. We also aimed to study the prevalence of pulmonary fibrosis using high-resolution computed tomography (HRCT) scans of another group of previously exposed drill floor workers. Pulmonary function was measured before and after a 14-day work period in a follow-up study of 65 drill floor workers and 65 referents. Additionally, 57 other drill floor workers exposed to drilling fluids during the 1980s were examined with HRCT of the lungs in a cross-sectional study. The drill floor workers had a statistically significant decline in forced expiratory volume in 1 s (FEV 1 ) across the 14-day work period after adjustment for diurnal variations in pulmonary function (mean 90 mL, range 30-140 mL), while the small decline among the referents (mean 20 mL, range - 30 to 70 mL) was not of statistical significance. Larger declines in FEV 1 among drill workers were associated with the fewer number of days of active drilling. There were no signs of pulmonary fibrosis related to oil mist exposure among the other previously exposed drill floor workers. After 14 days offshore, a statistically significant decline in FEV 1 was observed in the drill floor workers, which may not be related to oil mist exposure. No pulmonary fibrosis related to oil mist exposure was observed.

Physiologic assessment before video thoracoscopic resection for lung cancer in patients with abnormal pulmonary function.

PubMed

Benattia, Amira; Debeaumont, David; Guyader, Vincent; Tardif, Catherine; Peillon, Christophe; Cuvelier, Antoine; Baste, Jean-Marc

2016-06-01

Impaired respiratory function may prevent curative surgery for patients with non-small cell lung cancer (NSCLC). Video-assisted thoracoscopic surgery (VATS) reduces postoperative morbility-mortality and could change preoperative assessment practices and therapeutic decisions. We evaluated the relation between preoperative pulmonary function tests and the occurrence of postoperative complications after VATS pulmonary resection in patients with abnormal pulmonary function. We included 106 consecutive patients with ≤80% predicted value of presurgical expiratory volume in one second (FEV1) and/or diffusing capacity of carbon monoxide (DLCO) and who underwent VATS pulmonary resection for NSCLC from a prospective surgical database. Patients (64±9.5 years) had lobectomy (n=91), segmentectomy (n=7), bilobectomy (n=4), or pneumonectomy (n=4). FEV1 and DLCO preoperative averages were 68%±21% and 60%±18%. Operative mortality was 1.89%. Only FEV1 was predictive of postoperative complications [odds ratio (OR), 0.96; 95% confidence interval (CI), 0.926-0.991, P=0.016], but there was no determinable threshold. Twenty-five patients underwent incremental exercise testing. Desaturations during exercise (OR, 0.462; 95% CI, 0.191-0.878, P=0.039) and heart rate (HR) response (OR, 0.953; 95% CI, 0.895-0.993, P=0.05) were associated with postoperative complications. FEV1 but not DLCO was a significant predictor of pulmonary complications after VATS pulmonary resection despite a low rate of severe morbidity. Incremental exercise testing seems more discriminating. Further investigation is required in a larger patient population to change current pre-operative threshold in a new era of minimally invasive surgery.

Automated Quantitative Computed Tomography Versus Visual Computed Tomography Scoring in Idiopathic Pulmonary Fibrosis: Validation Against Pulmonary Function.

PubMed

Jacob, Joseph; Bartholmai, Brian J; Rajagopalan, Srinivasan; Kokosi, Maria; Nair, Arjun; Karwoski, Ronald; Raghunath, Sushravya M; Walsh, Simon L F; Wells, Athol U; Hansell, David M

2016-09-01

The aim of the study was to determine whether a novel computed tomography (CT) postprocessing software technique (CALIPER) is superior to visual CT scoring as judged by functional correlations in idiopathic pulmonary fibrosis (IPF). A total of 283 consecutive patients with IPF had CT parenchymal patterns evaluated quantitatively with CALIPER and by visual scoring. These 2 techniques were evaluated against: forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), diffusing capacity for carbon monoxide (DLco), carbon monoxide transfer coefficient (Kco), and a composite physiological index (CPI), with regard to extent of interstitial lung disease (ILD), extent of emphysema, and pulmonary vascular abnormalities. CALIPER-derived estimates of ILD extent demonstrated stronger univariate correlations than visual scores for most pulmonary function tests (PFTs): (FEV1: CALIPER R=0.29, visual R=0.18; FVC: CALIPER R=0.41, visual R=0.27; DLco: CALIPER R=0.31, visual R=0.35; CPI: CALIPER R=0.48, visual R=0.44). Correlations between CT measures of emphysema extent and PFTs were weak and did not differ significantly between CALIPER and visual scoring. Intriguingly, the pulmonary vessel volume provided similar correlations to total ILD extent scored by CALIPER for FVC, DLco, and CPI (FVC: R=0.45; DLco: R=0.34; CPI: R=0.53). CALIPER was superior to visual scoring as validated by functional correlations with PFTs. The pulmonary vessel volume, a novel CALIPER CT parameter with no visual scoring equivalent, has the potential to be a CT feature in the assessment of patients with IPF and requires further exploration.

Adenovirus vector expressing keratinocyte growth factor using CAG promoter impairs pulmonary function of mice with elastase-induced emphysema.

PubMed

Oki, Hiroshi; Yazawa, Takuya; Baba, Yasuko; Kanegae, Yumi; Sato, Hanako; Sakamoto, Seiko; Goto, Takahisa; Saito, Izumu; Kurahashi, Kiyoyasu

2017-07-01

Pulmonary emphysema impairs quality of life and increases mortality. It has previously been shown that administration of adenovirus vector expressing murine keratinocyte growth factor (KGF) before elastase instillation prevents pulmonary emphysema in mice. We therefore hypothesized that therapeutic administration of KGF would restore damage to lungs caused by elastase instillation and thus improve pulmonary function in an animal model. KGF expressing adenovirus vector, which prevented bleomycin-induced pulmonary fibrosis in a previous study, was constructed. Adenovirus vector (1.0 × 10 9 plaque-forming units) was administered intratracheally one week after administration of elastase into mouse lungs. One week after administration of KGF-vector, exercise tolerance testing and blood gas analysis were performed, after which the lungs were removed under deep anesthesia. KGF-positive pneumocytes were more numerous, surfactant protein secretion in the airspace greater and mean linear intercept of lungs shorter in animals that had received KGF than in control animals. Unexpectedly, however, arterial blood oxygenation was worse in the KGF group and maximum running speed, an indicator of exercise capacity, had not improved after KGF in mice with elastase-induced emphysema, indicating that KGF-expressing adenovirus vector impaired pulmonary function in these mice. Notably, vector lacking KGF-expression unit did not induce such impairment, implying that the KGF expression unit itself may cause the damage to alveolar cells. Possible involvement of the CAG promoter used for KGF expression in impairing pulmonary function is discussed. © 2017 The Societies and John Wiley & Sons Australia, Ltd.

Pulmonary Outcomes in Survivors of Childhood Cancer

PubMed Central

Hudson, Melissa M.; Stokes, Dennis C.; Krasin, Matthew J.; Spunt, Sheri L.; Ness, Kirsten K.

2011-01-01

Background: The purpose of this article is to summarize the literature that documents the long-term impact of cancer treatment modalities on pulmonary function among survivors of cancer and to identify potential areas for further research. Methods: Systematic reviews of clinical trials, observational studies, case series, and review articles were conducted. Articles were limited to the studies that discussed pulmonary toxicity or late effects among pediatric cancer survivors and to follow-up investigations that were conducted a minimum of 2 years after completion of cancer-related treatment or 1 year after hematopoietic stem cell transplant. Results: Sixty publications (51 clinical studies/reports and nine reviews) published from January 1970 to June 2010 in PubMed met the inclusion criteria. Data showed an association between radiotherapy, alkylating agents, bleomycin, hematopoietic stem cell transplant, and thoracic surgery and pulmonary toxicity, as well as possible interactions among these modalities. Conclusions: Pulmonary toxicity is a common long-term complication of exposure to certain anticancer therapies in childhood and can vary from subclinical to life threatening. Pulmonary function and associated loss of optimal exercise capacity may have adverse effects on long-term quality of life in survivors. Lung function diminishes as a function of normal aging, and the effects of early lung injury from cancer therapy may compound these changes. The information presented in this review is designed to provide a stimulus to promote both observational and interventional research that expands our knowledge and aids in the design of interventions to prevent or ameliorate pulmonary late effects among survivors of childhood cancer. PMID:21415131

Using Operational Analysis to Improve Access to Pulmonary Function Testing.

PubMed

Ip, Ada; Asamoah-Barnieh, Raymond; Bischak, Diane P; Davidson, Warren J; Flemons, W Ward; Pendharkar, Sachin R

2016-01-01

Background. Timely pulmonary function testing is crucial to improving diagnosis and treatment of pulmonary diseases. Perceptions of poor access at an academic pulmonary function laboratory prompted analysis of system demand and capacity to identify factors contributing to poor access. Methods. Surveys and interviews identified stakeholder perspectives on operational processes and access challenges. Retrospective data on testing demand and resource capacity was analyzed to understand utilization of testing resources. Results. Qualitative analysis demonstrated that stakeholder groups had discrepant views on access and capacity in the laboratory. Mean daily resource utilization was 0.64 (SD 0.15), with monthly average utilization consistently less than 0.75. Reserved testing slots for subspecialty clinics were poorly utilized, leaving many testing slots unfilled. When subspecialty demand exceeded number of reserved slots, there was sufficient capacity in the pulmonary function schedule to accommodate added demand. Findings were shared with stakeholders and influenced scheduling process improvements. Conclusion. This study highlights the importance of operational data to identify causes of poor access, guide system decision-making, and determine effects of improvement initiatives in a variety of healthcare settings. Importantly, simple operational analysis can help to improve efficiency of health systems with little or no added financial investment.

Transient Receptor Potential Channels in the Vasculature

PubMed Central

Earley, Scott; Brayden, Joseph E.

2015-01-01

The mammalian genome encodes 28 distinct members of the transient receptor potential (TRP) superfamily of cation channels, which exhibit varying degrees of selectivity for different ionic species. Multiple TRP channels are present in all cells and are involved in diverse aspects of cellular function, including sensory perception and signal transduction. Notably, TRP channels are involved in regulating vascular function and pathophysiology, the focus of this review. TRP channels in vascular smooth muscle cells participate in regulating contractility and proliferation, whereas endothelial TRP channel activity is an important contributor to endothelium-dependent vasodilation, vascular wall permeability, and angiogenesis. TRP channels are also present in perivascular sensory neurons and astrocytic endfeet proximal to cerebral arterioles, where they participate in the regulation of vascular tone. Almost all of these functions are mediated by changes in global intracellular Ca2+ levels or subcellular Ca2+ signaling events. In addition to directly mediating Ca2+ entry, TRP channels influence intracellular Ca2+ dynamics through membrane depolarization associated with the influx of cations or through receptor- or store-operated mechanisms. Dysregulation of TRP channels is associated with vascular-related pathologies, including hypertension, neointimal injury, ischemia-reperfusion injury, pulmonary edema, and neurogenic inflammation. In this review, we briefly consider general aspects of TRP channel biology and provide an in-depth discussion of the functions of TRP channels in vascular smooth muscle cells, endothelial cells, and perivascular cells under normal and pathophysiological conditions. PMID:25834234

TLR4 deficiency promotes autophagy during cigarette smoke-induced pulmonary emphysema.

PubMed

An, Chang Hyeok; Wang, Xiao Mei; Lam, Hilaire C; Ifedigbo, Emeka; Washko, George R; Ryter, Stefan W; Choi, Augustine M K

2012-11-01

Toll-like receptors (TLRs) exert important nonimmune functions in lung homeostasis. TLR4 deficiency promotes pulmonary emphysema. We examined the role of TLR4 in regulating cigarette smoke (CS)-induced autophagy, apoptosis, and emphysema. Lung tissue was obtained from chronic obstructive lung disease (COPD) patients. C3H/HeJ (Tlr4-mutated) mice and C57BL/10ScNJ (Tlr4-deficient) mice and their respective control strains were exposed to chronic CS or air. Human or mouse epithelial cells (wild-type, Tlr4-knockdown, and Tlr4-deficient) were exposed to CS-extract (CSE). Samples were analyzed for TLR4 expression, and for autophagic or apoptotic proteins by Western blot analysis or confocal imaging. Chronic obstructive lung disease lung tissues and human pulmonary epithelial cells exposed to CSE displayed increased TLR4 expression, and increased autophagic [microtubule-associated protein-1 light-chain-3B (LC3B)] and apoptotic (cleaved caspase-3) markers. Beas-2B cells transfected with TLR4 siRNA displayed increased expression of LC3B relative to control cells, basally and after exposure to CSE. The basal and CSE-inducible expression of LC3B and cleaved caspase-3 were elevated in pulmonary alveolar type II cells from Tlr4-deficient mice. Wild-type mice subjected to chronic CS-exposure displayed airspace enlargement;, however, the Tlr4-mutated or Tlr4-deficient mice exhibited a marked increase in airspace relative to wild-type mice after CS-exposure. The Tlr4-mutated or Tlr4-deficient mice showed higher levels of LC3B under basal conditions and after CS exposure. The expression of cleaved caspase-3 was markedly increased in Tlr4-deficient mice exposed to CS. We describe a protective regulatory function of TLR4 against emphysematous changes of the lung in response to CS.

TLR4 deficiency promotes autophagy during cigarette smoke-induced pulmonary emphysema

PubMed Central

An, Chang Hyeok; Wang, Xiao Mei; Lam, Hilaire C.; Ifedigbo, Emeka; Washko, George R.; Ryter, Stefan W.

2012-01-01

Toll-like receptors (TLRs) exert important nonimmune functions in lung homeostasis. TLR4 deficiency promotes pulmonary emphysema. We examined the role of TLR4 in regulating cigarette smoke (CS)-induced autophagy, apoptosis, and emphysema. Lung tissue was obtained from chronic obstructive lung disease (COPD) patients. C3H/HeJ (Tlr4-mutated) mice and C57BL/10ScNJ (Tlr4-deficient) mice and their respective control strains were exposed to chronic CS or air. Human or mouse epithelial cells (wild-type, Tlr4-knockdown, and Tlr4-deficient) were exposed to CS-extract (CSE). Samples were analyzed for TLR4 expression, and for autophagic or apoptotic proteins by Western blot analysis or confocal imaging. Chronic obstructive lung disease lung tissues and human pulmonary epithelial cells exposed to CSE displayed increased TLR4 expression, and increased autophagic [microtubule-associated protein-1 light-chain-3B (LC3B)] and apoptotic (cleaved caspase-3) markers. Beas-2B cells transfected with TLR4 siRNA displayed increased expression of LC3B relative to control cells, basally and after exposure to CSE. The basal and CSE-inducible expression of LC3B and cleaved caspase-3 were elevated in pulmonary alveolar type II cells from Tlr4-deficient mice. Wild-type mice subjected to chronic CS-exposure displayed airspace enlargement;, however, the Tlr4-mutated or Tlr4-deficient mice exhibited a marked increase in airspace relative to wild-type mice after CS-exposure. The Tlr4-mutated or Tlr4-deficient mice showed higher levels of LC3B under basal conditions and after CS exposure. The expression of cleaved caspase-3 was markedly increased in Tlr4-deficient mice exposed to CS. We describe a protective regulatory function of TLR4 against emphysematous changes of the lung in response to CS. PMID:22983353

Inhalation exposure of rats to asphalt fumes generated at paving temperatures alters pulmonary xenobiotic metabolism pathways without lung injury.

PubMed Central

Ma, Jane Y C; Rengasamy, Apavoo; Frazer, Dave; Barger, Mark W; Hubbs, Ann F; Battelli, Lori; Tomblyn, Seith; Stone, Samuel; Castranova, Vince

2003-01-01

Asphalt fumes are complex mixtures of various organic compounds, including polycyclic aromatic hydrocarbons (PAHs). PAHs require bioactivation by the cytochrome P-450 monooxygenase system to exert toxic/carcinogenic effects. The present study was carried out to characterize the acute pulmonary inflammatory responses and the alterations of pulmonary xenobiotic pathways in rats exposed to asphalt fumes by inhalation. Rats were exposed at various doses and time periods to air or to asphalt fumes generated at paving temperatures. To assess the acute damage and inflammatory responses, differential cell counts, acellular lactate dehydrogenase (LDH) activity, and protein content of bronchoalveolar lavage fluid were determined. Alveolar macrophage (AM) function was assessed by monitoring generation of chemiluminescence and production of tumor necrosis factor-alpha and interleukin-1. Alteration of pulmonary xenobiotic pathways was determined by monitoring the protein levels and activities of P-450 isozymes (CYP1A1 and CYP2B1), glutathioneS-transferase (GST), and NADPH:quinone oxidoreductase (QR). The results show that acute asphalt fume exposure did not cause neutrophil infiltration, alter LDH activity or protein content, or affect AM function, suggesting that short-term asphalt fume exposure did not induce acute lung damage or inflammation. However, acute asphalt fume exposure significantly increased the activity and protein level of CYP1A1 whereas it markedly reduced the activity and protein level of CYP2B1 in the lung. The induction of CYP1A1 was localized in nonciliated bronchiolar epithelial (Clara) cells, alveolar septa, and endothelial cells by immunofluorescence microscopy. Cytosolic QR activity was significantly elevated after asphalt fume exposure, whereas GST activity was not affected by the exposure. This induction of CYP1A1 and QR with the concomitant down-regulation of CYP2B1 after asphalt fume exposure could alter PAH metabolism and may lead to potential toxic effects in the lung. PMID:12842776

The purinergic receptor subtype P2Y2 mediates chemotaxis of neutrophils and fibroblasts in fibrotic lung disease

PubMed Central

Karmouty-Quintana, Harry; Cicko, Sanja; Ayata, Korcan; Zissel, Gernot; Goldmann, Torsten; Lungarella, Giuseppe; Ferrari, Davide; Di Virgilio, Francesco; Robaye, Bernard; Boeynaems, Jean-Marie; Blackburn, Michael R.; Idzko, Marco

2017-01-01

Idiopathic pulmonary fibrosis (IPF) is a devastating disease with few available treatment options. Recently, the involvement of purinergic receptor subtypes in the pathogenesis of different lung diseases has been demonstrated. Here we investigated the role of the purinergic receptor subtype P2Y2 in the context of fibrotic lung diseases. The concentration of different nucleotides was measured in the broncho-alveolar lavage (BAL) fluid derived from IPF patients and animals with bleomycin-induced pulmonary fibrosis. In addition expression of P2Y2 receptors by different cell types was determined. To investigate the functional relevance of P2Y2 receptors for the pathogenesis of the disease the bleomycin model of pulmonary fibrosis was used. Finally, experiments were performed in pursuit of the involved mechanisms. Compared to healthy individuals or vehicle treated animals, extracellular nucleotide levels in the BAL fluid were increased in patients with IPF and in mice after bleomycin administration, paralleled by a functional up-regulation of P2Y2R expression. Both bleomycin-induced inflammation and fibrosis were reduced in P2Y2R-deficient compared to wild type animals. Mechanistic studies demonstrated that recruitment of neutrophils into the lungs, proliferation and migration of lung fibroblasts as well as IL6 production are key P2Y2R mediated processes. Our results clearly demonstrate the involvement of P2Y2R subtypes in the pathogenesis of fibrotic lung diseases in humans and mice and hence support the development of selective P2Y2R antagonists for the treatment of IPF. PMID:28415591

Correction of nonsense BMPR2 and SMAD9 mutations by ataluren in pulmonary arterial hypertension.

PubMed

Drake, Kylie M; Dunmore, Benjamin J; McNelly, Lauren N; Morrell, Nicholas W; Aldred, Micheala A

2013-09-01

Heritable pulmonary arterial hypertension (HPAH) is a serious lung vascular disease caused by heterozygous mutations in the bone morphogenetic protein (BMP) pathway genes, BMPR2 and SMAD9. One noncanonical function of BMP signaling regulates biogenesis of a subset of microRNAs. We have previously shown that this function is abrogated in patients with HPAH, making it a highly sensitive readout of BMP pathway integrity. Ataluren (PTC124) is an investigational drug that permits ribosomal readthrough of premature stop codons, resulting in a full-length protein. It exhibits oral bioavailability and limited toxicity in human trials. Here, we tested ataluren in lung- or blood-derived cells from patients with HPAH with nonsense mutations in BMPR2 (n = 6) or SMAD9 (n = 1). Ataluren significantly increased BMP-mediated microRNA processing in six of the seven cases. Moreover, rescue was achieved even for mutations exhibiting significant nonsense-mediated mRNA decay. Response to ataluren was dose dependent, and complete correction was achieved at therapeutic doses currently used in clinical trials for cystic fibrosis. BMP receptor (BMPR)-II protein levels were normalized and ligand-dependent phosphorylation of downstream target Smads was increased. Furthermore, the usually hyperproliferative phenotype of pulmonary artery endothelial and smooth muscle cells was reversed by ataluren. These results indicate that ataluren can effectively suppress a high proportion of BMPR2 and SMAD9 nonsense mutations and correct BMP signaling in vitro. Approximately 29% of all HPAH mutations are nonsense point mutations. In light of this, we propose ataluren as a potential new personalized therapy for this significant subgroup of patients with PAH.

Effect of re-expansion after short-period lung collapse on pulmonary capillary permeability and pro-inflammatory cytokine gene expression in isolated rabbit lungs.

PubMed

Funakoshi, T; Ishibe, Y; Okazaki, N; Miura, K; Liu, R; Nagai, S; Minami, Y

2004-04-01

Re-expansion pulmonary oedema is a rare complication caused by rapid re-expansion of a chronically collapsed lung. Several cases of pulmonary oedema associated with one-lung ventilation (OLV) have been reported recently. Elevated levels of pro-inflammatory cytokines in pulmonary oedema fluid are suggested to play important roles in its development. Activation of cytokines after re-expansion of collapsed lung during OLV has not been thoroughly investigated. Here we investigated the effects of re-expansion of the collapsed lung on pulmonary oedema formation and pro-inflammatory cytokine expression. Lungs isolated from female white Japanese rabbits were perfused and divided into a basal (BAS) group (n=7, baseline measurement alone), a control (CONT) group (n=9, ventilated without lung collapse for 120 min) and an atelectasis (ATEL) group (n=9, lung collapsed for 55 min followed by re-expansion and ventilation for 65 min). Pulmonary vascular resistance (PVR) and the coefficient of filtration (Kfc) were measured at baseline and 60 and 120 min. At the end of perfusion, bronchoalveolar lavage fluid/plasma protein ratio (B/P), wet/dry lung weight ratio (W/D) and mRNA expressions of tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta and myeloperoxidase (MPO) were determined. TNF-alpha and IL-1beta mRNA were significantly up-regulated in lungs of the ATEL group compared with BAS and CONT, though no significant differences were noted in PVR, Kfc, B/P and W/D within and between groups. MPO increased at 120 min in CONT and ATEL groups. Pro-inflammatory cytokines were up-regulated upon re-expansion and ventilation after short-period lung collapse, though no changes were noted in pulmonary capillary permeability.

Repurposing rosiglitazone, a PPAR-γ agonist and oral antidiabetic, as an inhaled formulation, for the treatment of PAH.

PubMed

Rashid, Jahidur; Alobaida, Ahmad; Al-Hilal, Taslim A; Hammouda, Samia; McMurtry, Ivan F; Nozik-Grayck, Eva; Stenmark, Kurt R; Ahsan, Fakhrul

2018-06-28

Peroxisome-proliferator-activated-receptor-gamma (PPAR-γ) is implicated, in some capacity, in the pathogenesis of pulmonary arterial hypertension (PAH). Rosiglitazone, an oral antidiabetic and PPAR-γ agonist, has the potential to dilate pulmonary arteries and to attenuate arterial remodeling in PAH. Here, we sought to test the hypothesis that rosiglitazone can be repurposed as inhaled formulation for the treatment of PAH. We have tested this conjecture by preparing and optimizing poly(lactic-co-glycolic) acid (PLGA) based particles of rosiglitazone, assessing the drug particles for pulmonary absorption, investigating the efficacy of the plain versus particulate drug formulation in improving the respiratory hemodynamics in PAH animals, and finally studying the effect of the drug in regulating the molecular markers associated with PAH pathogenesis. The optimized particles were slightly porous and spherical, and released 87.9% ± 6.7% of the drug in 24 h. The elimination half-life of the drug formulated in PLGA particles was 2.5-fold greater than that of the plain drug administered via the same route at the same dose. The optimized formulation, given via the pulmonary route, produced pulmonary selective vasodilation in PAH animals, but oral rosiglitazone had no effect in pulmonary hemodynamics. Rosiglitazone ameliorates the pathogenesis of PAH by balancing the molecular regulators involved in the vasoconstriction and vasodilation of human pulmonary arterial smooth muscle cells. All in all, data generated using intact animal and cellular models point to the conclusion that PLGA particles of an antidiabetic drug can be used for the treatment of a different disease, PAH. Copyright © 2018 Elsevier B.V. All rights reserved.

Lung imaging in pulmonary disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Taplin, G.V.; Chopra, S.K.

1976-01-01

Although it has been recognized for several years that chronic obstructive pulmonary disease (COPD) can cause lung perfusion defects which may simulate pulmonary embolism, relatively little use has been made of either the radioxenon or the radioaerosol inhalation lung imaging procedures until the last few years as a means of distinguishing pulmonary embolism (P.E.) from COPD is reported. Recent experience is reported with the use of both of these procedures in comparison with pulmonary function tests for the early detection of COPD in population studies and also in P.E. suspects. Equal emphasis is given to simultaneous aerosol ventilation-perfusion (V/P) imagingmore » in the differential diagnosis of P.E. Finally, this paper is concerned with new developments in regional lung diffusion imaging following the inhalation of radioactive gases and rapidly absorbed radioaerosols. Their experimental basis is presented and their potential clinical applications in pulmonary embolism are discussed. As a result of these investigations, a functional (V/P) diagnosis of pulmonary embolism in patients may be possible in the near future with a sequential radioaerosol inhalation procedure alone.« less

The angiogenic related functions of bone marrow mesenchymal stem cells are promoted by CBDL rat serum via the Akt/Nrf2 pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shen, Cheng-Cheng; Chen, Bing; Gu, Jian-Teng

Hepatopulmonary syndrome (HPS) is a complication of severe liver disease. It is characterized by an arterial oxygenation defect. Recent studies have demonstrated that pulmonary angiogenesis contributes to the abnormal gas exchange found in HPS. Additionally, mesenchymal stem cells (MSCs) are considered the stable source of VEGF-producing cells and have the potential to differentiate into multiple cell types. However, it has not been determined whether bone marrow mesenchymal stem cells (BM-MSCs) are mobilized and involved in the pulmonary angiogenesis in HPS. In this study, a CFU-F assay showed that the number of peripheral blood MSCs was increased in common bile ductmore » ligation (CBDL) rats; however, there was no significant difference found in the number of BM-MSCs. In vitro, CBDL rat serum induced the overexpression of CXCR4 and PCNA in BM-MSCs. Consistently, the directional migration as well as the proliferation ability of BM-MSCs were enhanced by CBDL rat serum, as determined by a transwell migration and MTT assays. Moreover, the secretion of VEGF by BM-MSCs increased after treatment with CBDL rat serum. We also found that the expression of phospho-Akt, phospho-ERK, and Nrf2 in BM-MSCs was significantly up-regulated by CBDL rat serum in a time dependent manner, and the blockage of the Akt/Nrf2 signalling pathway with an Akt Inhibitor or Nrf2 siRNA, instead of an ERK inhibitor, attenuated the migration, proliferation and paracrine capacity of BM-MSCs. In conclusion, these findings indicated that the number of MSCs increased in the peripheral blood of CBDL rats, and the Akt/Nrf2 pathway plays a vital role in promoting the angiogenic related functions of BM-MSCs, which could be a potent contributor to pulmonary angiogenesis in HPS. - Highlights: • Peripheral blood MSCs was increased in CBDL rats; however, the difference found for the number of BM-MSCs was not significant. • The directional migration, proliferation and ability to secrete VEGF of BM-MSCs were enhanced by CBDL rat serum. • The Akt/Nrf2 instead of ERK/Nrf2 pathway regulates the angiogenic related functions of BM-MSCs.« less

Effects of Aerobic Exercise Applied Early After Coronary Artery Bypass Grafting on Pulmonary Function, Respiratory Muscle Strength, and Functional Capacity: A Randomized Controlled Trial.

PubMed

Borges, Daniel L; Silva, Mayara Gabrielle; Silva, Luan Nascimento; Fortes, João Vyctor; Costa, Erika Thalita; Assunção, Rebeca Pessoa; Lima, Carlos Magno; da Silva Nina, Vinícius José; Bernardo-Filho, Mário; Caputo, Danúbia Sá

2016-09-01

Physical activity is beneficial in several clinical situations and recommended for patients with ischemic heart disease, as well as for those undergoing cardiac surgery. In a randomized controlled trial, 34 patients underwent coronary artery bypass grafting. A randomized control group (n = 15) submitted to conventional physiotherapy. The intervention group (n = 19) received the same protocol plus additional aerobic exercise with cycle ergometer. Pulmonary function by spirometry, respiratory muscle strength by manovacuometry, and functional capacity through 6-minute walking test was assessed before surgery and at hospital discharge. There was significant reduction in pulmonary function in both groups. In both groups, inspiratory muscle strength was maintained while expiratory muscle strength significantly decreased. Functional capacity was maintained in the intervention group (364.5 [324.5 to 428] vs. 348 [300.7 to 413.7] meters, P = .06), but it decreased significantly in control group patients (320 [288.5 to 393.0] vs. 292 [237.0 to 336.0] meters, P = .01). A significant difference in functional capacity was also found in intergroup analyses at hospital discharge (P = .03). Aerobic exercise applied early on coronary artery bypass grafting patients may promote maintenance of functional capacity, with no impact on pulmonary function and respiratory muscle strength when compared with conventional physiotherapy.

Fibroblast growth factor 10 haploinsufficiency causes chronic obstructive pulmonary disease.

PubMed

Klar, Joakim; Blomstrand, Peter; Brunmark, Charlott; Badhai, Jitendra; Håkansson, Hanna Falk; Brange, Charlotte Sollie; Bergendal, Birgitta; Dahl, Niklas

2011-10-01

Genetic factors influencing lung function may predispose to chronic obstructive pulmonary disease (COPD). The fibroblast growth factor 10 (FGF10) signalling pathway is critical for lung development and lung epithelial renewal. The hypothesis behind this study was that constitutive FGF10 insufficiency may lead to pulmonary disorder. Therefore investigation of the pulmonary functions of patients heterozygous for loss of function mutations in the FGF10 gene was performed. The spirometric measures of lung function from patients and non-carrier siblings were compared and both groups were related to matched reference data for normal human lung function. The patients show a significant decrease in lung function parameters when compared to control values. The average FEV1/IVC quota (FEV1%) for the patients is 0.65 (80% of predicted) and reversibility test using Terbutalin resulted in a 3.7% increase in FEV1. Patients with FGF10 haploinsufficiency have lung function parameters indicating COPD. A modest response to Terbutalin confirms an irreversible obstructive lung disease. These findings support the idea that genetic variants affecting the FGF10 signalling pathway are important determinants of lung function that may ultimately contribute to COPD. Specifically, the results show that FGF10 haploinsufficiency affects lung function measures providing a model for a dosage sensitive effect of FGF10 in the development of COPD.

Innate Lymphoid Cells: A Promising New Regulator in Fibrotic Diseases.

PubMed

Zhang, Yi; Tang, Jun; Tian, Zhiqiang; van Velkinburgh, Jennifer C; Song, Jianxun; Wu, Yuzhang; Ni, Bing

2016-09-02

Fibrosis is a consequence of chronic inflammation and the persistent accumulation of extracellular matrix, for which the cycle of tissue injury and repair becomes a predominant feature. Both the innate and adaptive immune systems play key roles in the progress of fibrosis. The recently identified subsets of innate lymphoid cells (ILCs), which are mainly localize to epithelial surfaces, have been characterized as regulators of chronic inflammation and tissue remodeling, representing a functional bridge between the innate and adaptive immunity. Moreover, recent research has implicated ILCs as potential contributing factors to several kinds of fibrosis diseases, such as hepatic fibrosis and pulmonary fibrosis. Here, we will summarize and discuss the key roles of ILCs and their related factors in fibrotic diseases and their potential for translation to the clinic.

Loss of the DNA Damage Repair Kinase ATM Impairs Inflammasome-Dependent Anti-Bacterial Innate Immunity.

PubMed

Erttmann, Saskia F; Härtlova, Anetta; Sloniecka, Marta; Raffi, Faizal A M; Hosseinzadeh, Ava; Edgren, Tomas; Rofougaran, Reza; Resch, Ulrike; Fällman, Maria; Ek, Torben; Gekara, Nelson O

2016-07-19

The ATM kinase is a central component of the DNA damage repair machinery and redox balance. ATM dysfunction results in the multisystem disease ataxia-telangiectasia (AT). A major cause of mortality in AT is respiratory bacterial infections. Whether ATM deficiency causes innate immune defects that might contribute to bacterial infections is not known. Here we have shown that loss of ATM impairs inflammasome-dependent anti-bacterial innate immunity. Cells from AT patients or Atm(-/-) mice exhibited diminished interleukin-1β (IL-1β) production in response to bacteria. In vivo, Atm(-/-) mice were more susceptible to pulmonary S. pneumoniae infection in a manner consistent with inflammasome defects. Our data indicate that such defects were due to oxidative inhibition of inflammasome complex assembly. This study reveals an unanticipated function of reactive oxygen species (ROS) in negative regulation of inflammasomes and proposes a theory for the notable susceptibility of AT patients to pulmonary bacterial infection. Copyright © 2016 Elsevier Inc. All rights reserved.

The regulation of inflammation and oxidative status against lung injury of residue polysaccharides by Lentinula edodes.

PubMed

Ren, Zhenzhen; Li, Juan; Song, Xinling; Zhang, Jianjun; Wang, Wenshuai; Wang, Xiuxiu; Gao, Zheng; Jing, Huijuan; Li, Shangshang; Jia, Le

2018-01-01

In present study, two hydrolyzed residue polysaccharides (RPS) of enzymatic-RPS (ERPS) and acidic-RPS (ARPS) were successfully obtained from the residue of Lentinula edodes, and the anti-inflammatory as well as antioxidative effects on lipopolysaccharide-induced (LPS-induced) lung injured mice were investigated. The results demonstrated that ERPS showed superior lung protective effects by ameliorating the lung wet-to-dry weight (W/D) ratio, reducing the TNF-α, IL-6, and IL-1β levels in BALF, lowing the pulmonary MPO activity, decreasing the serum C3 and hs-CPR contents, as well as improving the antioxidant status by enhancing pulmonary enzyme activities (SOD, GSH-Px, CAT, and T-AOC) and eliminating the lipid peroxidation (MDA and LPO), respectively. These conclusions indicated that both RPS and its hydrolysates (ARPS and ERPS) might be suitable for functional foods and a potentially effective candidate medicine for the treatment of lung injury. Copyright © 2017 Elsevier B.V. All rights reserved.

Pulmonary vascular function and exercise capacity in black sub-Saharan Africans.

PubMed

Simaga, Bamodi; Vicenzi, Marco; Faoro, Vitalie; Caravita, Sergio; Di Marco, Giovanni; Forton, Kevin; Deboeck, Gael; Lalande, Sophie; Naeije, Robert

2015-09-01

Sex and age affect the pulmonary circulation. Whether there may be racial differences in pulmonary vascular function is unknown. Thirty white European Caucasian subjects (15 women) and age and body-size matched 30 black sub-Saharan African subjects (15 women) underwent a cardiopulmonary exercise test and exercise stress echocardiography with measurements of pulmonary artery pressure (PAP) and cardiac output (CO). A pulmonary vascular distensibility coefficient α was mathematically determined from the natural curvilinearity of multipoint mean PAP (mPAP)-CO plots. Maximum oxygen uptake (V̇o2max) and workload were higher in the whites, while maximum respiratory exchange ratio and ventilatory equivalents for CO2 were the same. Pulmonary hemodynamics were not different at rest. Exercise was associated with a higher maximum total pulmonary vascular resistance, steeper mPAP-CO relationships, and lower α-coefficients in the blacks. These differences were entirely driven by higher slopes of mPAP-CO relationships (2.5 ± 0.7 vs. 1.4 ± 0.7 mmHg·l(-1)·min; P < 0.001) and lower α-coefficients (0.85 ± 0.33 vs. 1.35 ± 0.51%/mmHg; P < 0.01) in black men compared with white men. There were no differences in any of the hemodynamic variables between black and white women. In men only, the slopes of mPAP-CO relationships were inversely correlated to V̇o2max (P < 0.01). Thus the pulmonary circulation is intrinsically less distensible in black sub-Saharan African men compared with white Caucasian Europeans men, and this is associated with a lower exercise capacity. This study did not identify racial differences in pulmonary vascular function in women. Copyright © 2015 the American Physiological Society.

Acute control of pulmonary regurgitation with a balloon "valve". An experimental investigation.

PubMed

Siwek, L G; Applebaum, R E; Jones, M; Clark, R E

1985-09-01

Operations for certain congenital cardiac lesions can produce pulmonary regurgitation. Pulmonary regurgitation contributes to right ventricular dysfunction, which may cause early postoperative morbidity and mortality. To ameliorate the problems of pulmonary regurgitation during the early postoperative period, we evaluated a method for its acute control. Complete pulmonary valvectomy was performed utilizing inflow occlusion in eight sheep. A catheter with a 15 ml spherical balloon was positioned in the pulmonary arterial trunk; its inflation and deflation were regulated by an intra-aortic balloon pump unit. Blood flow from the pulmonary arterial trunk and forward and regurgitant fraction were determined from electromagnetic flow transducer recordings. The regurgitant fraction with uncontrolled pulmonary regurgitation was 38% +/- 3% (forward flow = 42 +/- 5 ml/beat and regurgitant flow = 16 +/- 2 ml/beat). Inflation of the balloon during diastole was timed to completely eliminate pulmonary regurgitation. This balloon control of pulmonary regurgitation increased pulmonary arterial diastolic pressure from 12 +/- 1 to 17 +/- 1 mm Hg (p less than 0.0001) and decreased pulmonary arterial systolic pressure from 31 +/- 3 to 27 +/- 1 mm Hg (p = 0.06). Pulmonary arterial pulse pressure decreased from 19 +/- 3 to 9 +/- 1 mm Hg (p less than 0.003). Elimination of pulmonary regurgitation decreased right ventricular stroke volume (25 +/- 3 versus 42 +/- 5 ml/beat, p less than 0.0002) and resulted in a 46% reduction in right ventricular stroke work (5.0 +/- 0.6 versus 9.4 +/- 1.0 gm-m/beat, p less than 0.001) with no change in net forward pulmonary artery flow. Thus, acute pulmonary regurgitation can be controlled and this control improves overall hemodynamic status and decreases right ventricular work.

Pulmonary function test in formalin exposed and nonexposed subjects: A comparative study

PubMed Central

Uthiravelu, P.; Saravanan, A.; Kumar, C. Kishor; Vaithiyanandane, V.

2015-01-01

Background: The main function of the lung is gas exchange, which can be assessed in several ways. A spirometer measures the flow and the volumes of the inspired and expired air. The thoracic and abdominal muscle strength plays an important role in pulmonary function and diffusing lung capacity. Aims and Objectives: The aim of this study was to assess the effects of formalin exposure on the pulmonary function to compare with healthy individuals. To assess the chronic effects of formalin exposure on Pulmonary function tests (PFTs) in the faculties, lab technicians and attender of the Department of Anatomy and Pathology of SRM Medical Hospital and Research Centre, Kattankulathur. Materials and Methods: This prospective study was carried out in 50 healthy formalin exposed subjects (at least 5 years exposure) from Department of Anatomy and Pathology of SRM Medical College Hospital and Research Centre, Kattankulathur and 50 healthy controls of same age group of this study were included after obtaining ethical clearance and consent ‘Easy One Pro Spirometer (Ndd Medical Technologies, Cheshire SK 101LT, United Kingdom) was used to find out the PFT. Results: Student's t-test was applied to compare the PFT parameters between formalin exposed and formalin nonexposed group. There was a significant difference in mean and standard deviation of pulmonary parameters with the P < 0.005 in formalin exposed, which shows that they have lesser ventilatory drive. Conclusion: The formalin exposed subjects in our study presented with a mixed disorder of both obstructive and restrictive type. We also found that there was a negative correlation of pulmonary function with that of the degree and duration of exposure to formalin. PMID:26015743

Pulmonary function in space

NASA Technical Reports Server (NTRS)

West, J. B.; Elliott, A. R.; Guy, H. J.; Prisk, G. K.

1997-01-01

The lung is exquisitely sensitive to gravity, and so it is of interest to know how its function is altered in the weightlessness of space. Studies on National Aeronautics and Space Administration (NASA) Spacelabs during the last 4 years have provided the first comprehensive data on the extensive changes in pulmonary function that occur in sustained microgravity. Measurements of pulmonary function were made on astronauts during space shuttle flights lasting 9 and 14 days and were compared with extensive ground-based measurements before and after the flights. Compared with preflight measurements, cardiac output increased by 18% during space flight, and stroke volume increased by 46%. Paradoxically, the increase in stroke volume occurred in the face of reductions in central venous pressure and circulating blood volume. Diffusing capacity increased by 28%, and the increase in the diffusing capacity of the alveolar membrane was unexpectedly large based on findings in normal gravity. The change in the alveolar membrane may reflect the effects of uniform filling of the pulmonary capillary bed. Distributions of blood flow and ventilation throughout the lung were more uniform in space, but some unevenness remained, indicating the importance of nongravitational factors. A surprising finding was that airway closing volume was approximately the same in microgravity and in normal gravity, emphasizing the importance of mechanical properties of the airways in determining whether they close. Residual volume was unexpectedly reduced by 18% in microgravity, possibly because of uniform alveolar expansion. The findings indicate that pulmonary function is greatly altered in microgravity, but none of the changes observed so far will apparently limit long-term space flight. In addition, the data help to clarify how gravity affects pulmonary function in the normal gravity environment on Earth.

Continuous Flow Left Ventricular Assist Device Implant Significantly Improves Pulmonary Hypertension, Right Ventricular Contractility, and Tricuspid Valve Competence

PubMed Central

Atluri, Pavan; Fairman, Alexander S.; MacArthur, John W.; Goldstone, Andrew B.; Cohen, Jeffrey E.; Howard, Jessica L.; Zalewski, Christyna M.; Shudo, Yasuhiro; Woo, Y. Joseph

2014-01-01

Background Continuous flow left ventricular assist devices (CF LVAD) are being implanted with increasing frequency for end-stage heart failure. At the time of LVAD implant, a large proportion of patients have pulmonary hypertension, right ventricular (RV) dysfunction, and tricuspid regurgitation (TR). RV dysfunction and TR can exacerbate renal dysfunction, hepatic dysfunction, coagulopathy, edema, and even prohibit isolated LVAD implant. Repairing TR mandates increased cardiopulmonary bypass time and bicaval cannulation, which should be reserved for the time of orthotopic heart transplantation. We hypothesized that CF LVAD implant would improve pulmonary artery pressures, enhance RV function, and minimize TR, obviating need for surgical tricuspid repair. Methods One hundred fourteen continuous flow LVADs implanted from 2005 through 2011 at a single center, with medical management of functional TR, were retrospectively analyzed. Pulmonary artery pressures were measured immediately prior to and following LVAD implant. RV function and TR were graded according to standard echocardiographic criteria, prior to, immediately following, and long-term following LVAD. Results There was a significant improvement in post-VAD mean pulmonary arterial pressures (26.6 ± 4.9 vs. 30.2 ± 7.4 mmHg, p = 0.008) with equivalent loading pressures (CVP = 12.0 ± 4.0 vs. 12.1 ± 5.1 p = NS). RV function significantly improved, as noted by right ventricular stroke work index (7.04 ± 2.60 vs. 6.05 ± 2.54, p = 0.02). There was an immediate improvement in TR grade and RV function following LVAD implant, which was sustained long term. Conclusion Continuous flow LVAD implant improves pulmonary hypertension, RV function, and tricuspid regurgitation. TR may be managed nonoperatively during CF LVAD implant. PMID:24118109

Pulmonary Function, Muscle Strength, and Incident Mobility Disability in Elders

PubMed Central

Buchman, Aron S.; Boyle, Patricia A.; Leurgans, Sue E.; Evans, Denis A.; Bennett, David A.

2009-01-01

Muscle strength, including leg strength and respiratory muscle strength, are relatively independently associated with mobility disability in elders. However, the factors linking muscle strength with mobility disability are unknown. To test the hypothesis that pulmonary function mediates the association of muscle strength with the development of mobility disability in elders, we used data from a longitudinal cohort study of 844 ambulatory elders without dementia participating in the Rush Memory and Aging Project with a mean follow-up of 4.0 years (SD = 1.39). A composite measure of pulmonary function was based on spirometric measures of forced vital capacity, forced expiratory volume, and peak expiratory flow. Respiratory muscle strength was based on maximal inspiratory pressure and expiratory pressure and leg strength based on hand-held dynamometry. Mobility disability was defined as a gait speed less than or equal to 0.55 m/s based on annual assessment of timed walk. Secondary analyses considered time to loss of the ability to ambulate. In separate proportional hazards models which controlled for age, sex, and education, composite measures of pulmonary function, respiratory muscle strength, and leg strength were each associated with incident mobility disability (all P values < 0.001). Further, all three were related to the development of incident mobility disability when considered together in a single model (pulmonary function: hazard ratio [HR], 0.721; 95% confidence interval [CI], 0.577, 0.902; respiratory muscle strength: HR, 0.732; 95% CI, 0.593, 0.905; leg strength: HR, 0.791; 95% CI, 0.640, 0.976). Secondary analyses examining incident loss of the ability to ambulate revealed similar findings. Overall, these findings suggest that lower levels of pulmonary function and muscle strength are relatively independently associated with the development of mobility disability in the elderly. PMID:19934353

Pectus carinatum: the effects of orthotic bracing on pulmonary function and gradual compression on patient compliance.

PubMed

Ateş, Oğuz; Karakuş, Osman Z; Hakgüder, Gülce; Olguner, Mustafa; Akgür, Feza M

2013-09-01

The treatment of pectus carinatum (PC) deformity has been considered to be operative. Some authors have shown that postoperative pulmonary function is worsened. They have suggested that compromised chest wall expansion secondary to surgery leads to compromised pulmonary function. Several authors have advocated an orthotic brace for the treatment of PC. Pulmonary functions after orthotic brace treatment have not been investigated. Between April 2006 and October 2012, 61 patients presented with PC. Orthotic braces allowing gradual compression were prepared according to the anthropometric measurements of individual patients. The brace belt was tightened gradually. The brace was worn 6 h a day during the first week and the bracing time was prolonged for an additional hour per week till 16 h per day has been reached. Pre- and post-treatment echocardiography, pulmonary function tests and thorax computed tomography (CT) were obtained. The pectus severity index (Haller index) and the angle of sternal rotation were measured using CT. Satisfaction from bracing was evaluated by parents or patients at the end of the treatment. While the mean pretreatment Haller index was 1.96 ± 0.24, the mean post-treatment index was 2.26 ± 0.32. The angle of rotation was improved by 47.5%. Forced vital capacity and forced expiratory volume in 1 second were correlated with the predicted values for age. There was no statistically significant difference between pre- and post-treatment values. No skin breakdown or bruising was encountered. The overall average satisfaction score was 3.92 ± 0.27. We conclude that pulmonary function tests are not affected after brace treatment and gradual progression of bracing increases the patient's compliance.

Activation and overexpression of Sirt1 attenuates lung fibrosis via P300.

PubMed

Zeng, Zhilin; Cheng, Sheng; Chen, Huilong; Li, Qinghai; Hu, Yinan; Wang, Qi; Zhu, Xianying; Wang, Jun

2017-05-13

Persistent fibroblast activation is a predominant feature of idiopathic pulmonary fibrosis (IPF), but the transcriptional and epigenetic mechanisms controlling this process are not well understood. Silent information regulator type-1 (Sirt1) is a member of class Ⅲ histone deacetylase with important regulatory roles in a variety of pathophysiologic processes, but its role in fibrotic lung diseases is not clearly elucidated. Sirt1 expression in lung tissues of IPF patients and in a mouse model of bleomycin (BLM)-induced lung fibrosis were evaluated by immunofluorescence. The function of Sirt1 in BLM-induced lung fibrosis in the mouse model or transforming growth factor β1 (TGF-β1)-mediated lung fibroblast cellular model was investigated by Sirt1 activation, overexpression and knockdown of Sirt1. Finally, the involvement of p300 signaling pathways was assessed. In this study, we found up-regulation of Sirt1 in BLM-induced lung fibrosis, as well as in the lungs of IPF patients, including in the aggregated pulmonary fibroblasts of fibrotic foci. Activation or overexpression of Sirt1 attenuated TGF-β1-mediated lung fibroblast differentiation and activation and diminished the severity of experimental lung fibrosis in mice. Whereas knockdown of Sirt1 promoted the pro-fibrogenic activity of TGF-β1 in lung fibroblasts. A potential mechanism for the role of Sirt1 in lung fibrosis was through regulating the expression of p300. Thus, we characterized Sirt1 as an important regulator of lung fibrosis and provides a proof of principle for activation or overexpression of Sirt1 as a potential novel therapeutic strategy for IPF. Copyright © 2017 Elsevier Inc. All rights reserved.

Pulmonary vasodilation in acute and chronic heart failure: empiricism and evidence.

PubMed

Guglin, Maya

2011-09-01

Pulmonary hypertension in heart failure is associated with exercise intolerance and adverse outcomes. With the availability of multiple drugs that cause pulmonary vasodilation and decrease pulmonary arterial pressure, pulmonary hypertension becomes an attractive therapeutic target. Out of several classes of medications, oral phosphodiesterase inhibitors emerge as the most promising in terms of symptomatic improvement, hemodynamic benefits, reverse cardiac remodeling, and functional capacity. Future trials will show whether the use of these drugs translates to decreased morbidity and mortality in heart failure.

CFTR gene variant IVS8-5T in disseminated bronchiectasis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pignatti, P.F.; Bombieri, C.; Benetazzo, M.

1996-04-01

Obstructive pulmonary disease includes asthma, chronic obstructive pulmonary disease (COPD; i.e., pulmonary emphysema and chronic bronchitis), bronchiectasis, and cystic fibrosis (CF). It represents a leading cause of death in developed countries. Both familial clustering of non-CF obstructive pulmonary disease and familial aggregation of impaired lung function have been described. This suggests that genetic factors contribute to non-CF obstructive pulmonary disease, even if it is difficult to determine the relative contribution of environmental factors. 11 refs., 1 tab.

Pulmonary hypertension in older adults.

PubMed

McArdle, John R; Trow, Terence K; Lerz, Kathryn

2007-12-01

Pulmonary hypertension is a frequently encountered problem in older patients. True idiopathic pulmonary arterial hypertension can also be seen and requires careful exclusion in older patients. Institution of therapies must be tempered with an appreciation of individual comorbidities and functional limitations that may affect patients' ability to comply and benefit from the complex treatments available for pulmonary arterial hypertension. This article reviews the existing data on the various forms of pulmonary hypertension presenting in older patients and on appropriate therapy in this challenging population.

What Is Cough?

MedlinePlus

... Visit Children and Clinical Studies to hear experts, parents, and children talk about their experiences with clinical ... Pneumonitis Idiopathic Pulmonary Fibrosis Pneumonia Pulmonary Function ...

Molecular Mechanisms Regulating the Vascular Prostacyclin Pathways and Their Adaptation during Pregnancy and in the Newborn

PubMed Central

Majed, Batoule H.

2012-01-01

Prostacyclin (PGI2) is a member of the prostanoid group of eicosanoids that regulate homeostasis, hemostasis, smooth muscle function and inflammation. Prostanoids are derived from arachidonic acid by the sequential actions of phospholipase A2, cyclooxygenase (COX), and specific prostaglandin (PG) synthases. There are two major COX enzymes, COX1 and COX2, that differ in structure, tissue distribution, subcellular localization, and function. COX1 is largely constitutively expressed, whereas COX2 is induced at sites of inflammation and vascular injury. PGI2 is produced by endothelial cells and influences many cardiovascular processes. PGI2 acts mainly on the prostacyclin (IP) receptor, but because of receptor homology, PGI2 analogs such as iloprost may act on other prostanoid receptors with variable affinities. PGI2/IP interaction stimulates G protein-coupled increase in cAMP and protein kinase A, resulting in decreased [Ca2+]i, and could also cause inhibition of Rho kinase, leading to vascular smooth muscle relaxation. In addition, PGI2 intracrine signaling may target nuclear peroxisome proliferator-activated receptors and regulate gene transcription. PGI2 counteracts the vasoconstrictor and platelet aggregation effects of thromboxane A2 (TXA2), and both prostanoids create an important balance in cardiovascular homeostasis. The PGI2/TXA2 balance is particularly critical in the regulation of maternal and fetal vascular function during pregnancy and in the newborn. A decrease in PGI2/TXA2 ratio in the maternal, fetal, and neonatal circulation may contribute to preeclampsia, intrauterine growth restriction, and persistent pulmonary hypertension of the newborn (PPHN), respectively. On the other hand, increased PGI2 activity may contribute to patent ductus arteriosus (PDA) and intraventricular hemorrhage in premature newborns. These observations have raised interest in the use of COX inhibitors and PGI2 analogs in the management of pregnancy-associated and neonatal vascular disorders. The use of aspirin to decrease TXA2 synthesis has shown little benefit in preeclampsia, whereas indomethacin and ibuprofen are used effectively to close PDA in the premature newborn. PGI2 analogs have been used effectively in primary pulmonary hypertension in adults and have shown promise in PPHN. Careful examination of PGI2 metabolism and the complex interplay with other prostanoids will help design specific modulators of the PGI2-dependent pathways for the management of pregnancy-related and neonatal vascular disorders. PMID:22679221

Molecular mechanisms regulating the vascular prostacyclin pathways and their adaptation during pregnancy and in the newborn.

PubMed

Majed, Batoule H; Khalil, Raouf A

2012-07-01

Prostacyclin (PGI(2)) is a member of the prostanoid group of eicosanoids that regulate homeostasis, hemostasis, smooth muscle function and inflammation. Prostanoids are derived from arachidonic acid by the sequential actions of phospholipase A(2), cyclooxygenase (COX), and specific prostaglandin (PG) synthases. There are two major COX enzymes, COX1 and COX2, that differ in structure, tissue distribution, subcellular localization, and function. COX1 is largely constitutively expressed, whereas COX2 is induced at sites of inflammation and vascular injury. PGI(2) is produced by endothelial cells and influences many cardiovascular processes. PGI(2) acts mainly on the prostacyclin (IP) receptor, but because of receptor homology, PGI(2) analogs such as iloprost may act on other prostanoid receptors with variable affinities. PGI(2)/IP interaction stimulates G protein-coupled increase in cAMP and protein kinase A, resulting in decreased [Ca(2+)](i), and could also cause inhibition of Rho kinase, leading to vascular smooth muscle relaxation. In addition, PGI(2) intracrine signaling may target nuclear peroxisome proliferator-activated receptors and regulate gene transcription. PGI(2) counteracts the vasoconstrictor and platelet aggregation effects of thromboxane A(2) (TXA(2)), and both prostanoids create an important balance in cardiovascular homeostasis. The PGI(2)/TXA(2) balance is particularly critical in the regulation of maternal and fetal vascular function during pregnancy and in the newborn. A decrease in PGI(2)/TXA(2) ratio in the maternal, fetal, and neonatal circulation may contribute to preeclampsia, intrauterine growth restriction, and persistent pulmonary hypertension of the newborn (PPHN), respectively. On the other hand, increased PGI(2) activity may contribute to patent ductus arteriosus (PDA) and intraventricular hemorrhage in premature newborns. These observations have raised interest in the use of COX inhibitors and PGI(2) analogs in the management of pregnancy-associated and neonatal vascular disorders. The use of aspirin to decrease TXA(2) synthesis has shown little benefit in preeclampsia, whereas indomethacin and ibuprofen are used effectively to close PDA in the premature newborn. PGI(2) analogs have been used effectively in primary pulmonary hypertension in adults and have shown promise in PPHN. Careful examination of PGI(2) metabolism and the complex interplay with other prostanoids will help design specific modulators of the PGI(2)-dependent pathways for the management of pregnancy-related and neonatal vascular disorders.

Effect of exercise test on pulmonary function of obese adolescents.

PubMed

Faria, Alethéa Guimarães; Ribeiro, Maria Angela G O; Marson, Fernando Augusto Lima; Schivinski, Camila Isabel S; Severino, Silvana Dalge; Ribeiro, José Dirceu; Barros Filho, Antônio A

2014-01-01

to investigate the pulmonary response to exercise of non-morbidly obese adolescents, considering the gender. a prospective cross-sectional study was conducted with 92 adolescents (47 obese and 45 eutrophic), divided in four groups according to obesity and gender. Anthropometric parameters, pulmonary function (spirometry and oxygen saturation [SatO2]), heart rate (HR), blood pressure (BP), respiratory rate (RR), and respiratory muscle strength were measured. Pulmonary function parameters were measured before, during, and after the exercise test. BP and HR were higher in obese individuals during the exercise test (p = 0.0001). SatO2 values decreased during exercise in obese adolescents (p = 0.0001). Obese males had higher levels of maximum inspiratory and expiratory pressures (p = 0.0002) when compared to obese and eutrophic females. Obese males showed lower values of maximum voluntary ventilation, forced vital capacity, and forced expiratory volume in the first second when compared to eutrophic males, before and after exercise (p = 0.0005). Obese females had greater inspiratory capacity compared to eutrophic females (p = 0.0001). Expiratory reserve volume was lower in obese subjects when compared to controls (p ≤ 0,05). obese adolescents presented changes in pulmonary function at rest and these changes remained present during exercise. The spirometric and cardiorespiratory values were different in the four study groups. The present data demonstrated that, in spite of differences in lung growth, the model of fat distribution alters pulmonary function differently in obese female and male adolescents. Copyright © 2013 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

Raw milk consumption and other early-life farm exposures and adult pulmonary function in the Agricultural Lung Health Study.

PubMed

Wyss, Annah B; House, John S; Hoppin, Jane A; Richards, Marie; Hankinson, John L; Long, Stuart; Henneberger, Paul K; Beane Freeman, Laura E; Sandler, Dale P; O'Connell, Elizabeth Long; Cummings, Christie Barker; Umbach, David M; London, Stephanie J

2018-03-01

Literature suggests that early exposure to the farming environment protects against atopy and asthma; few studies have examined pulmonary function. We evaluated associations between early-life farming exposures and pulmonary function in 3061 adults (mean age=63) from a US farming population using linear regression. Childhood raw milk consumption was associated with higher FEV 1 (β=49.5 mL, 95% CI 2.8 to 96.1 mL, p=0.04) and FVC (β=66.2 mL, 95% CI 13.2 to 119.1 mL, p=0.01). We did not find appreciable associations with other early-life farming exposures. We report a novel association between raw milk consumption and higher pulmonary function that lasts into older adulthood. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Functional Imaging of the Lungs with Gas Agents

PubMed Central

Kruger, Stanley J.; Nagle, Scott K.; Couch, Marcus J.; Ohno, Yoshiharu; Albert, Mitchell; Fain, Sean B.

2015-01-01

This review focuses on the state-of-the-art of the three major classes of gas contrast agents used in magnetic resonance imaging (MRI) – hyperpolarized (HP) gas, molecular oxygen, and fluorinated gas – and their application to clinical pulmonary research. During the past several years there has been accelerated development of pulmonary MRI. This has been driven in part by concerns regarding ionizing radiation using multi-detector computed tomography (CT). However, MRI also offers capabilities for fast multi-spectral and functional imaging using gas agents that are not technically feasible with CT. Recent improvements in gradient performance and radial acquisition methods using ultra-short echo time (UTE) have contributed to advances in these functional pulmonary MRI techniques. Relative strengths and weaknesses of the main functional imaging methods and gas agents are compared and applications to measures of ventilation, diffusion, and gas exchange are presented. Functional lung MRI methods using these gas agents are improving our understanding of a wide range of chronic lung diseases, including chronic obstructive pulmonary disease (COPD), asthma, and cystic fibrosis (CF) in both adults and children. PMID:26218920

Prediction of forced expiratory volume in pulmonary function test using radial basis neural networks and k-means clustering.

PubMed

Manoharan, Sujatha C; Ramakrishnan, Swaminathan

2009-10-01

In this work, prediction of forced expiratory volume in pulmonary function test, carried out using spirometry and neural networks is presented. The pulmonary function data were recorded from volunteers using commercial available flow volume spirometer in standard acquisition protocol. The Radial Basis Function neural networks were used to predict forced expiratory volume in 1 s (FEV1) from the recorded flow volume curves. The optimal centres of the hidden layer of radial basis function were determined by k-means clustering algorithm. The performance of the neural network model was evaluated by computing their prediction error statistics of average value, standard deviation, root mean square and their correlation with the true data for normal, restrictive and obstructive cases. Results show that the adopted neural networks are capable of predicting FEV1 in both normal and abnormal cases. Prediction accuracy was more in obstructive abnormality when compared to restrictive cases. It appears that this method of assessment is useful in diagnosing the pulmonary abnormalities with incomplete data and data with poor recording.

Molecular basis and function of voltage-gated K+ channels in pulmonary arterial smooth muscle cells.

PubMed

Yuan, X J; Wang, J; Juhaszova, M; Golovina, V A; Rubin, L J

1998-04-01

K(+)-channel activity-mediated alteration of the membrane potential and cytoplasmic free Ca2+ concentration ([Ca2+]cyt) is a pivotal mechanism in controlling pulmonary vasomotor tone. By using combined approaches of patch clamp, imaging fluorescent microscopy, and molecular biology, we examined the electrophysiological properties of K+ channels and the role of different K+ currents in regulating [Ca2+]cyt and explored the molecular identification of voltage-gated K+ (KV)- and Ca(2+)-activated K+ (KCa)-channel genes expressed in pulmonary arterial smooth muscle cells (PASMC). Two kinetically distinct KV currents [IK(V)], a rapidly inactivating (A-type) and a noninactivating delayed rectifier, as well as a slowly activated KCa current [IK(Ca)] were identified. IK(V) was reversibly inhibited by 4-aminopyridine (5 mM), whereas IK(Ca) was significantly inhibited by charybdotoxin (10-20 nM). K+ channels are composed of pore-forming alpha-subunits and auxiliary beta-subunits. Five KV-channel alpha-subunit genes from the Shaker subfamily (KV1.1, KV1.2, KV1.4, KV1.5, and KV1.6), a KV-channel alpha-subunit gene from the Shab subfamily (KV2.1), a KV-channel modulatory alpha-subunit (KV9.3), and a KCa-channel alpha-subunit gene (rSlo), as well as three KV-channel beta-subunit genes (KV beta 1.1, KV beta 2, and KV beta 3) are expressed in PASMC. The data suggest that 1) native K+ channels in PASMC are encoded by multiple genes; 2) the delayed rectifier IK(V) may be generated by the KV1.1, KV1.2, KV1.5, KV1.6, KV2.1, and/or KV2.1/KV9.3 channels; 3) the A-type IK(V) may be generated by the KV1.4 channel and/or the delayed rectifier KV channels (KV1 subfamily) associated with beta-subunits; and 4) the IK(Ca) may be generated by the rSlo gene product. The function of the KV channels plays an important role in the regulation of membrane potential and [Ca2+]cyt in PASMC.

Association between marijuana exposure and pulmonary function over 20 years.

PubMed

Pletcher, Mark J; Vittinghoff, Eric; Kalhan, Ravi; Richman, Joshua; Safford, Monika; Sidney, Stephen; Lin, Feng; Kertesz, Stefan

2012-01-11

Marijuana smoke contains many of the same constituents as tobacco smoke, but whether it has similar adverse effects on pulmonary function is unclear. To analyze associations between marijuana (both current and lifetime exposure) and pulmonary function. The Coronary Artery Risk Development in Young Adults (CARDIA) study, a longitudinal study collecting repeated measurements of pulmonary function and smoking over 20 years (March 26, 1985-August 19, 2006) in a cohort of 5115 men and women in 4 US cities. Mixed linear modeling was used to account for individual age-based trajectories of pulmonary function and other covariates including tobacco use, which was analyzed in parallel as a positive control. Lifetime exposure to marijuana joints was expressed in joint-years, with 1 joint-year of exposure equivalent to smoking 365 joints or filled pipe bowls. Forced expiratory volume in the first second of expiration (FEV(1)) and forced vital capacity (FVC). Marijuana exposure was nearly as common as tobacco exposure but was mostly light (median, 2-3 episodes per month). Tobacco exposure, both current and lifetime, was linearly associated with lower FEV(1) and FVC. In contrast, the association between marijuana exposure and pulmonary function was nonlinear (P < .001): at low levels of exposure, FEV(1) increased by 13 mL/joint-year (95% CI, 6.4 to 20; P < .001) and FVC by 20 mL/joint-year (95% CI, 12 to 27; P < .001), but at higher levels of exposure, these associations leveled or even reversed. The slope for FEV(1) was -2.2 mL/joint-year (95% CI, -4.6 to 0.3; P = .08) at more than 10 joint-years and -3.2 mL per marijuana smoking episode/mo (95% CI, -5.8 to -0.6; P = .02) at more than 20 episodes/mo. With very heavy marijuana use, the net association with FEV(1) was not significantly different from baseline, and the net association with FVC remained significantly greater than baseline (eg, at 20 joint-years, 76 mL [95% CI, 34 to 117]; P < .001). Occasional and low cumulative marijuana use was not associated with adverse effects on pulmonary function.

Decreased pulmonary c-Cbl expression and tyrosine phosphorylation in the nitrofen-induced rat model of congenital diaphragmatic hernia.

PubMed

Friedmacher, Florian; Gosemann, Jan-Hendrik; Takahashi, Hiromizu; Corcionivoschi, Nicolae; Puri, Prem

2013-01-01

The high morbidity of newborn infants with congenital diaphragmatic hernia (CDH) is attributed to pulmonary hypoplasia (PH), which is characterized by a failure of alveolar development. The nitrofen-induced CDH model has been widely used to investigate the pathogenesis of PH in CDH. It has previously been shown that the fibroblast growth factor receptor (FGFR) pathway, which is essential for a proper lung development, is disrupted during late gestation of nitrofen-induced CDH. Casitas B-lineage lymphoma (c-Cbl) proteins are known regulators of signal transduction through FGFRs, indicating their important role during alveolarization in developing lungs. Furthermore, it has been demonstrated that tyrosine phosphorylation of c-Cbl proteins has a pivotal role for their physiological function and activity during fetal lung development. We designed this study to test the hypothesis that pulmonary c-Cbl expression and tyrosine phosphorylation status are decreased in the nitrofen-induced CDH model. Timed-pregnant rats received either 100 mg nitrofen or vehicle on gestation day 9 (D9). Fetuses were harvested on D18 and D21, and lungs were divided into two groups: control and hypoplastic lungs with CDH (CDH(+)) (n = 10 at each time-point, respectively). Pulmonary gene expression levels of c-Cbl were analyzed by quantitative real-time polymerase chain reaction. Western blotting combined with densitometry analysis was used for semi-quantification of protein levels of pulmonary c-Cbl and tyrosine phosphorylation status. Confocal-immunofluorescence staining was performed to evaluate c-Cbl protein expression and distribution. Relative mRNA expression levels of pulmonary c-Cbl were significantly decreased in CDH(+) on D18 and D21 compared to controls. Western blotting showed markedly decreased protein levels of pulmonary c-Cbl and tyrosine phosphorylation status in CDH(+) on D18 and D21. Confocal-immunofluorescence analysis confirmed decreased c-Cbl expression in CDH(+) on D18 and D21 mainly in the distal alveolar epithelium compared to controls. Decreased pulmonary c-Cbl gene and protein expression accompanied by a decreased tyrosine phosphorylation status during the late stages of fetal lung development may result in reduced c-Cbl activity, and thus interfere with the FGFR-mediated alveolarization in the nitrofen-induced CDH model.

Lung function, transfusion, pulmonary capillary blood volume and sickle cell disease.

PubMed

Lunt, Alan; McGhee, Emily; Robinson, Polly; Rees, David; Height, Susan; Greenough, Anne

2016-02-01

Lung function abnormalities occur in children with sickle cell disease (SCD) and may be associated with elevated pulmonary blood volume. To investigate that association, we determined whether blood transfusion in SCD children acutely increased pulmonary capillary blood volume (PCBV) and increased respiratory system resistance (Rrs5). Measurements of Rrs5 and spirometry were made before and after blood transfusion in 18 children, median age 14.2 (6.6-18.5) years. Diffusing capacity for carbon monoxide and nitric oxide were assessed to calculate the PCBV. Post transfusion, the median Rrs5 had increased from 127.4 to 141.3% predicted (p<0.0001) and pulmonary capillary blood volume from 39.7 to 64.1 ml/m2 (p<0.0001); forced expiratory volume in one second (p=0.0056) and vital capacity (p=0.0008) decreased. The increase in Rrs5 correlated with the increase in PCBV (r=0.50, p=0.0493). Increased pulmonary capillary blood volume may at least partially explain the lung function abnormalities in SCD children. Copyright © 2015 Elsevier B.V. All rights reserved.

Use of a Doppler pulmonary artery catheter for continuous measurement of right ventricular pump function and contractility during single lung transplantation.

PubMed

Heerdt, P M; Pond, C G; Kussman, M K; Triantafillou, A N

1993-01-01

Despite numerous technologic advances in intraoperative monitoring, the only methods routinely available for assessment of right ventricular function in lung transplant recipients are continuous measurement of right heart pressures and intermittent thermodilution determination of cardiac output and ejection fraction. Additional data may now be obtained with transesophageal echocardiography, although this technology is expensive and not widely available and requires diverting attention from a potentially unstable patient for data acquisition and analysis. Recently, a Doppler pulmonary artery catheter was introduced that measures beat-to-beat pulmonary artery blood flow-velocity, cross sectional area, and volume flow. Because of data indicating that acceleration of blood in the pulmonary artery (measured as the first derivative of either the velocity or flow waveform) is a sensitive indicator of right ventricular contractility, we have used waveforms obtained with the catheter for assessment of right ventricular pump function (stroke volume and peak pulmonary artery flow rate) and contractility in heart surgery patients. We report here our experience with this method in two patients undergoing left single lung transplantation.

[System analytical approach of lung function and hemodynamics].

PubMed

Naszlady, Attila; Kiss, Lajos

2009-02-15

The authors critically analyse the traditional views in physiology and complete them with new statements based on computer model simulations of lung function and of hemodynamics. Conclusions are derived for the clinical practice as follows: the four-dimensional function curves are similar in both systems; there is a "waterfall" zone in the pulmonary blood perfusion; the various time constants of pulmonary regions can modify the blood gas values; pulmonary capillary pressure is equal to pulmonary arterial diastole pressure; heart is not a pressure pump, but a flow source; ventricles are loaded by the input impedance of the arterial systems and not by the total vascular (ohmlike) resistance; optimum heart rate in rest depends on the length of the aorta; this law of heart rate, based on the principle of resonance is valid along the mammalian allometric line; tachycardia decreases the input impedance; using positive end expiratory pressure respirators the blood gas of pulmonary artery should be followed; coronary circulation should be assessed in beat per milliliter, the milliliter per minute may be false. These statements are compared to related references.

Pulmonary vascular and right ventricular dysfunction in adult critical care: current and emerging options for management: a systematic literature review.

PubMed

Price, Laura C; Wort, Stephen J; Finney, Simon J; Marino, Philip S; Brett, Stephen J

2010-01-01

Pulmonary vascular dysfunction, pulmonary hypertension (PH), and resulting right ventricular (RV) failure occur in many critical illnesses and may be associated with a worse prognosis. PH and RV failure may be difficult to manage: principles include maintenance of appropriate RV preload, augmentation of RV function, and reduction of RV afterload by lowering pulmonary vascular resistance (PVR). We therefore provide a detailed update on the management of PH and RV failure in adult critical care. A systematic review was performed, based on a search of the literature from 1980 to 2010, by using prespecified search terms. Relevant studies were subjected to analysis based on the GRADE method. Clinical studies of intensive care management of pulmonary vascular dysfunction were identified, describing volume therapy, vasopressors, sympathetic inotropes, inodilators, levosimendan, pulmonary vasodilators, and mechanical devices. The following GRADE recommendations (evidence level) are made in patients with pulmonary vascular dysfunction: 1) A weak recommendation (very-low-quality evidence) is made that close monitoring of the RV is advised as volume loading may worsen RV performance; 2) A weak recommendation (low-quality evidence) is made that low-dose norepinephrine is an effective pressor in these patients; and that 3) low-dose vasopressin may be useful to manage patients with resistant vasodilatory shock. 4) A weak recommendation (low-moderate quality evidence) is made that low-dose dobutamine improves RV function in pulmonary vascular dysfunction. 5) A strong recommendation (moderate-quality evidence) is made that phosphodiesterase type III inhibitors reduce PVR and improve RV function, although hypotension is frequent. 6) A weak recommendation (low-quality evidence) is made that levosimendan may be useful for short-term improvements in RV performance. 7) A strong recommendation (moderate-quality evidence) is made that pulmonary vasodilators reduce PVR and improve RV function, notably in pulmonary vascular dysfunction after cardiac surgery, and that the side-effect profile is reduced by using inhaled rather than systemic agents. 8) A weak recommendation (very-low-quality evidence) is made that mechanical therapies may be useful rescue therapies in some settings of pulmonary vascular dysfunction awaiting definitive therapy. This systematic review highlights that although some recommendations can be made to guide the critical care management of pulmonary vascular and right ventricular dysfunction, within the limitations of this review and the GRADE methodology, the quality of the evidence base is generally low, and further high-quality research is needed.

N-acetylcysteine improves established monocrotaline-induced pulmonary hypertension in rats

PubMed Central

2014-01-01

Background The outcome of patients suffering from pulmonary arterial hypertension (PAH) are predominantly determined by the response of the right ventricle to the increase afterload secondary to high vascular pulmonary resistance. However, little is known about the effects of the current available or experimental PAH treatments on the heart. Recently, inflammation has been implicated in the pathophysiology of PAH. N-acetylcysteine (NAC), a well-known safe anti-oxidant drug, has immuno-modulatory and cardioprotective properties. We therefore hypothesized that NAC could reduce the severity of pulmonary hypertension (PH) in rats exposed to monocrotaline (MCT), lowering inflammation and preserving pulmonary vascular system and right heart function. Methods Saline-treated control, MCT-exposed, MCT-exposed and NAC treated rats (day 14–28) were evaluated at day 28 following MCT for hemodynamic parameters (right ventricular systolic pressure, mean pulmonary arterial pressure and cardiac output), right ventricular hypertrophy, pulmonary vascular morphometry, lung inflammatory cells immunohistochemistry (monocyte/macrophages and dendritic cells), IL-6 expression, cardiomyocyte hypertrophy and cardiac fibrosis. Results The treatment with NAC significantly decreased pulmonary vascular remodeling, lung inflammation, and improved total pulmonary resistance (from 0.71 ± 0.05 for MCT group to 0.50 ± 0.06 for MCT + NAC group, p < 0.05). Right ventricular function was also improved with NAC treatment associated with a significant decrease in cardiomyocyte hypertrophy (625 ± 69 vs. 439 ± 21 μm2 for MCT and MCT + NAC group respectively, p < 0.001) and heart fibrosis (14.1 ± 0.8 vs. 8.8 ± 0.1% for MCT and MCT + NAC group respectively, p < 0.001). Conclusions Through its immuno-modulatory and cardioprotective properties, NAC has beneficial effect on pulmonary vascular and right heart function in experimental PH. PMID:24929652

Homology of lungs and gas bladders: insights from arterial vasculature.

PubMed

Longo, Sarah; Riccio, Mark; McCune, Amy R

2013-06-01

Gas bladders of ray-finned fishes serve a variety of vital functions and are thus an important novelty of most living vertebrates. The gas bladder has long been regarded as an evolutionary modification of lungs. Critical evidence for this hypothesized homology is whether pulmonary arteries supply the gas bladder as well as the lungs. Pulmonary arteries, paired branches of the fourth efferent branchial arteries, deliver blood to the lungs in osteichthyans with functional lungs (lungfishes, tetrapods, and the ray-finned polypterid fishes). The fact that pulmonary arteries also supply the respiratory gas bladder of Amia calva (bowfin) has been used to support the homology of lungs and gas bladders, collectively termed air-filled organs (AO). However, the homology of pulmonary arteries in bowfin and lunged osteichthyans has been uncertain, given the apparent lack of pulmonary arteries in critical taxa. To re-evaluate the homology of pulmonary arteries in bowfin and lunged osteichthyans, we studied, using micro-CT technology, the arterial vasculature of Protopterus, Polypterus, Acipenser, Polyodon, Amia, and Lepisosteus, and analyzed these data using a phylogenetic approach. Our data reveal that Acipenser and Polyodon have paired posterior branches of the fourth efferent branchial arteries, which are thus similar in origin to pulmonary arteries. We hypothesize that these arteries are vestigial pulmonary arteries that have been coopted for new functions due to the dorsal shift of the AO and/or the loss of respiration in these taxa. Ancestral state reconstructions support pulmonary arteries as a synapomorphy of the Osteichthyes, provide the first concrete evidence for the retention of pulmonary arteries in Amia, and support thehomology of lungs and gas bladders due to a shared vascular supply. Finally, we use ancestral state reconstructions to show that arterial AO supplies from the celiacomesenteric artery or dorsal aorta appear to be convergent between teleosts and nonteleost actinopterygians. Copyright © 2013 Wiley Periodicals, Inc.

Dysregulation of Antiviral Function of CD8(+) T Cells in the Chronic Obstructive Pulmonary Disease Lung. Role of the PD-1-PD-L1 Axis.

PubMed

McKendry, Richard T; Spalluto, C Mirella; Burke, Hannah; Nicholas, Ben; Cellura, Doriana; Al-Shamkhani, Aymen; Staples, Karl J; Wilkinson, Tom M A

2016-03-15

Patients with chronic obstructive pulmonary disease (COPD) are susceptible to respiratory viral infections that cause exacerbations. The mechanisms underlying this susceptibility are not understood. Effectors of the adaptive immune response-CD8(+) T cells that clear viral infections-are present in increased numbers in the lungs of patients with COPD, but they fail to protect against infection and may contribute to the immunopathology of the disease. CD8(+) function and signaling through the programmed cell death protein (PD)-1 exhaustion pathway were investigated as a potential key mechanism of viral exacerbation of the COPD lung. Tissue from control subjects and patients with COPD undergoing lung resection was infected with live influenza virus ex vivo. Viral infection and expression of lung cell markers were analyzed using flow cytometry. The proportion of lung CD8(+) T cells expressing PD-1 was greater in COPD (mean, 16.2%) than in controls (4.4%, P = 0.029). Only epithelial cells and macrophages were infected with influenza, and there was no difference in the proportion of infected cells between controls and COPD. Infection up-regulated T-cell PD-1 expression in control and COPD samples. Concurrently, influenza significantly up-regulated the marker of cytotoxic degranulation (CD107a) on CD8(+) T cells (P = 0.03) from control subjects but not on those from patients with COPD. Virus-induced expression of the ligand PD-L1 was decreased on COPD macrophages (P = 0.04) with a corresponding increase in IFN-γ release from infected COPD explants compared with controls (P = 0.04). This study has established a signal of cytotoxic immune dysfunction and aberrant immune regulation in the COPD lung that may explain both the susceptibility to viral infection and the excessive inflammation associated with exacerbations.

Dysregulation of Antiviral Function of CD8+ T Cells in the Chronic Obstructive Pulmonary Disease Lung. Role of the PD-1–PD-L1 Axis

PubMed Central

McKendry, Richard T.; Spalluto, C. Mirella; Burke, Hannah; Nicholas, Ben; Cellura, Doriana; Al-Shamkhani, Aymen; Staples, Karl J.

2016-01-01

Rationale: Patients with chronic obstructive pulmonary disease (COPD) are susceptible to respiratory viral infections that cause exacerbations. The mechanisms underlying this susceptibility are not understood. Effectors of the adaptive immune response—CD8+ T cells that clear viral infections—are present in increased numbers in the lungs of patients with COPD, but they fail to protect against infection and may contribute to the immunopathology of the disease. Objectives: CD8+ function and signaling through the programmed cell death protein (PD)-1 exhaustion pathway were investigated as a potential key mechanism of viral exacerbation of the COPD lung. Methods: Tissue from control subjects and patients with COPD undergoing lung resection was infected with live influenza virus ex vivo. Viral infection and expression of lung cell markers were analyzed using flow cytometry. Measurements and Main Results: The proportion of lung CD8+ T cells expressing PD-1 was greater in COPD (mean, 16.2%) than in controls (4.4%, P = 0.029). Only epithelial cells and macrophages were infected with influenza, and there was no difference in the proportion of infected cells between controls and COPD. Infection up-regulated T-cell PD-1 expression in control and COPD samples. Concurrently, influenza significantly up-regulated the marker of cytotoxic degranulation (CD107a) on CD8+ T cells (P = 0.03) from control subjects but not on those from patients with COPD. Virus-induced expression of the ligand PD-L1 was decreased on COPD macrophages (P = 0.04) with a corresponding increase in IFN-γ release from infected COPD explants compared with controls (P = 0.04). Conclusions: This study has established a signal of cytotoxic immune dysfunction and aberrant immune regulation in the COPD lung that may explain both the susceptibility to viral infection and the excessive inflammation associated with exacerbations. PMID:26517304

KRASG12D expression in lung-resident myeloid cells promotes pulmonary LCH-like neoplasm sensitive to statin treatment

PubMed Central

Giblett, Susan; Pritchard, Catrin

2017-01-01

Langerhans cell histiocytosis (LCH) is a rare histiocytic neoplasm associated with somatic mutations in the genes involved in the RAF/MEK/extracellular signal-regulated kinase (ERK) signaling pathway. Recently, oncogenic mutations in NRAS/KRAS, upstream regulators of the RAF/MEK/ERK pathway, have been reported in pulmonary, but not in nonpulmonary, LCH cases, suggesting organ-specific contribution of oncogenic RAS to LCH pathogenesis. Using a mouse model expressing KRASG12D in the lung by nasal delivery of adenoviral Cre recombinase (Cre), here we show that KRASG12D expression in lung-resident myeloid cells induces pulmonary LCH-like neoplasms composed of pathogenic CD11chighF4/80+CD207+ cells. The pathogenic cells were mitotically inactive, but proliferating precursors were detected in primary cultures of lung tissue. These precursors were derived, at least in part, from CD11cdimCD11bintGr1− lung-resident monocytic cells transformed by KRASG12D. In contrast, BRAFV600E expression induced by the same method failed to develop LCH-like neoplasms, suggesting that each oncogene may initiate pulmonary LCH by transforming different types of lung-resident myeloid cells. In vivo treatment of the KRASG12D-induced LCH-like mouse with the cholesterol-lowering drug atorvastatin ameliorated the pathology, implicating statins as potential therapeutics against a subset of pulmonary LCH. PMID:28550040

Computer-Based Techniques for Collection of Pulmonary Function Variables during Rest and Exercise.

DTIC Science & Technology

1991-03-01

routinely Included in experimental protocols involving hyper- and hypobaric excursions. Unfortunately, the full potential of those tests Is often not...for a Pulmonary Function data acquisition system that has proven useful in the hyperbaric research laboratory. It illustrates how computers can

A cross-sectional study of pulmonary function in autobody repair workers.

PubMed Central

Parker, D L; Waller, K; Himrich, B; Martinez, A; Martin, F

1991-01-01

This study evaluated pulmonary function in workers from 39 autobody repair shops. Based on 152 White male workers with known smoking status, the mean percent predicted FEV1, FVC, and FEV1/FVC were 93.6, 96.8, and 96.6, respectively. Twenty-three percent of workers had a FEV1/FVC ratio less than the fifth percentile. Isocyanate levels ranged from nondetectable to 0.06 parts per million (STEL = 0.02 ppm). No shop had an adequate respiratory protection program. We concluded that there was an increase in abnormal pulmonary function in autobody workers. Three recommendations were made to shop owners: functional paint booths should be maintained, respiratory protection programs should be developed, and isocyanate-free paints should be used. PMID:2029053

Sleep-Disordered Breathing in Patients with Pulmonary Valve Incompetence Complicating Congenital Heart Disease.

PubMed

Miles, Susan; Ahmad, Waheed; Bailey, Amy; Hatton, Rachael; Boyle, Andrew; Collins, Nicholas

2016-12-01

Long standing pulmonary regurgitation results in deleterious effects on right heart size and function with late consequences of right heart volume overload including ventricular dilatation, propensity to arrhythmia and right heart failure. As sleep disordered breathing may predispose to elevations in pulmonary vascular resistance and associated negative effects on right ventricular function, we sought to assess this in patients with underlying congenital heart disease. We performed a pilot study to evaluate the incidence of sleep-disordered breathing in a patient population with a history of long standing pulmonary valve incompetence in patients with congenital heart disease using overnight oximetry. Patients with a background of tetralogy of Fallot repair or residual pulmonary incompetence following previous pulmonary valve intervention for congenital pulmonary stenosis were included. Twenty-two patients underwent overnight oximetry. The mean age of the cohort was 34.3 ± 15.2 years with no patients observed to have severe underlying pulmonary hypertension. Abnormal overnight oximetry was seen in 13/22 patients (59.1%) with 2/22 (9.1%) patients considered to have severe abnormalities. An important proportion of patients with a background of pulmonary incompetence complicating congenital heart disease are prone to the development of sleep-disordered breathing as assessed by overnight oximetry. Further study into the prevalence and mechanisms of sleep-disordered breathing in a larger cohort are warranted. © 2016 Wiley Periodicals, Inc.

Impact of nutritional status on body functioning in chronic obstructive pulmonary disease and how to intervene.

PubMed

Aniwidyaningsih, Wahju; Varraso, Raphaëlle; Cano, Noel; Pison, Christophe

2008-07-01

Chronic obstructive pulmonary disease is the fifth leading cause of mortality in the world. This study reviews diet as a risk or protective factor for chronic obstructive pulmonary disease, mechanisms of malnutrition, undernutrition consequences on body functioning and how to modulate nutritional status of patients with chronic obstructive pulmonary disease. Different dietary factors (dietary pattern, foods, nutrients) have been associated with chronic obstructive pulmonary disease and the course of the disease. Mechanical disadvantage, energy imbalance, disuse muscle atrophy, hypoxemia, systemic inflammation and oxidative stress have been reported to cause systemic consequences such as cachexia and compromise whole body functioning. Nutritional intervention makes it possible to modify the natural course of the disease provided that it is included in respiratory rehabilitation combining bronchodilators optimization, infection control, exercise and, in some patients, correction of hypogonadism. Diet, as a modifiable risk factor, appears more as an option to prevent and modify the course of chronic obstructive pulmonary disease. Reduction of mechanical disadvantage, physical training and anabolic agents should be used conjointly with oral nutrition supplements to overcome undernutrition and might change the prognosis of the disease in some cases. Major research challenges address the role of systemic inflammation and the best interventions for controlling it besides smoking cessation.

Left atrial function in cats with left-sided cardiac disease and pleural effusion or pulmonary edema.

PubMed

Johns, S M; Nelson, O L; Gay, J M

2012-01-01

Congestive heart failure (CHF) in cats with left-sided heart disease is sometimes manifest as pleural effusion, in other cases as pulmonary edema. Those cats with pleural effusion have more severe left atrial (LA) dysfunction than cats with pulmonary edema. 30 healthy cats, 22 cats with pleural effusion, and 12 cats with pulmonary edema. All cats were client owned. Retrospective study. Measurements of LA size and function were made using commercial software on archived echocardiograms. Cases were identified through searches of medical records and of archived echocardiograms for cats with these conditions. There was no difference (P = .3) in LA size between cats with pleural effusion and cats with pulmonary edema. Cats with pleural effusion had poorer (P = .04) LA active emptying and increased (P = .006) right ventricular (RV) diameter when compared with cats with pulmonary edema and healthy cats. Cats that exhibited LA active emptying of <7.9%, total emptying of <13.6% (diameter) or <19.4% (area), or RV diameter of >3.6 mm were significantly (P < .001) more likely to manifest pleural effusion. Poorer LA function and increased RV dimensions are associated with pleural effusion in cats with left-sided heart disease. Copyright © 2012 by the American College of Veterinary Internal Medicine.

Progressive ventilation inhomogeneity in infants with cystic fibrosis after pulmonary infection.

PubMed

Simpson, Shannon J; Ranganathan, Sarath; Park, Judy; Turkovic, Lidija; Robins-Browne, Roy M; Skoric, Billy; Ramsey, Kathryn A; Rosenow, Tim; Banton, Georgia L; Berry, Luke; Stick, Stephen M; Hall, Graham L

2015-12-01

Measures of ventilation distribution are promising for monitoring early lung disease in cystic fibrosis (CF). This study describes the cross-sectional and longitudinal impacts of pulmonary inflammation and infection on ventilation homogeneity in infants with CF.Infants diagnosed with CF underwent multiple breath washout (MBW) testing and bronchoalveolar lavage at three time points during the first 2 years of life.Measures were obtained for 108 infants on 156 occasions. Infants with a significant pulmonary infection at the time of MBW showed increases in lung clearance index (LCI) of 0.400 units (95% CI 0.150-0.648; p=0.002). The impact was long lasting, with previous pulmonary infection leading to increased ventilation inhomogeneity over time compared to those who remained free of infection (p<0.05). Infection with Haemophilus influenzae was particularly detrimental to the longitudinal lung function in young children with CF where LCI was increased by 1.069 units for each year of life (95% CI 0.484-1.612; p<0.001).Pulmonary infection during the first year of life is detrimental to later lung function. Therefore, strategies aimed at prevention, surveillance and eradication of pulmonary pathogens are paramount to preserve lung function in infants with CF. Copyright ©ERS 2015.

Right heart adaptation to pulmonary arterial hypertension: physiology and pathobiology.

PubMed

Vonk-Noordegraaf, Anton; Haddad, François; Chin, Kelly M; Forfia, Paul R; Kawut, Steven M; Lumens, Joost; Naeije, Robert; Newman, John; Oudiz, Ronald J; Provencher, Steve; Torbicki, Adam; Voelkel, Norbert F; Hassoun, Paul M

2013-12-24

Survival in patients with pulmonary arterial hypertension (PAH) is closely related to right ventricular (RV) function. Although pulmonary load is an important determinant of RV systolic function in PAH, there remains a significant variability in RV adaptation to pulmonary hypertension. In this report, the authors discuss the emerging concepts of right heart pathobiology in PAH. More specifically, the discussion focuses on the following questions. 1) How is right heart failure syndrome best defined? 2) What are the underlying molecular mechanisms of the failing right ventricle in PAH? 3) How are RV contractility and function and their prognostic implications best assessed? 4) What is the role of targeted RV therapy? Throughout the report, the authors highlight differences between right and left heart failure and outline key areas of future investigation. Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

A systematic review of the role of vitamin insufficiencies and supplementation in COPD.

PubMed

Tsiligianni, Ioanna G; van der Molen, Thys

2010-12-06

Pulmonary inflammation, oxidants-antioxidants imbalance, as well as innate and adaptive immunity have been proposed as playing a key role in the development of COPD. The role of vitamins, as assessed either by food frequency questionnaires or measured in serum levels, have been reported to improve pulmonary function, reduce exacerbations and improve symptoms. Vitamin supplements have therefore been proposed to be a potentially useful additive to COPD therapy. A systematic literature review was performed on the association of vitamins and COPD. The role of vitamin supplements in COPD was then evaluated. The results of this review showed that various vitamins (vitamin C, D, E, A, beta and alpha carotene) are associated with improvement in features of COPD such as symptoms, exacerbations and pulmonary function. High vitamin intake would probably reduce the annual decline of FEV1. There were no studies that showed benefit from vitamin supplementation in improved symptoms, decreased hospitalization or pulmonary function.

Pulmonary artery relative area change detects mild elevations in pulmonary vascular resistance and predicts adverse outcome in pulmonary hypertension.

PubMed

Swift, Andrew J; Rajaram, Smitha; Condliffe, Robin; Capener, Dave; Hurdman, Judith; Elliot, Charlie; Kiely, David G; Wild, Jim M

2012-10-01

The aim of this study was to evaluate the clinical use of magnetic resonance imaging measurements related to pulmonary artery stiffness in the evaluation of pulmonary hypertension (PH). A total of 134 patients with suspected PH underwent right heart catheterization (RHC) and magnetic resonance imaging on a 1.5-T scanner within 2 days. Phase contrast imaging at the pulmonary artery trunk and cine cardiac views were acquired. Pulmonary artery area change (AC), relative AC (RAC), compliance (AC/pulse pressure from RHC), distensibility (RAC/pulse pressure from RHC), right ventricular functional indices, and right ventricular mass were all derived. Regression curve fitting identified the statistical model of best fit between RHC measurements and pulmonary artery stiffness indices. The diagnostic accuracy and prognostic value of noninvasive AC and RAC were also assessed. The relationship between pulmonary vascular resistance and pulmonary artery RAC was best reflected by an inverse linear model. Patients with mild elevation in pulmonary vascular resistance (<4 Woods units) demonstrated reduced RAC (P = 0.02) and increased right ventricular mass index (P < 0.0001) without significant loss of right ventricular function (P = 0.17). At follow-up of 0 to 40 months, 18 patients with PH had died (16%). Analysis of Kaplan-Meier plots showed that both AC and RAC predicted mortality (log-rank test, P = 0.046 and P = 0.012, respectively). Area change and RAC were also predictors of mortality using univariate Cox proportional hazards regression analysis (P = 0.046 and P = 0.03, respectively). Noninvasive assessment of pulmonary artery RAC is a marker sensitive to early increased vascular resistance in PH and is a predictor of adverse outcome.

Effect of Emphysema Extent on Serial Lung Function in Patients with Idiopathic Pulmonary Fibrosis.

PubMed

Cottin, Vincent; Hansell, David M; Sverzellati, Nicola; Weycker, Derek; Antoniou, Katerina M; Atwood, Mark; Oster, Gerry; Kirchgaessler, Klaus-Uwe; Collard, Harold R; Wells, Athol U

2017-11-01

Patients with idiopathic pulmonary fibrosis and emphysema may have artificially preserved lung volumes. In this post hoc analysis, we investigated the relationship between baseline emphysema and fibrosis extents, as well as pulmonary function changes, over 48 weeks. Data were pooled from two phase III, randomized, double-blind, placebo-controlled trials of IFN-γ-1b in idiopathic pulmonary fibrosis (GIPF-001 [NCT00047645] and GIPF-007 [NCT00075998]). Patients with Week 48 data, baseline high-resolution computed tomographic images, and FEV 1 /FVC ratios less than 0.8 or greater than 0.9 (<0.7 or >0.9 in GIPF-007), as well as randomly selected patients with ratios of 0.8-0.9 and 0.7-0.8, were included. Changes from baseline in pulmonary function at Week 48 were analyzed by emphysema extent. The relationship between emphysema and fibrosis extents and change in pulmonary function was assessed using multivariate linear regression. Emphysema was identified in 38% of patients. A negative correlation was observed between fibrosis and emphysema extents (r = -0.232; P < 0.001). In quartile analysis, patients with the greatest emphysema extent (28 to 65%) showed the smallest FVC decline, with a difference of 3.32% at Week 48 versus patients with no emphysema (P = 0.047). In multivariate analyses, emphysema extent greater than or equal to 15% was associated with significantly reduced FVC decline over 48 weeks versus no emphysema or emphysema less than 15%. No such association was observed for diffusing capacity of the lung for carbon monoxide or composite physiologic index. FVC measurements may not be appropriate for monitoring disease progression in patients with idiopathic pulmonary fibrosis and emphysema extent greater than or equal to 15%.

Evaluation of recently validated non-invasive formula using basic lung functions as new screening tool for pulmonary hypertension in idiopathic pulmonary fibrosis patients

PubMed Central

Ghanem, Maha K.; Makhlouf, Hoda A.; Agmy, Gamal R.; Imam, Hisham M. K.; Fouad, Doaa A.

2009-01-01

BACKGROUND: A prediction formula for mean pulmonary artery pressure (MPAP) using standard lung function measurement has been recently validated to screen for pulmonary hypertension (PH) in idiopathic pulmonary fibrosis (IPF) patients. OBJECTIVE: To test the usefulness of this formula as a new non invasive screening tool for PH in IPF patients. Also, to study its correlation with patients' clinical data, pulmonary function tests, arterial blood gases (ABGs) and other commonly used screening methods for PH including electrocardiogram (ECG), chest X ray (CXR), trans-thoracic echocardiography (TTE) and computerized tomography pulmonary angiography (CTPA). MATERIALS AND METHODS: Cross-sectional study of 37 IPF patients from tertiary hospital. The accuracy of MPAP estimation was assessed by examining the correlation between the predicted MPAP using the formula and PH diagnosed by other screening tools and patients' clinical signs of PH. RESULTS: There was no statistically significant difference in the prediction of PH using cut off point of 21 or 25 mm Hg (P = 0.24). The formula-predicted MPAP greater than 25 mm Hg strongly correlated in the expected direction with O2 saturation (r = −0.95, P < 0.000), partial arterial O2 tension (r = −0.71, P < 0.000), right ventricular systolic pressure measured by TTE (r = 0.6, P < 0.000) and hilar width on CXR (r = 0.31, P = 0.03). Chest symptoms, ECG and CTPA signs of PH poorly correlated with the same formula (P > 0.05). CONCLUSIONS: The prediction formula for MPAP using standard lung function measurements is a simple non invasive tool that can be used as TTE to screen for PH in IPF patients and select those who need right heart catheterization. PMID:19881164

Intermedin Stabilized Endothelial Barrier Function and Attenuated Ventilator-induced Lung Injury in Mice

PubMed Central

Müller-Redetzky, Holger Christian; Kummer, Wolfgang; Pfeil, Uwe; Hellwig, Katharina; Will, Daniel; Paddenberg, Renate; Tabeling, Christoph; Hippenstiel, Stefan; Suttorp, Norbert; Witzenrath, Martin

2012-01-01

Background Even protective ventilation may aggravate or induce lung failure, particularly in preinjured lungs. Thus, new adjuvant pharmacologic strategies are needed to minimize ventilator-induced lung injury (VILI). Intermedin/Adrenomedullin-2 (IMD) stabilized pulmonary endothelial barrier function in vitro. We hypothesized that IMD may attenuate VILI-associated lung permeability in vivo. Methodology/Principal Findings Human pulmonary microvascular endothelial cell (HPMVEC) monolayers were incubated with IMD, and transcellular electrical resistance was measured to quantify endothelial barrier function. Expression and localization of endogenous pulmonary IMD, and its receptor complexes composed of calcitonin receptor-like receptor (CRLR) and receptor activity-modifying proteins (RAMPs) 1–3 were analyzed by qRT-PCR and immunofluorescence in non ventilated mouse lungs and in lungs ventilated for 6 h. In untreated and IMD treated mice, lung permeability, pulmonary leukocyte recruitment and cytokine levels were assessed after mechanical ventilation. Further, the impact of IMD on pulmonary vasoconstriction was investigated in precision cut lung slices (PCLS) and in isolated perfused and ventilated mouse lungs. IMD stabilized endothelial barrier function in HPMVECs. Mechanical ventilation reduced the expression of RAMP3, but not of IMD, CRLR, and RAMP1 and 2. Mechanical ventilation induced lung hyperpermeability, which was ameliorated by IMD treatment. Oxygenation was not improved by IMD, which may be attributed to impaired hypoxic vasoconstriction due to IMD treatment. IMD had minor impact on pulmonary leukocyte recruitment and did not reduce cytokine levels in VILI. Conclusions/Significance IMD may possibly provide a new approach to attenuate VILI. PMID:22563471

Pulmonary function recovery demonstrated by ventilation-perfusion scan after posterior vertebral column resection for severe adolescent idiopathic scoliosis: a case report.

PubMed

Fujii, Takeshi; Watanabe, Kota; Toyama, Yoshiaki; Matsumoto, Morio

2014-09-01

Case report. To describe a case in which a patient regained pulmonary function, assessed by ventilation-perfusion scans, after undergoing posterior vertebral column resection (VCR) to correct severe adolescent idiopathic scoliosis (AIS) with associated pulmonary dysfunction. Pulmonary improvement after corrective surgery for AIS has been reported. Ventilation-perfusion scans are useful for assessing pulmonary function. However, these scans have not been used to examine the recovery of pulmonary function after VCR for severe AIS with pulmonary dysfunction. A patient was described in whom ventilation-perfusion scans were used to examine improvements in impaired air ventilation and blood perfusion after VCR surgery for severe AIS. The relevant literature was reviewed. An 18-year-old male came to Keio University Hospital with exertional dyspnea associated with severe AIS. Radiographs showed severe scoliosis of 91° at T6-T12, and hypokyphosis of 6° at T5-T12. Computed tomographic scans showed narrowing of the thoracic cage on the convex side of the main thoracic curve, with the vertebral bodies at the apex of the curve obstructing the right main bronchus. Pulmonary function tests revealed a percent vital capacity of 44% and percent forced expiratory volume in 1 second of 76%. A ventilation-perfusion scan showed decreased air ventilation and blood perfusion in the right lung. The patient underwent posterior correction surgery, which used segmental pedicle screws with a VCR at T9. The scoliosis was corrected to 28°, and the kyphosis to 14°. Postoperative computed tomographic scans showed expansion of the right main bronchus. A ventilation-perfusion scan conducted 1 year after surgery showed clear improvement in both ventilation and blood perfusion in the right lung. The patient's forced expiratory volume in 1 second had increased to 91%. This is the first report in which ventilation-perfusion scans were used to examine improvements in impaired air ventilation and blood perfusion after VCR surgery in a patient with severe AIS. N/A.

Comparison of Linear and Non-linear Regression Analysis to Determine Pulmonary Pressure in Hyperthyroidism.

PubMed

Scarneciu, Camelia C; Sangeorzan, Livia; Rus, Horatiu; Scarneciu, Vlad D; Varciu, Mihai S; Andreescu, Oana; Scarneciu, Ioan

2017-01-01

This study aimed at assessing the incidence of pulmonary hypertension (PH) at newly diagnosed hyperthyroid patients and at finding a simple model showing the complex functional relation between pulmonary hypertension in hyperthyroidism and the factors causing it. The 53 hyperthyroid patients (H-group) were evaluated mainly by using an echocardiographical method and compared with 35 euthyroid (E-group) and 25 healthy people (C-group). In order to identify the factors causing pulmonary hypertension the statistical method of comparing the values of arithmetical means is used. The functional relation between the two random variables (PAPs and each of the factors determining it within our research study) can be expressed by linear or non-linear function. By applying the linear regression method described by a first-degree equation the line of regression (linear model) has been determined; by applying the non-linear regression method described by a second degree equation, a parabola-type curve of regression (non-linear or polynomial model) has been determined. We made the comparison and the validation of these two models by calculating the determination coefficient (criterion 1), the comparison of residuals (criterion 2), application of AIC criterion (criterion 3) and use of F-test (criterion 4). From the H-group, 47% have pulmonary hypertension completely reversible when obtaining euthyroidism. The factors causing pulmonary hypertension were identified: previously known- level of free thyroxin, pulmonary vascular resistance, cardiac output; new factors identified in this study- pretreatment period, age, systolic blood pressure. According to the four criteria and to the clinical judgment, we consider that the polynomial model (graphically parabola- type) is better than the linear one. The better model showing the functional relation between the pulmonary hypertension in hyperthyroidism and the factors identified in this study is given by a polynomial equation of second degree where the parabola is its graphical representation.

Effect of Vandetanib on Andes virus survival in the hamster model of Hantavirus pulmonary syndrome.

PubMed

Bird, Brian H; Shrivastava-Ranjan, Punya; Dodd, Kimberly A; Erickson, Bobbie R; Spiropoulou, Christina F

2016-08-01

Hantavirus pulmonary syndrome (HPS) is a severe disease caused by hantavirus infection of pulmonary microvascular endothelial cells leading to microvascular leakage, pulmonary edema, pleural effusion and high case fatality. Previously, we demonstrated that Andes virus (ANDV) infection caused up-regulation of vascular endothelial growth factor (VEGF) and concomitant downregulation of the cellular adhesion molecule VE-cadherin leading to increased permeability. Analyses of human HPS-patient sera have further demonstrated increased circulating levels of VEGF. Here we investigate the impact of a small molecule antagonist of the VEGF receptor 2 (VEGFR-2) activation in vitro, and overall impact on survival in the Syrian hamster model of HPS. Copyright © 2016. Published by Elsevier B.V.

The prognostic value of natural killer cell infiltration in resected pulmonary adenocarcinoma.

PubMed

Takanami, I; Takeuchi, K; Giga, M

2001-06-01

Natural cytotoxicity caused by mediated natural killer cells is believed to play an important role in host-cancer defense mechanisms. Immunohistochemically, we have detected natural killer cells in tissue specimens from patients with pulmonary adenocarcinoma and have assessed their clinical characteristics. Using the monoclonal antibody for CD57 specific marker for natural killer cells, we quantified natural killer cell infiltration in 150 patients with pulmonary adenocarcinoma who underwent curative tumor resection to investigate the relationship between natural killer cell counts and clinicopathologic factors and prognosis. The natural killer cell count was significantly related to the regulation of tumor progression, involving T classification, N classification, and stage (P =.01 for T classification or stage; P =.02 for N classification). A significant difference in the rate of patient survival was detected between those patients whose tumors had either high or low natural killer cell counts in both the overall and stage I groups (P =.0002 for the overall group; P =.049 for the stage I group). These data indicate that natural killer infiltration may contribute to the regulation of tumor progression and that the natural killer cell count can serve as a useful prognostic marker in overall and stage I pulmonary adenocarcinoma.

Effects of exercise training on pulmonary mechanics and functional status in patients with prolonged mechanical ventilation.

PubMed

Chen, Yen-Huey; Lin, Hui-Ling; Hsiao, Hsiu-Feng; Chou, Lan-Ti; Kao, Kuo-Chin; Huang, Chung-Chi; Tsai, Ying-Huang

2012-05-01

The functional status and outcomes in patients with prolonged mechanical ventilation (PMV) are often limited by poor endurance and pulmonary mechanics, which result from the primary diseases or prolonged time bedridden. We evaluate the impact of exercise training on pulmonary mechanics, physical functional status, and hospitalization outcomes in PMV patients. Twenty-seven subjects with PMV in our respiratory care center (RCC) were divided randomly into an exercise training group (n = 12) and a control group (n = 15). The exercise program comprised 10 sessions of exercise training. The measurement of pulmonary mechanics and physical functional status (Functional Independence Measurement and Barthel index) were performed pre-study and post-study. The hospitalization outcomes included: days of mechanical ventilation, hospitalization days, and weaning and mortality rates during RCC stay. The training group had significant improvement in tidal volume (143.6 mL vs 192.5 mL, P = .02) and rapid shallow breathing index after training (162.2 vs 110.6, P = .009). No significant change was found in the control group except respiratory rate. Both groups had significant improvement in functional status during the study. However, the training group had greater changes in FIM score than the control group (44.6 vs 34.2, P = .024). The training group also had shorter RCC stay and higher weaning and survival rates than the control group, although no statistical difference was found. Subjects with PMV in our RCC demonstrated significant improvement in pulmonary mechanics and functional status after exercise training. The application of exercise training may be helpful for PMV patients to improve hospitalization outcomes.

MicroRNA-Dependent Control of Serotonin-Induced Pulmonary Arterial Contraction.

PubMed

Dahan, Diana; Hien, Tran Thi; Tannenberg, Philip; Ekman, Mari; Rippe, Catarina; Boettger, Thomas; Braun, Thomas; Tran-Lundmark, Karin; Tran, Phan-Kiet; Swärd, Karl; Albinsson, Sebastian

2017-01-01

Serotonin (5-HT) is considered to play a role in pulmonary arterial hypertension by regulating vascular remodeling and smooth muscle contractility. Here, arteries from mice with inducible and smooth muscle-specific deletion of Dicer were used to address mechanisms by which microRNAs control 5-HT-induced contraction. Mice were used 5 weeks after Dicer deletion, and pulmonary artery contractility was analyzed by wire myography. No change was seen in right ventricular systolic pressure following dicer deletion, but systemic blood pressure was reduced. Enhanced 5-HT-induced contraction in Dicer KO pulmonary arteries was associated with increased 5-HT2A receptor mRNA expression whereas 5-HT1B and 5-HT2B receptor mRNAs were unchanged. Contraction by the 5-HT2A agonist TCB-2 was increased in Dicer KO as was the response to the 5-HT2B agonist BW723C86. Effects of Src and protein kinase C inhibition were similar in control and KO arteries, but the effect of inhibition of Rho kinase was reduced. We identified miR-30c as a potential candidate for 5-HT2A receptor regulation as it repressed 5-HT2A mRNA and protein. Our findings show that 5-HT receptor signaling in the arterial wall is subject to regulation by microRNAs and that this entails altered 5-HT2A receptor expression and signaling. © 2017 S. Karger AG, Basel.

[Regulation of airway stem cell proliferation in idiopathic pulmonary fibrosis].

PubMed

Yang, S X; Wu, Q; Sun, X; Li, X; Li, K; Xu, L; Li, Y; Zhang, Q Y; Zhang, Y C; Chen, H Y

2016-09-01

To investigate the effect of fibroblasts on regulating airway stem cell proliferation in idiopathic pulmonary fibrosis. Lung cell suspension was prepared from β-actin-GFP mice. Airway stem cells were obtained by fluorescence activated cell sorting and co-cultured with lung fibroblasts. The fibroblasts were treated with TGF-β inhibitor SB43142. The expression of growth factors FGF1/2 and the effect of FGF1/2 on stem cell proliferation were observed. The cloning efficiency of airway stem cells, when co-cultured with normal lung fibroblast cells for 8 days, was (3.5±1.1)%, while the cloning efficiency was reduced to (0.04±0.04)% when co-cultured with lung fibroblasts from idiopathic pulmonary fibrosis patients. The difference between the 2 groups was statistically significant(P=0.002 5). TGF-β receptor inhibitor SB431542 increased lung fibroblast growth factors FGF1/2 expression.FGF1 mRNA expression was increased to the experimental group 0.005 5 from 0.000 2 in the control group.FGF2 mRNA expression of the amount raised to the experimental group 0.000 15 from 0.000 8 in the control group.FGF1/2 promoted the growth of airway stem cells. After FGF1/2 was co-cultured with normal lung fibroblast cells for 8 days, the cloning efficiency of airway stem cells was (0.3±0.1)%. During the development of idiopathic pulmonary fibrosis, fibroblast secreted FGF1/2 regulate airway stem cell proliferation.

The role of necroptosis in pulmonary diseases.

PubMed

Mizumura, Kenji; Maruoka, Shuichiro; Gon, Yasuhiro; Choi, Augustine M K; Hashimoto, Shu

2016-11-01

By regulating the cell number and eliminating harmful cells, programmed cell death plays a critical role in development, homeostasis, and disease. While apoptosis is a recognized form of programmed cell death, necrosis was considered a type of uncontrolled cell death induced by extreme physical or chemical stress. However, recent studies have revealed the existence of a genetically programmed and regulated form of necrosis, termed necroptosis. Necroptosis is defined as necrotic cell death that is dependent on receptor-interacting protein kinase 3 (RIPK3). RIPK3, receptor-interacting protein kinase 1 (RIPK1), and a mixed-lineage kinase domain-like protein (MLKL) form a multiprotein complex called a necrosome. Although necroptosis generally provides a cell-autonomous host defense, on the other hand, cell rupture caused by necroptosis induces inflammation through the release of damage-associated molecular patterns, such as mitochondrial DNA, HMGB1, and IL-1. Previously, necroptosis was considered an alternative to apoptosis, but it is becoming increasingly clear that necroptosis itself is relevant to clinical disease, independent of apoptosis. According to some recent studies, autophagy, a cellular process for organelle and protein turnover, regulates necroptosis. This review outlines the principal components of necroptosis and provides an overview of the emerging importance of necroptosis in the pathogenesis of pulmonary disease, including chronic obstructive pulmonary disease, lung cancer, infection, and sepsis. We also discuss the molecular relationship between necroptosis and autophagy. Strategies targeting necroptosis may yield novel therapies for pulmonary diseases. Copyright © 2016 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

Novel putative pharmacological therapies to protect the right ventricle in pulmonary hypertension: a review of current literature

PubMed Central

Schulz, Rainer; Sliwa, Karen; Schermuly, Ralph Theo; Lecour, Sandrine

2017-01-01

Pulmonary hypertension (PH) is defined by elevated mean pulmonary artery pressure following the pathological remodelling of small pulmonary arteries. An increase in right ventricular (RV) afterload results in RV hypertrophy and RV failure. The pathophysiology of PH, and RV remodelling in particular, is not well understood, thus explaining, at least in part, why current PH therapies have a limited effect. Existing therapies mostly target the pulmonary circulation. Because the remodelled RV fails to support normal cardiac function, patients eventually succumb from RV failure. Developing novel therapies that directly target the function of the RV may therefore benefit patients with PH. In the past decade, several promising studies have investigated novel cardioprotective strategies in experimental models of PH. This review aims to comprehensively discuss and highlight these novel experimental approaches to confer, in the long‐term, greater health benefit in patients with PH. PMID:28099680

Electrocardiographic screening for emphysema: the frontal plane P axis.

PubMed

Baljepally, R; Spodick, D H

1999-03-01

Because the most characteristic and sensitive electrocardiographic (ECG) correlate of pulmonary emphysema in adults is verticalization of the frontal plane P-wave vector (P axis), we investigated its strength as a lone criterion to screen for obstructive pulmonary disease (OPD) in an adult hospital population. In all, 954 consecutive unselected ECGs were required to yield 100 with P axis > or = +70 degrees (unequivocally negative P in a VL during sinus rhythm) and pulmonary function tests. and 100 with P axis < or = +50 degrees (unequivocally positive P-aVL). Obstructive pulmonary disease by both pulmonary function test and clinical criteria was present in 89 of 100 patients with vertical P axes and 4 of 100 patients without OPD. The high sensitivity (89% for this series) and high specificity (96%) makes vertical P axis a useful screening criterion. Its at-a-glance simplicity makes it "user-friendly."

Perfusion defects in pulmonary perfusion iodine maps: causes and semiology.

PubMed

Bustos Fiore, A; González Vázquez, M; Trinidad López, C; Mera Fernández, D; Costas Álvarez, M

2017-12-14

to describe the usefulness of dual-energy CT for obtaining pulmonary perfusion maps to provide morphological and functional information in patients with pulmonary embolisms. To review the semiology of perfusion defects due to pulmonary embolism so they can be differentiated from perfusion defects due to other causes: alterations outside the range used in the iodine map caused by other diseases of the lung parenchyma or artifacts. CT angiography of the pulmonary arteries is the technique of choice for the diagnosis of pulmonary embolisms. New dual-energy CT scanners are useful for detecting perfusion defects secondary to complete or partial obstruction of pulmonary arteries and is most useful for detecting pulmonary embolisms in subsegmental branches. Copyright © 2017 SERAM. Publicado por Elsevier España, S.L.U. All rights reserved.

Cardiopulmonary Exercise Testing in Patients Following Massive and Submassive Pulmonary Embolism.

PubMed

Albaghdadi, Mazen S; Dudzinski, David M; Giordano, Nicholas; Kabrhel, Christopher; Ghoshhajra, Brian; Jaff, Michael R; Weinberg, Ido; Baggish, Aaron

2018-03-03

Little data exist regarding the functional capacity of patients following acute pulmonary embolism. We sought to characterize the natural history of symptom burden, right ventricular (RV) structure and function, and exercise capacity among survivors of massive and submassive pulmonary embolism. Survivors of submassive or massive pulmonary embolism (n=20, age 57±13.3 years, 8/20 female) underwent clinical evaluation, transthoracic echocardiography, and cardiopulmonary exercise testing at 1 and 6 months following hospital discharge. At 1 month, 9/20 (45%) patients had New York Heart Association II or greater symptoms, 13/20 (65%) demonstrated either persistent RV dilation or systolic dysfunction, and 14/20 (70%) had objective exercise impairment as defined by a peak oxygen consumption (V˙O 2 ) of <80% of age-sex predicted maximal values (16.25 [13.4-20.98] mL/kg per minute). At 6 months, no appreciable improvements in symptom severity, RV structure or function, and peak V˙O 2 (17.45 [14.08-22.48] mL/kg per minute, P =NS) were observed. No patients demonstrated an exercise limitation attributable to either RV/pulmonary vascular coupling, as defined by a VE/VCO 2 slope >33, or a pulmonary mechanical limit to exercise at either time point. Similarly, persistent RV dilation or dysfunction was not significantly related to symptom burden or peak V˙O 2 at either time point. Persistent symptoms, abnormalities of RV structure and function, and objective exercise limitation are common among survivors of massive and submassive pulmonary embolism. Functional impairment appears to be attributable to general deconditioning rather than intrinsic cardiopulmonary limitation, suggesting an important role for prescribed exercise rehabilitation as a means toward improved patient outcomes and quality of life. © 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

A combined pulmonary function and emphysema score prognostic index for staging in Chronic Obstructive Pulmonary Disease.

PubMed

Boutou, Afroditi K; Nair, Arjun; Douraghi-Zadeh, Dariush; Sandhu, Ranbir; Hansell, David M; Wells, Athol U; Polkey, Michael I; Hopkinson, Nicholas S

2014-01-01

Chronic Obstructive Pulmonary Disease (COPD) is characterized by high morbidity and mortality. Lung computed tomography parameters, individually or as part of a composite index, may provide more prognostic information than pulmonary function tests alone. To investigate the prognostic value of emphysema score and pulmonary artery measurements compared with lung function parameters in COPD and construct a prognostic index using a contingent staging approach. Predictors of mortality were assessed in COPD outpatients whose lung computed tomography, spirometry, lung volumes and gas transfer data were collected prospectively in a clinical database. Univariate and multivariate Cox proportional hazard analysis models with bootstrap techniques were used. 169 patients were included (59.8% male, 61.1 years old; Forced Expiratory Volume in 1 second % predicted: 40.5±19.2). 20.1% died; mean survival was 115.4 months. Age (HR = 1.098, 95% Cl = 1.04-1.252) and emphysema score (HR = 1.034, 95% CI = 1.007-1.07) were the only independent predictors of mortality. Pulmonary artery dimensions were not associated with survival. An emphysema score of 55% was chosen as the optimal threshold and 30% and 65% as suboptimals. Where emphysema score was between 30% and 65% (intermediate risk) the optimal lung volume threshold, a functional residual capacity of 210% predicted, was applied. This contingent staging approach separated patients with an intermediate risk based on emphysema score alone into high risk (Functional Residual Capacity ≥210% predicted) or low risk (Functional Residual Capacity <210% predicted). This approach was more discriminatory for survival (HR = 3.123; 95% CI = 1.094-10.412) than either individual component alone. Although to an extent limited by the small sample size, this preliminary study indicates that the composite Emphysema score-Functional Residual Capacity index might provide a better separation of high and low risk patients with COPD, than other individual predictors alone.

The Influence of Type 1 Diabetes Mellitus on Pulmonary Function and Exercise Capacity - Results from the Study of Health in Pomerania (SHIP).

PubMed

Stubbe, Beate; Schipf, Sabine; Schäper, Christoph; Felix, Stephan B; Steveling, Antje; Nauck, Matthias; Völzke, Henry; Wallaschofski, Henri; Friedrich, Nele; Ewert, Ralf; Ittermann, Till; Gläser, Sven

2017-01-01

Background: Diabetes mellitus Type 1 (T1DM) is associated with metabolic and microvascular diseases as part of a multi-organ and multi-systemic disorder. The dense network of capillary vessels in the lungs may change during the course of the development of microangiopathy. The connective tissue as well as alveoli may be subjected to non-enzymatic glycosylation of proteins which may in turn affect pulmonary function. Previous studies investigating lung function in patients with type 1 diabetes have only been performed on small numbers of patients. Our study is based on population data of the Study of Health in Pomerania (SHIP). Objective: To investigate the influence of metabolic control on pulmonary system function and to establish a decreased pulmonary system function as a late complication of T1DM in a population based setting. Methods: The study is a case matched study with multiple controls based on participants with T1DM (SHIP-DM-1, n=73) and non-diabetics (SHIP-1, n=292) from the population based study of Pomerania. Data on lung function and exercise performance stratified by age, sex, body mass index and smoking habits in participants with T1DM and without diabetes were matched. Results: Participants with T1DM showed a significantly lower total lung capacity, residual volume and forced vital capacity. The transfer factor for carbon monoxide, the maximum power output and oxygen uptake during exercise were significantly decreased in comparison to the general population without diabetes. Conclusion: The pattern of abnormal pulmonary function as observed in the present study with a reduction in lung volume parameters and reduced oxygen uptake in participants with T1DM suggests a restrictive type of lung disease caused by an intrinsic lung tissue derangement as well as pulmonary microangiopathy. © Georg Thieme Verlag KG Stuttgart · New York.

Non-invasive pulmonary function test on Morquio Patients

PubMed Central

Kubaski, Francyne; Tomatsu, Shunji; Patel, Pravin; Shimada, Tsutomu; Xie, Li; Yasuda, Eriko; Mason, Robert; Mackenzie, William G.; Theroux, Mary; Bober, Michael B.; Oldham, Helen M.; Orii, Tadao; Shaffer, Thomas H.

2015-01-01

In clinical practice, respiratory function tests are difficult to perform in Morquio syndrome patients due to their characteristic skeletal dysplasia, small body size and lack of cooperation of young patients, where in some cases, conventional spirometry for pulmonary function is too challenging. To establish feasible clinical pulmonary endpoints and determine whether age impacts lung function in Morquio patients non-invasive pulmonary tests and conventional spirometry were evaluated. The non-invasive pulmonary tests: impulse oscillometry system, pneumotachography, and respiratory inductance plethysmography in conjunction with conventional spirometry were evaluated in twenty-two Morquio patients (18 Morquio A and 4 Morquio B) (7 males), ranging from 3 and 40 years of age. Twenty-two patients were compliant with non-invasive tests (100%) with exception of IOS (81.8%–18 patients). Seventeen patients (77.3%) were compliant with spirometry testing. All subjects had normal vital signs at rest including > 95% oxygen saturation, end tidal CO2 (38–44 mmHg), and age-appropriate heart rate (mean=98.3, standard deviation=19) (two patients were deviated). All patients preserved normal values in impulse oscillometry system, pneumotachography, and respiratory inductance plethysmography, although predicted forced expiratory volume total (72.8 ± 6.9 SE%) decreased with age and was below normal; phase angle (35.5 ± 16.5 Degrees), %Rib Cage (41.6 ± 12.7%), resonant frequency, and forced expiratory volume in one second/forced expiratory volume total (110.0 ± 3.2 SE%) were normal and not significantly impacted by age. The proposed non-invasive pulmonary function tests are able to cover a greater number of patients (young patients and/or wheel-chair bound), thus providing a new diagnostic approach for the assessment of lung function in Morquio syndrome which in many cases may be difficult to evaluate. Morquio patients studied herein demonstrated no clinical or functional signs of restrictive and/or obstructive lung disease. PMID:26116954

Sub-xyphoid pleural drain as a determinant of functional capacity and clinical results after off-pump coronary artery bypass surgery: a randomized clinical trial.

PubMed

Guizilini, Solange; Alves, Daniel F; Bolzan, Douglas W; Cancio, Andreia S A; Regenga, Marisa M; Moreira, Rita S L; Trimer, Renata; Gomes, Walter J

2014-09-01

The aim of this trial was to compare functional capacity, pulmonary shunt fraction and clinical outcomes between patients undergoing pleurotomy with a pleural drain inserted in the sub-xyphoid position and patients with a pleural drain placed in the intercostal position after off-pump coronary artery bypass surgery. Patients were randomized into two groups according to the pleural drain site: Group II (n = 33 intercostal pleural drain); and Group SI (n = 35 sub-xyphoid pleural drain). Functional capacity was assessed by the distance covered on the 6-min walking test performed preoperatively and on postoperative day (POD) 5; in addition, pulmonary function test was determined preoperatively and on POD 1 and 5. Pulmonary shunt fraction was evaluated preoperatively and on POD 1, and clinical outcomes were recorded throughout the study. Group SI had better preservation of lung volumes and capacities in POD compared with Group II (P <0.05). Pulmonary shunt fraction increased in both groups postoperatively; however, Group SI showed a smaller pulmonary shunt fraction (0.26 ± 0.04 vs 0.21 ± 0.04%; P = 0.0014). Functional capacity was significantly reduced in both groups on POD 5; however, Group SI showed better preservation of functional capacity (P = 0.0001). Group SI had better postoperative clinical results, with lower incidence of atelectasis and pleural effusion (P <0.05), lower pain scores (P <0.0001), and shorter orotracheal intubation and hospitalization lengths (P <0.001). Sub-xyphoid pleural drain determined better functional capacity and exercise tolerance with a smaller pulmonary shunt fraction and improved clinical outcomes compared with intercostal pleural drainage after off-pump coronary artery bypass surgery. © The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Functional characterization of pulmonary neuroendocrine cells in lung development, injury, and tumorigenesis

USDA-ARS?s Scientific Manuscript database

Pulmonary neuroendocrine cells (PNECs) are proposed to be the first specialized cell type to appear in the lung, but their ontogeny remains obscure. Although studies of PNECs have suggested their involvement in a number of lung functions, neither their in vivo significance nor the molecular mechanis...

EFFECTS OF OZONE ON THE PULMONARY FUNCTION OF CHILDREN

EPA Science Inventory

Healthy active children, 7 to 13 years old, in a summer recreational camp were chosen as subjects to investigate the acute effects of exposure to ambient air pollution. Pulmonary function tests were administered at the camp on 16 days during a five week period in 1982. Ambient ai...

38 CFR 4.96 - Special provisions regarding evaluation of respiratory conditions.

Code of Federal Regulations, 2013 CFR

2013-07-01

... purposes except when the results of pre-bronchodilator pulmonary function tests are normal or when the... schedule unless the post-bronchodilator results were poorer than the pre-bronchodilator results. In those...-6845. (1) Pulmonary function tests (PFT's) are required to evaluate these conditions except: (i) When...

38 CFR 4.96 - Special provisions regarding evaluation of respiratory conditions.

Code of Federal Regulations, 2010 CFR

2010-07-01

... purposes except when the results of pre-bronchodilator pulmonary function tests are normal or when the... schedule unless the post-bronchodilator results were poorer than the pre-bronchodilator results. In those...-6845. (1) Pulmonary function tests (PFT's) are required to evaluate these conditions except: (i) When...

38 CFR 4.96 - Special provisions regarding evaluation of respiratory conditions.

Code of Federal Regulations, 2014 CFR

2014-07-01

... purposes except when the results of pre-bronchodilator pulmonary function tests are normal or when the... schedule unless the post-bronchodilator results were poorer than the pre-bronchodilator results. In those...-6845. (1) Pulmonary function tests (PFT's) are required to evaluate these conditions except: (i) When...

38 CFR 4.96 - Special provisions regarding evaluation of respiratory conditions.

Code of Federal Regulations, 2011 CFR

2011-07-01

... purposes except when the results of pre-bronchodilator pulmonary function tests are normal or when the... schedule unless the post-bronchodilator results were poorer than the pre-bronchodilator results. In those...-6845. (1) Pulmonary function tests (PFT's) are required to evaluate these conditions except: (i) When...

Distinct right ventricle remodeling in response to pressure overload in the rat.

PubMed

Mendes-Ferreira, P; Santos-Ribeiro, D; Adão, R; Maia-Rocha, C; Mendes-Ferreira, M; Sousa-Mendes, C; Leite-Moreira, A F; Brás-Silva, C

2016-07-01

Pulmonary arterial hypertension (PAH), the most serious chronic disorder of the pulmonary circulation, is characterized by pulmonary vasoconstriction and remodeling, resulting in increased afterload on the right ventricle (RV). In fact, RV function is the main determinant of prognosis in PAH. The most frequently used experimental models of PAH include monocrotaline- and chronic hypoxia-induced PAH, which primarily affect the pulmonary circulation. Alternatively, pulmonary artery banding (PAB) can be performed to achieve RV overload without affecting the pulmonary vasculature, allowing researchers to determine the RV-specific effects of their drugs/interventions. In this work, using two different degrees of pulmonary artery constriction, we characterize, in full detail, PAB-induced adaptive and maladaptive remodeling of the RV at 3 wk after PAB surgery. Our results show that application of a mild constriction resulted in adaptive hypertrophy of the RV, with preserved systolic and diastolic function, while application of a severe constriction resulted in maladaptive hypertrophy, with chamber dilation and systolic and diastolic dysfunction up to the isolated cardiomyocyte level. By applying two different degrees of constriction, we describe, for the first time, a reliable and short-duration PAB model in which RV adaptation can be distinguished at 3 wk after surgery. We characterize, in full detail, structural and functional changes of the RV in its response to moderate and severe constriction, allowing researchers to better study RV physiology and transition to dysfunction and failure, as well as to determine the effects of new therapies. Copyright © 2016 the American Physiological Society.

Antenatal Saireito (TJ-114) Can Improve Pulmonary Hypoplasia and Pulmonary Vascular Remodeling in Nitrofen-Induced Congenital Diaphragmatic Hernia.

PubMed

Hirako, Shima; Tsuda, Hiroyuki; Kotani, Tomomi; Sumigama, Seiji; Mano, Yukio; Nakano, Tomoko; Imai, Kenji; Li, Hua; Toyokuni, Shinya; Kikkawa, Fumitaka

2016-09-01

Congenital diaphragmatic hernia (CDH) can induce lung hypoplasia and pulmonary hypertension and is associated with high mortality. The purpose of this study is to examine the efficacy and safety of antenatal Saireito (TJ-114), a traditional Japanese herbal medicine, in a rat CDH model. Sprague-Dawley rats were exposed to an herbicide (nitrofen, 100 mg) on embryonic day 9 (E9) to induce CDH, and antenatal Saireito (2000 mg/kg/day) was orally administered from E10 to E20. On E21, fetuses were delivered. Antenatal Saireito significantly decreased the incidence of CDH (p < 0.01), increased lung volume (p < 0.01), improved alveolarization and pulmonary artery remodeling using histological analysis, and improved respiratory function using gasometric analysis (pH; p < 0.05, and PCO2 ; p < 0.01). In addition, antenatal Saireito significantly decreased endothelin-1 and endothelin receptor A expression in the pulmonary arteries. Taken together, our results demonstrated that antenatal Saireito can improve fetal pulmonary hypoplasia and pulmonary vascular remodeling and, as a result, can improve respiratory function in a rat CDH model. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Effect of valsalva in the pulmonary prosthetic conduit valve on hemodynamic function in a mock circulatory system.

PubMed

Tsuboko, Yusuke; Shiraishi, Yasuyuki; Yamada, Akihiro; Yambe, Tomoyuki; Matsuo, Satoshi; Saiki, Yoshikatsu; Yamagishi, Masaaki

2015-01-01

Pulmonary conduit valves are used as one of the surgical treatment methods of congenital heart diseases. We have been designing a sophisticated pulmonary conduit valve for the right ventricular outflow tract reconstruction in pediatric patients. In this study, two types of polyester grafts with or without bulging structures for the conduit valves were used and evaluated from the hemodynamic point of view focusing on the application of these conduit valves in the grown-up congenital heart failure patients. We examined valvular function in the originally developed pulmonary mock circulatory system, which consisted of a pneumatic driven right ventricular model, a pulmonary valve chamber, and an elastic pulmonary compliance model with peripheral vascular resistance units. Prior to the measurement, a bileaflet valve was sutured in each conduit. Each conduit valve was installed in the mock right ventricular outflow portion, and its leaflet motion was obtained by using a high-speed camera synchronously with pressure and flow waveforms. As a result, we could obtain hemodynamic changes in two different types of conduits for pulmonary valves, and it was indicated that the presence of the Valsalva shape might be effective for promoting valvular response in the low cardiac output condition.

Pulmonary Th17 anti-fungal immunity is regulated by the gut microbiome12

PubMed Central

McAleer, Jeremy P.; Nguyen, Nikki L.H.; Chen, Kong; Kumar, Pawan; Ricks, David M.; Binnie, Matthew; Armentrout, Rachel A.; Pociask, Derek A.; Hein, Aaron; Yu, Amy; Vikram, Amit; Bibby, Kyle; Umesaki, Yoshinori; Rivera, Amariliz; Sheppard, Dean; Ouyang, Wenjun; Hooper, Lora V.; Kolls, Jay K.

2016-01-01

Commensal microbiota are critical for the development of local immune responses. Here, we show that gut microbiota can regulate CD4 T cell polarization during pulmonary fungal infections. Vancomycin drinking water significantly decreased lung Th17 cell numbers during acute infection, demonstrating that Gram-positive commensals contribute to systemic inflammation. We next tested a role for RegIIIγ, an IL-22 inducible anti-microbial protein with specificity for Gram-positive bacteria. Following infection, increased accumulation of Th17 cells in the lungs of RegIIIγ−/− and Il22−/− mice was associated with intestinal segmented filamentous bacteria (SFB) colonization. Although gastrointestinal delivery of recombinant RegIIIγ decreased lung inflammatory gene expression and protected Il22−/− mice from weight-loss during infection, RegIIIγ had no direct effect on SFB colonization, fungal clearance or lung Th17 immunity. We further show that vancomycin only decreased lung IL-17 production in mice colonized with SFB. To determine the link between gut microbiota and lung immunity, serum transfer experiments revealed that IL-1 receptor ligands increase the accumulation of lung Th17 cells. These data suggest that intestinal microbiota including SFB can regulate pulmonary adaptive immune responses. PMID:27217583

Cigarette Smoke Upregulates PDE3 and PDE4 to Decrease cAMP in Airway Cells.

PubMed

Zuo, Haoxiao; Han, Bing; Poppinga, Wilfred J; Ringnalda, Lennard; Kistemaker, Loes E M; Halayko, Andrew J; Gosens, Reinoud; Nikolaev, Viacheslav O; Schmidt, Martina

2018-05-03

3', 5'-cyclic adenosine monophosphate (cAMP) is a central second messenger that broadly regulates cell function and can underpin pathophysiology. In chronic obstructive pulmonary disease (COPD), a lung disease primarily provoked by cigarette smoke (CS), the induction of cAMP-dependent pathways, via inhibition of hydrolyzing phosphodiesterases (PDEs), is a prime therapeutic strategy. Mechanisms that disrupt cAMP signaling in airway cells, in particular regulation of endogenous PDEs are poorly understood. We used a novel Förster resonance energy transfer (FRET) based cAMP biosensor in mouse in vivo, ex vivo precision cut lung slices (PCLS), and in human in vitro cell models to track the effects of CS exposure. Under fenoterol stimulated conditions, FRET responses to cilostamide were significantly increased in in vivo, ex vivo PCLS exposed to CS and in human airway smooth muscle cells exposed to CS extract. FRET signals to rolipram were only increased in the in vivo CS model. Under basal conditions, FRET responses to cilostamide and rolipram were significantly increased in in vivo, ex vivo PCLS exposed to CS. Elevated FRET signals to rolipram correlated with a protein upregulation of PDE4 subtypes. In ex vivo PCLS exposed to CS extract, rolipram reversed downregulation of ciliary beating frequency, whereas only cilostamide significantly increased airway relaxation of methacholine pre-contracted airways. We show that CS upregulates expression and activity of both PDE3 and PDE4, which regulate real-time cAMP dynamics. These mechanisms determine the availability of cAMP and can contribute to CS-induced pulmonary pathophysiology. This article is protected by copyright. All rights reserved.

Regulatory T cells and type 2 innate lymphoid cell-dependent asthma.

PubMed

Aron, J L; Akbari, O

2017-08-01

Group 2 innate lymphoid cells (ILC2s) are a recently identified group of cells with the potent capability to produce Th2-type cytokines such as interleukin (IL)-5 and IL-13. Several studies suggest that ILC2s play an important role in the development of allergic diseases and asthma. Activation of pulmonary ILC2s in murine models lacking T and B cells induces eosinophilia and airway hyper-reactivity (AHR), which are cardinal features of asthma. More importantly, numerous recent studies have highlighted the role of ILC2s in asthma persistence and exacerbation among human subjects, and thus, regulation of pulmonary ILC2s is a major area of investigation aimed at curbing allergic lung inflammation and exacerbation. Emerging evidence reveals that a group of regulatory T cells, induced Tregs (iTregs), effectively suppress the production of ILC2-driven, pro-inflammatory cytokines IL-5 and IL-13. The inhibitory effects of iTregs are blocked by preventing direct cellular contact or by inhibiting the ICOS-ICOS-ligand (ICOSL) pathway, suggesting that both direct contact and ICOS-ICOSL interaction are important in the regulation of ILC2 function. Also, cytokines such as IL-10 and TGF-β1 significantly reduce cytokine secretion by ILC2s. Altogether, these new findings uncover iTregs as potent regulators of ILC2 activation and implicate their utility as a therapeutic approach for the treatment of ILC2-mediated allergic asthma and respiratory disease. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Clinical characterization of children with resistant airflow obstruction, a multicenter study.

PubMed

Krishnan, Sankaran; Dozor, Allen J; Bacharier, Leonard; Lang, Jason E; Irvin, Charles G; Kaminsky, David; Farber, Harold J; Gerald, Lynn; Brown, Mark; Holbrook, Janet T; Wise, Robert A; Ryu, Julie; Bose, Sonali; Yasin, Razan; Saams, Joy; Henderson, Robert J; Teague, William G

2018-05-17

To characterize a cohort of children with airflow limitation resistant to bronchodilator (BD) therapy. Pulmonary function tests performed in children 6-17 years of age at 15 centers in a clinical research consortium were screened for resistant airflow limitation, defined as a post-BD FEV 1 and/or an FEV 1 /FVC less than the lower limits of normal. Demographic and clinical data were analyzed for associations with pulmonary function. 582 children were identified. Median age was 13 years (IQR: 11, 16), 60% were males; 62% were Caucasian, 28% were African-American; 19% were obese; 32% were born prematurely and 21% exposed to second hand smoke. Pulmonary diagnoses included asthma (93%), prior significant pneumonia (28%), and bronchiectasis (5%). 65% reported allergic rhinitis, and 11% chronic sinusitis. Subjects without a history of asthma had significantly lower post-BD FEV 1 % predicted (p = 0.008). Subjects without allergic rhinitis had lower post-BD FEV 1 % predicted (p = 0.003). Children with allergic rhinitis, male sex, obesity and Black race had better pulmonary function post-BD. There was lower pulmonary function in children after age 11 years without a history of allergic rhinitis, as compared to those with a history of allergic rhinitis. The most prevalent diagnosis in children with BD-resistant airflow limitation is asthma. Allergic rhinitis and premature birth are common co-morbidities. Children without a history of asthma, as well as those with asthma but no allergic rhinitis, had lower pulmonary function. Children with BD-resistant airflow limitation may represent a sub-group of children with persistent obstruction and high risk for life-long airway disease.

Outcome following phrenic nerve transfer to musculocutaneous nerve in patients with traumatic brachial palsy: a qualitative systematic review.

PubMed

de Mendonça Cardoso, Marcio; Gepp, Ricardo; Correa, José Fernando Guedes

2016-09-01

The phrenic nerve can be transferred to the musculocutaneous nerve in patients with traumatic brachial plexus palsy in order to recover biceps strength, but the results are controversial. There is also a concern about pulmonary function after phrenic nerve transection. In this paper, we performed a qualitative systematic review, evaluating outcomes after this procedure. A systematic review of published studies was undertaken in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement. Data were extracted from the selected papers and related to: publication, study design, outcome (biceps strength in accordance with BMRC and pulmonary function) and population. Study quality was assessed using the "strengthening the reporting of observational studies in epidemiology" (STROBE) standard or the CONSORT checklist, depending on the study design. Seven studies were selected for this systematic review after applying inclusion and exclusion criteria. One hundred twenty-four patients completed follow-up, and most of them were graded M3 or M4 (70.1 %) for biceps strength at the final evaluation. Pulmonary function was analyzed in five studies. It was not possible to perform a statistical comparison between studies because the authors used different parameters for evaluation. Most of the patients exhibited a decrease in pulmonary function tests immediately after surgery, with recovery in the following months. Study quality was determined using STROBE in six articles, and the global score varied from 8 to 21. Phrenic nerve transfer to the musculocutaneous nerve can recover biceps strength ≥M3 (BMRC) in most patients with traumatic brachial plexus injury. Early postoperative findings revealed that the development of pulmonary symptoms is rare, but it cannot be concluded that the procedure is safe because there is no study evaluating pulmonary function in old age.

Effects of extended pleurectomy and decortication on quality of life and pulmonary function in patients with malignant pleural mesothelioma.

PubMed

Burkholder, David; Hadi, Duraid; Kunnavakkam, Rangesh; Kindler, Hedy; Todd, Kristy; Celauro, Amy Durkin; Vigneswaran, Wickii T

2015-05-01

Maximal cytoreductive surgeries--extrapleural pneumonectomy and extended pleurectomy and decortication (EPD)--are effective surgical treatments in selected patients with malignant pleural mesothelioma. Extended pleurectomy and decortication results in equivalent survival yet better health-related quality of life (HRQoL). Patients with malignant pleural mesothelioma were studied for the effects of EPD on HRQoL and pulmonary function. The European Organization for Research and Treatment of Cancer Core Quality of Life Questionaire-C30 was used to evaluate HRQoL before operation, and at 4 to 5 and 7 to 8 months postoperatively. Pulmonary function tests were measured immediately before and 5 to 7 months after the operation. Patients were compared according to World Health Organization baseline performance status (PS). Of the 36 patients enrolled, 17 were PS 0 and 19 were PS 1 or PS 2 at baseline. Patients in groups PS 1 and PS 2 had significantly worse global health, functional, and symptoms scores. After EPD, PS 0 patients had no change in global health or function and symptoms scores except for emotional function, whereas PS 1 or PS 2 patients showed improvements at 4 to 5 months with further improvements at 7 to 8 months. The PS 0 patients demonstrated a significant decrease in forced vital capacity (p = 0.001), forced expiratory volume in 1 second (p = 0.002), total lung capacity (p = 0.0006) and diffusing capacity of the lung for carbon monoxide (p = 0.003) after EPD, whereas no change was observed in PS 1 and PS 2 patients. Extended pleurectomy and decortication did not improve overall HRQoL and had a negative impact in pulmonary function in minimally symptomatic patients. In symptomatic patients, a significant improvement in HRQoL was observed after EPD, which continued at late follow-up, although the pulmonary function was not affected. As changes in HRQoL are multidimensional, the preservation of the pulmonary function may have contributed to the net benefit observed in PS 1 and PS 2 patients. Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Benefits of pulmonary rehabilitation in idiopathic pulmonary fibrosis.

PubMed

Swigris, Jeffrey J; Fairclough, Diane L; Morrison, Marianne; Make, Barry; Kozora, Elizabeth; Brown, Kevin K; Wamboldt, Frederick S

2011-06-01

Information on the benefits of pulmonary rehabilitation (PR) in patients with idiopathic pulmonary fibrosis (IPF) is growing, but PR's effects on certain important outcomes is lacking. We conducted a pilot study of PR in IPF and analyzed changes in functional capacity, fatigue, anxiety, depression, sleep, and health status from baseline to after completion of a standard, 6-week PR program. Six-min walk distance improved a mean ± standard error 202 ± 135 feet (P = .01) from baseline. Fatigue Severity Scale score also improved significantly, declining an average 1.5 ± 0.5 points from baseline. There were trends toward improvement in anxiety, depression, and health status. PR improves functional capacity and fatigue in patients with IPF. (Clinical Trials.gov registration NCT00692796.)

beta(2)-adrenoceptor antagonist ICI 118,551 decreases pulmonary vascular tone in mice via a G(i/o) protein/nitric oxide-coupled pathway.

PubMed

Wenzel, Daniela; Knies, Ralf; Matthey, Michaela; Klein, Alexandra M; Welschoff, Julia; Stolle, Vanessa; Sasse, Philipp; Röll, Wilhelm; Breuer, Johannes; Fleischmann, Bernd K

2009-07-01

beta(2)-adrenoceptors are important modulators of vascular tone, particularly in the pulmonary circulation. Because neurohormonal activation occurs in pulmonary arterial hypertension, we have investigated the effect of different adrenergic vasoactive substances on tone regulation in large and small pulmonary arteries, as well as in systemic vessels of mice. We found that the beta(2)-adrenoceptor antagonist ICI 118,551 (ICI) evoked a decrease of vascular tone in large pulmonary arteries and reduced the sensitivity of pulmonary arteries toward different contracting agents, eg, norepinephrine, serotonin, or endothelin. ICI proved to act specifically on pulmonary vessels, because it shifted the dose-response curve of norepinephrine to the right in pulmonary arteries, whereas there was no effect in the aorta. Pharmacological experiments proved that the right shift of the norepinephrine dose-response curve by ICI was mediated via a beta(2)-adrenoceptor/G(i/o) protein-dependent pathway enhancing NO production in the endothelium; these results were corroborated in beta-adrenoceptor and endothelial NO synthase knockout mice where ICI had no effect. ICI increased vascular lumen diameter in lung sections and reduced pulmonary arterial pressure under normoxia and under hypoxia in the isolated perfused lung model. These effects were found to be physiologically relevant, because ICI specifically decreased pulmonary but not systemic blood pressure in vivo. Thus, the beta(2)-adrenoceptor antagonist ICI is a pulmonary arterial-specific vasorelaxant and, therefore, a potentially interesting novel therapeutic agent for the treatment of pulmonary arterial hypertension.

Beneficial effects of a novel agonist of the adenosine A2A receptor on monocrotaline-induced pulmonary hypertension in rats

PubMed Central

Alencar, Allan K N; Pereira, Sharlene L; Montagnoli, Tadeu L; Maia, Rodolfo C; Kümmerle, Arthur E; Landgraf, Sharon S; Caruso-Neves, Celso; Ferraz, Emanuelle B; Tesch, Roberta; Nascimento, José H M; de Sant'Anna, Carlos M R; Fraga, Carlos A M; Barreiro, Eliezer J; Sudo, Roberto T; Zapata-Sudo, Gisele

2013-01-01

Background and Purpose Pulmonary arterial hypertension (PAH) is characterized by enhanced pulmonary vascular resistance, right ventricular hypertrophy and increased right ventricular systolic pressure. Here, we investigated the effects of a N-acylhydrazone derivative, 3,4-dimethoxyphenyl-N-methyl-benzoylhydrazide (LASSBio-1359), on monocrotaline (MCT)-induced pulmonary hypertension in rats. Experimental Approach PAH was induced in male Wistar rats by a single i.p. injection of MCT (60 mg·kg−1) and 2 weeks later, oral LASSBio-1359 (50 mg·kg−1) or vehicle was given once daily for 14 days. Echocardiography was used to measure cardiac function and pulmonary artery dimensions, with histological assay of vascular collagen. Studies of binding to human recombinant adenosine receptors (A1, A2A, A3) and of docking with A2A receptors were also performed. Key Results MCT administration induced changes in vascular and ventricular structure and function, characteristic of PAH. These changes were reversed by treatment with LASSBio-1359. MCT also induced endothelial dysfunction in pulmonary artery, as measured by diminished relaxation of pre-contracted arterial rings, and this dysfunction was reversed by LASSBio-1359. In pulmonary artery rings from normal Wistar rats, LASSBio-1359 induced relaxation, which was decreased by the adenosine A2A receptor antagonist, ZM 241385. In adenosine receptor binding studies, LASSBio-1359 showed most affinity for the A2A receptor and in the docking analyses, binding modes of LASSBio-1359 and the A2A receptor agonist, CGS21680, were very similar. Conclusion and Implications In rats with MCT-induced PAH, structural and functional changes in heart and pulmonary artery were reversed by treatment with oral LASSBio-1359, most probably through the activation of adenosine A2A receptors. PMID:23530610

Sildenafil therapy in thalassemia patients with Doppler-defined risk of pulmonary hypertension

PubMed Central

Morris, Claudia R.; Kim, Hae-Young; Wood, John; Porter, John B.; Klings, Elizabeth S.; Trachtenberg, Felicia L.; Sweeters, Nancy; Olivieri, Nancy F.; Kwiatkowski, Janet L.; Virzi, Lisa; Singer, Sylvia T.; Taher, Ali; Neufeld, Ellis J.; Thompson, Alexis A.; Sachdev, Vandana; Larkin, Sandra; Suh, Jung H.; Kuypers, Frans A.; Vichinsky, Elliott P.

2013-01-01

Pulmonary hypertension is a common but often overlooked complication associated with thalassemia syndromes. There are limited data on the safety and efficacy of selective pulmonary vasodilators in this at-risk population. We, therefore, designed a 12-week, open-label, phase 1/2, pilot-scale, proof-of-principle trial of sildenafil therapy in 10 patients with β-thalassemia and at increased risk of pulmonary hypertension based on an elevated tricuspid regurgitant jet velocity >2.5 m/s on Doppler-echocardiography. Variables compared at baseline and after 12 weeks of sildenafil treatment included Doppler-echocardiographic parameters, 6-minute walked distance, Borg Dyspnea Score, New York Heart Association functional class, pulmonary function, and laboratory parameters. Treatment with sildenafil resulted in a significant decrease in tricuspid regurgitant jet velocity by 13.3% (3.0±0.7 versus 2.6±0.5 m/s, P=0.04), improved left ventricular end systolic/diastolic volume, and a trend towards a improved New York Heart Association functional class. No significant change in 6-minute walked distance was noted. Sildenafil was well tolerated, although minor expected adverse events were commonly reported. The total dose of sildenafil (mg) was strongly correlated with percent change in nitric oxide metabolite concentration in the plasma (ρ=0.80, P=0.01). There were also significant increases in plasma and erythrocyte arginine concentrations. Our study suggests that sildenafil is safe and may improve pulmonary hemodynamics in patients at risk of pulmonary hypertension; however, it was not demonstrated to improve the distance walked in 6 minutes. Clinical trials are needed to identify the best treatment strategy for pulmonary hypertension in patients with β-thalassemia. (clinicaltrials.gov identifier: NCT00872170) PMID:23585527

Adaptation to low body temperature influences pulmonary surfactant composition thereby increasing fluidity while maintaining appropriately ordered membrane structure and surface activity.

PubMed

Suri, Lakshmi N M; McCaig, Lynda; Picardi, Maria V; Ospina, Olga L; Veldhuizen, Ruud A W; Staples, James F; Possmayer, Fred; Yao, Li-Juan; Perez-Gil, Jesus; Orgeig, Sandra

2012-07-01

The interfacial surface tension of the lung is regulated by phospholipid-rich pulmonary surfactant films. Small changes in temperature affect surfactant structure and function in vitro. We compared the compositional, thermodynamic and functional properties of surfactant from hibernating and summer-active 13-lined ground squirrels (Ictidomys tridecemlineatus) with porcine surfactant to understand structure-function relationships in surfactant membranes and films. Hibernating squirrels had more surfactant large aggregates with more fluid monounsaturated molecular species than summer-active animals. The latter had more unsaturated species than porcine surfactant. Cold-adapted surfactant membranes displayed gel-to-fluid transitions at lower phase transition temperatures with reduced enthalpy. Both hibernating and summer-active squirrel surfactants exhibited lower enthalpy than porcine surfactant. LAURDAN fluorescence and DPH anisotropy revealed that surfactant bilayers from both groups of squirrels possessed similar ordered phase characteristics at low temperatures. While ground squirrel surfactants functioned well during dynamic cycling at 3, 25, and 37 degrees C, porcine surfactant demonstrated poorer activity at 3 degrees C but was superior at 37 degrees C. Consequently the surfactant composition of ground squirrels confers a greater thermal flexibility relative to homeothermic mammals, while retaining tight lipid packing at low body temperatures. This may represent the most critical feature contributing to sustained stability of the respiratory interface at low lung volumes. Thus, while less effective than porcine surfactant at 37 degrees C, summer-active surfactant functions adequately at both 37 degrees C and 3 degrees C allowing these animals to enter hibernation. Here further compositional alterations occur which improve function at low temperatures by maintaining adequate stability at low lung volumes and when temperature increases during arousal from hibernation.

Role of human pulmonary fibroblast-derived MCP-1 in cell activation and migration in experimental silicosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Xueting; Fang, Shencun; Liu, Haijun

Background: Silicosis is a systemic disease caused by inhaling silicon dioxide (SiO{sub 2}). Phagocytosis of SiO{sub 2} in the lung initiates an inflammatory cascade that results in fibroblast proliferation and migration and subsequent fibrosis. Clinical evidence indicates that the activation of alveolar macrophages by SiO{sub 2} produces rapid and sustained inflammation that is characterized by the generation of monocyte chemotactic protein 1 (MCP-1), which induces fibrosis. Pulmonary fibroblast-derived MCP-1 may play a critical role in fibroblast proliferation and migration. Methods and results: Experiments using primary cultured adult human pulmonary fibroblasts (HPF-a) demonstrated the following results: 1) SiO{sub 2} treatment resultedmore » in the rapid and sustained induction of MCP-1 as well as the elevation of the CC chemokine receptor type 2 (CCR2) protein levels; 2) pretreatment of HPF-a with RS-102895, a specific CCR2 inhibitor, abolished the SiO{sub 2}-induced increase in cell activation and migration in both 2D and 3D culture systems; and 3) RNA interference targeting CCR2 prevented the SiO{sub 2}-induced increase in cell migration. Conclusion: These data demonstrated that the up-regulation of pulmonary fibroblast-derived MCP-1 is involved in pulmonary fibroblast migration induced by SiO{sub 2}. CCR2 was also up-regulated in response to SiO{sub 2}, and this up-regulation facilitated the effect of MCP-1 on fibroblasts. Our study deciphered the link between fibroblast-derived MCP-1 and SiO{sub 2}-induced cell migration. This finding provides novel insight into the potential of MCP-1 in the development of novel therapeutic strategies for silicosis. - Highlights: • Role of pulmonary fibroblast-derived MCP-1 in experimental silicosis was studied. • SiO{sub 2} induced MCP-1 release from cultured human pulmonary fibroblast (HPF-a). • SiO{sub 2} directly activated HPF-a via the MCP-1/CCR2 pathway. • SiO{sub 2} increased HPF-a migration in both 2D and 3D model via the MCP-1/CCR2 pathway. • RNA-i of MCP-1/CCR2 decreased HPF-a activation and migration induced by SiO{sub 2}.« less

Pulmonary artery wave propagation and reservoir function in conscious man: impact of pulmonary vascular disease, respiration and dynamic stress tests.

PubMed

Su, Junjing; Manisty, Charlotte; Simonsen, Ulf; Howard, Luke S; Parker, Kim H; Hughes, Alun D

2017-10-15

Wave travel plays an important role in cardiovascular physiology. However, many aspects of pulmonary arterial wave behaviour remain unclear. Wave intensity and reservoir-excess pressure analyses were applied in the pulmonary artery in subjects with and without pulmonary hypertension during spontaneous respiration and dynamic stress tests. Arterial wave energy decreased during expiration and Valsalva manoeuvre due to decreased ventricular preload. Wave energy also decreased during handgrip exercise due to increased heart rate. In pulmonary hypertension patients, the asymptotic pressure at which the microvascular flow ceases, the reservoir pressure related to arterial compliance and the excess pressure caused by waves increased. The reservoir and excess pressures decreased during Valsalva manoeuvre but remained unchanged during handgrip exercise. This study provides insights into the influence of pulmonary vascular disease, spontaneous respiration and dynamic stress tests on pulmonary artery wave propagation and reservoir function. Detailed haemodynamic analysis may provide novel insights into the pulmonary circulation. Therefore, wave intensity and reservoir-excess pressure analyses were applied in the pulmonary artery to characterize changes in wave propagation and reservoir function during spontaneous respiration and dynamic stress tests. Right heart catheterization was performed using a pressure and Doppler flow sensor tipped guidewire to obtain simultaneous pressure and flow velocity measurements in the pulmonary artery in control subjects and patients with pulmonary arterial hypertension (PAH) at rest. In controls, recordings were also obtained during Valsalva manoeuvre and handgrip exercise. The asymptotic pressure at which the flow through the microcirculation ceases, the reservoir pressure related to arterial compliance and the excess pressure caused by arterial waves increased in PAH patients compared to controls. The systolic and diastolic rate constants also increased, while the diastolic time constant decreased. The forward compression wave energy decreased by ∼8% in controls and ∼6% in PAH patients during expiration compared to inspiration, while the wave speed remained unchanged throughout the respiratory cycle. Wave energy decreased during Valsalva manoeuvre (by ∼45%) and handgrip exercise (by ∼27%) with unaffected wave speed. Moreover, the reservoir and excess pressures decreased during Valsalva manoeuvre but remained unaltered during handgrip exercise. In conclusion, reservoir-excess pressure analysis applied to the pulmonary artery revealed distinctive differences between controls and PAH patients. Variations in the ventricular preload and afterload influence pulmonary arterial wave propagation as demonstrated by changes in wave energy during spontaneous respiration and dynamic stress tests. © 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.

Down-regulation of lung Kruppel-like factor in the nitrofen-induced hypoplastic lung.

PubMed

Lukošiūtė, A; Doi, T; Dingemann, J; Ruttenstock, E M; Puri, P

2011-01-01

Pulmonary hypoplasia is a primary cause of high morbidity and mortality in neonates with Congenital Diaphragmatic Hernia (CDH). However, the precise pathogenesis of PH associated with CDH is still not clearly understood. It has been recently reported that lung Kruppel-like factor (LKLF), a member of the Kruppel-like factor family of transcription factors, is predominantly expressed in lungs and plays an important role in lung morphogenesis and functional maturation. It has been reported that homozygous deletion of LKLF gene in mice results in reduced lung morphogenesis. It is further reported that chimeric mice derived from LKLF (-/-) embryonic stem cells exhibit delayed lung development especially in the later gestational stages. We therefore designed this study to test the hypothesis that the LKLF gene is down-regulated during later stages of lung development in nitrofen-induced hypoplastic lungs. Pregnant rats were exposed to either olive oil or nitrofen on day 9 of gestation (D9). Fetal lungs were harvested on D15, D18, and D21 and divided into 3 groups:control, nitrofen without CDH(CDH(-)) and nitrofen with CDH(CDH(+)) (n=24 for each group). Real-time RT-PCR analysis was performed to investigate pulmonary gene expression levels of LKLF. Differences between the 3 groups at each time point were tested statistically and significance was accepted at p<0.05. Immunohistochemistry was also performed to evaluate LKLF protein expression and distribution. The relative mRNA expression levels of LKLF on D18 and D21 were significantly decreased (p<0.01) in CDH(-) and CDH(+) groups compared to controls. The gene expression levels of LKLF on D15 did not differ significantly between the nitrofen group and controls. Immunohistochemical study showed strong LKLF immunoreactivity on D18 and D21 in nitrofen-induced hypoplastic lung compared to controls, whereas no difference was seen on D15. Our results provide evidence for the first time that LKLF is down-regulated in the later stages of lung development in nitrofen-induced hypoplastic lungs. These data suggest that the down-regulation of LKLF during this critical period of lung morphogenesis may impair lung development and maturation, resulting in pulmonary hypoplasia in the nitrofen CDH model. © Georg Thieme Verlag KG Stuttgart · New York.

Pulmonary annulus growth after the modified Blalock-Taussig shunt in tetralogy of Fallot.

PubMed

Nakashima, Kouki; Itatani, Keiichi; Oka, Norihiko; Kitamura, Tadashi; Horai, Tetsuya; Hari, Yosuke; Miyaji, Kagami

2014-09-01

In tetralogy of Fallot (TOF), it is well known that postoperative pulmonary regurgitation reduces right ventricular function during long-term follow-up. Complete repair without a transannular patch should help avoid pulmonary regurgitation. Recently, primary complete repair has been preferred to the staged repair with use of a Blalock-Taussig shunt (BTS) even in neonates or small infants; however, little has been reported about the influence of a BTS on pulmonary annular growth. We examined 40 patients with TOF or double-outlet right ventricle with pulmonary stenosis. Twenty-one patients received a BTS before complete repair, whereas 19 patients underwent primary complete repair. Pulmonary annular size was measured by echocardiography before BTS, complete repair, or both, and ventricular volume was measured by cardiac catheterization. There were no significant differences in complete repair age or body size between the groups. Pulmonary annulus sizes in the BTS group were smaller than those in the primary repair group (Z score, -5.1 ± 2.5 vs -3.7 ± 1.8). After the BTS, significant annular growth (Z score, -2.8 ± 2.1) was observed (p = 0.0028), with a significant increase in left ventricular end-diastolic volume (p = 0.015). When patients with severe pulmonary stenosis (Z score > -7.0) were excluded, pulmonary annular preservation at complete repair was achieved in 64.7% (11/17) of the BTS group and 36.8% (7/19) of the primary repair group (p = 0.088). The BTS increased the pulmonary annular size and the left ventricular volume during the 6 months before complete repair, resulting in preservation of the pulmonary valve function. Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Normal expiratory flow rate and lung volumes in patients with combined emphysema and interstitial lung disease: a case series and literature review.

PubMed

Heathcote, Karen L; Cockcroft, Donald W; Fladeland, Derek A; Fenton, Mark E

2011-01-01

Pulmonary function tests in patients with idiopathic pulmonary fibrosis characteristically show a restrictive pattern including small lung volumes and increased expiratory flow rates resulting from a reduction in pulmonary compliance due to diffuse fibrosis. Conversely, an obstructive pattern with hyperinflation results in emphysema by loss of elastic recoil, expiratory collapse of the peripheral airways and air trapping. When the diseases coexist, pulmonary volumes are compensated, and a smaller than expected reduction or even normal lung volumes can be found. The present report describes 10 patients with progressive breathlessness, three of whom experienced severe limitation in their quality of life. All patients showed lung interstitial involvement and emphysema on computed tomography scan of the chest. The 10 patients showed normal spirometry and lung volumes with severe compromise of gas exchange. Normal lung volumes do not exclude diagnosis of idiopathic pulmonary fibrosis in patients with concomitant emphysema. The relatively preserved lung volumes may underestimate the severity of idiopathic pulmonary fibrosis and attenuate its effects on lung function parameters.

[Pulmonary function in patients with focal pulmonary tuberculosis].

PubMed

Nefedov, V B; Popova, L A; Shergina, E A

2008-01-01

Vital capacity (VC), forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), FEV1/VC%, PEF, MEF25, MEF50, MEF75, TLC, TGV, pulmonary residual volume (PRV), Raw, Rin, Rcx, DLCO-SB, DLCO-SS/VA, PaO2, and PaCO2 were determined in 40 patients with focal pulmonary tuberculosis. Changes were found in lung volumes and capacities in 75%, impaired bronchial patency and pulmonary gas exchange dysfunction were in 57.5 and 25%, respectively. The lung volume and capacity changes appeared mainly as increased TGV and PRV; impaired bronchial patency presented as decreased MEF50, MEF75, and FEV1/VC%; pulmonary gas exchange dysfunction manifested itself as reduced DLCO-SB, PaO2, and PaCO2. The magnitude of the observed functional changes was generally slight. TGV and PRL increased up to 148-187 and 142-223% of the normal values, respectively; MEF50, MEF75, FEV1/VC%, and DLCO decreased to 59-24, 58-26, 78-57, and 78-67% of the normal values and PaO2 and PaCO2 did to 79-69 and 34-30 cm Hg.

Sildenafil ameliorates right ventricular early molecular derangement during left ventricular pressure overload.

PubMed

Imai, Yousuke; Kariya, Taro; Iwakiri, Masaki; Yamada, Yoshitsugu; Takimoto, Eiki

2018-01-01

Right ventricular (RV) dysfunction following left ventricular (LV) failure is associated with poor prognosis. RV remodeling is thought initiated by the increase in the afterload of RV due to secondary pulmonary hypertension (PH) to impaired LV function; however, RV molecular changes might occur in earlier stages of the disease. cGMP (cyclic guanosine monophosphate)-phosphodiesterase 5 (PDE5) inhibitors, widely used to treat PH through their pulmonary vasorelaxation properties, have shown direct cardiac benefits, but their impacts on the RV in LV diseases are not fully determined. Here we show that RV molecular alterations occur early in the absence of RV hemodynamic changes during LV pressure-overload and are ameliorated by PDE5 inhibition. Two-day moderate LV pressure-overload (transverse aortic constriction) neither altered RV pressure/ function nor RV weight in mice, while it induced only mild LV hypertrophy. Importantly, pathological molecular features were already induced in the RV free wall myocardium, including up-regulation of gene markers for hypertrophy and inflammation, and activation of extracellular signal-regulated kinase (ERK) and calcineurin. Concomitant PDE5 inhibition (sildenafil) prevented induction of such pathological genes and activation of ERK and calcineurin in the RV as well as in the LV. Importantly, dexamethasone also prevented these RV molecular changes, similarly to sildenafil treatment. These results suggest the contributory role of inflammation to the early pathological interventricular interaction between RV and LV. The current study provides the first evidence for the novel early molecular cross-talk between RV and LV, preceding RV hemodynamic changes in LV disease, and supports the therapeutic strategy of enhancing cGMP signaling pathway to treat heart diseases.

Sustained activation of toll-like receptor 9 induces an invasive phenotype in lung fibroblasts: possible implications in idiopathic pulmonary fibrosis.

PubMed

Kirillov, Varvara; Siler, Jonathan T; Ramadass, Mahalakshmi; Ge, Lingyin; Davis, James; Grant, Geraldine; Nathan, Steven D; Jarai, Gabor; Trujillo, Glenda

2015-04-01

Idiopathic pulmonary fibrosis (IPF) is characterized by excessive scarring of the lung parenchyma, resulting in a steady decline of lung function and ultimately respiratory failure. The disease course of IPF is extremely variable, with some patients exhibiting stability of symptoms for prolonged periods of time, whereas others exhibit rapid progression and loss of lung function. Viral infections have been implicated in IPF and linked to disease severity; however, whether they directly contribute to progression is unclear. We previously classified patients as rapid and slow progressors on the basis of clinical features and expression of the pathogen recognition receptor, Toll-like receptor 9 (TLR9). Activation of TLR9 in vivo exacerbated IPF in mice and induced differentiation of myofibroblasts in vitro, but the mechanism of TLR9 up-regulation and progression of fibrosis are unknown. Herein, we investigate whether transforming growth factor (TGF)-β, a pleiotropic cytokine central to IPF pathogenesis, regulates TLR9 in lung myofibroblasts. Results showed induction of TLR9 expression by TGF-β in lung myofibroblasts and a distinct profibrotic myofibroblast phenotype driven by stimulation with the TLR9 agonist, CpG-DNA. Chronic TLR9 stimulation resulted in stably differentiated α-smooth muscle actin(+)/platelet-derived growth factor receptor α(+)/CD44(+)/matrix metalloproteinase-14(+)/matrix metalloproteinase-2(+) myofibroblasts, which secrete inflammatory cytokines, invade Matrigel toward platelet-derived growth factor, and resist hypoxia-induced apoptosis. These results suggest a mechanism by which TGF-β and TLR9 responses in myofibroblasts collaborate to drive rapid progression of IPF. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

H2O2 Regulates Lung Epithelial Sodium Channel (ENaC) via Ubiquitin-like Protein Nedd8

PubMed Central

Downs, Charles A.; Kumar, Amrita; Kreiner, Lisa H.; Johnson, Nicholle M.; Helms, My N.

2013-01-01

Redundancies in both the ubiquitin and epithelial sodium transport pathways allude to their importance of proteolytic degradation and ion transport in maintaining normal cell function. The classical pathway implicated in ubiquitination of the epithelial sodium channel (ENaC) involves Nedd4-2 regulation of sodium channel subunit expression and has been studied extensively studied. However, less attention has been given to the role of the ubiquitin-like protein Nedd8. Here we show that Nedd8 plays an important role in the ubiquitination of ENaC in alveolar epithelial cells. We report that the Nedd8 pathway is redox-sensitive and that under oxidizing conditions Nedd8 conjugation to Cullin-1 is attenuated, resulting in greater surface expression of α-ENaC. This observation was confirmed in our electrophysiology studies in which we inhibited Nedd8-activating enzyme using MLN4924 (a specific Nedd8-activating enzyme inhibitor) and observed a marked increase in ENaC activity (measured as the product of the number of channels (N) and the open probability (Po) of a channel). These results suggest that ubiquitination of lung ENaC is redox-sensitive and may have significant implications for our understanding of the role of ENaC in pulmonary conditions where oxidative stress occurs, such as pulmonary edema and acute lung injury. PMID:23362276

MTOR Suppresses Cigarette Smoke-Induced Epithelial Cell Death and Airway Inflammation in Chronic Obstructive Pulmonary Disease.

PubMed

Wang, Yong; Liu, Juan; Zhou, Jie-Sen; Huang, Hua-Qiong; Li, Zhou-Yang; Xu, Xu-Chen; Lai, Tian-Wen; Hu, Yue; Zhou, Hong-Bin; Chen, Hai-Pin; Ying, Song-Min; Li, Wen; Shen, Hua-Hao; Chen, Zhi-Hua

2018-04-15

Airway epithelial cell death and inflammation are pathological features of chronic obstructive pulmonary disease (COPD). Mechanistic target of rapamycin (MTOR) is involved in inflammation and multiple cellular processes, e.g., autophagy and apoptosis, but little is known about its function in COPD pathogenesis. In this article, we illustrate how MTOR regulates cigarette smoke (CS)-induced cell death, airway inflammation, and emphysema. Expression of MTOR was significantly decreased and its suppressive signaling protein, tuberous sclerosis 2 (TSC2), was increased in the airway epithelium of human COPD and in mouse lungs with chronic CS exposure. In human bronchial epithelial cells, CS extract (CSE) activated TSC2, inhibited MTOR, and induced autophagy. The TSC2-MTOR axis orchestrated CSE-induced autophagy, apoptosis, and necroptosis in human bronchial epithelial cells; all of which cooperatively regulated CSE-induced inflammatory cytokines IL-6 and IL-8 through the NF-κB pathway. Mice with a specific knockdown of Mtor in bronchial or alveolar epithelial cells exhibited significantly augmented airway inflammation and airspace enlargement in response to CS exposure, accompanied with enhanced levels of autophagy, apoptosis, and necroptosis in the lungs. Taken together, these data demonstrate that MTOR suppresses CS-induced inflammation and emphysema-likely through modulation of autophagy, apoptosis, and necroptosis-and thus suggest that activation of MTOR may represent a novel therapeutic strategy for COPD. Copyright © 2018 by The American Association of Immunologists, Inc.