Primary pulmonary plasmacytoma with diffuse alveolar consolidation: a case report.

PubMed

Mohammad Taheri, Zohreh; Mohammadi, Forouzan; Karbasi, Mehrdad; Seyfollahi, Leila; Kahkoei, Shahram; Ghadiany, Mojtaba; Fayazi, Nader; Mansouri, Davood

2010-06-13

Solitary extramedullary plasmacytomas are plasma cell tumors that tend to develop in mucosa-associated lymphoid tissues including the sinonasal or nasopharyngeal regions. Primary plasmacytoma of the lung is exceedingly rare and often presents as a solitary mass or nodule in mid-lung or hilar areas and diagnosed after resection. Herein, we report a case of primary pulmonary plasmacytoma that presented with diffuse alveolar consolidation and diagnosed by transbronchial lung biopsy.

Primary Pulmonary Plasmacytoma with Diffuse Alveolar Consolidation: A Case Report

PubMed Central

Mohammad Taheri, Zohreh; Mohammadi, Forouzan; Karbasi, Mehrdad; Seyfollahi, Leila; Kahkoei, Shahram; Ghadiany, Mojtaba; Fayazi, Nader; Mansouri, Davood

2010-01-01

Solitary extramedullary plasmacytomas are plasma cell tumors that tend to develop in mucosa-associated lymphoid tissues including the sinonasal or nasopharyngeal regions. Primary plasmacytoma of the lung is exceedingly rare and often presents as a solitary mass or nodule in mid-lung or hilar areas and diagnosed after resection. Herein, we report a case of primary pulmonary plasmacytoma that presented with diffuse alveolar consolidation and diagnosed by transbronchial lung biopsy. PMID:21151727

Alveolar epithelial cells undergo epithelial-mesenchymal transition in acute interstitial pneumonia: a case report

PubMed Central

2014-01-01

Background Acute interstitial pneumonia is a rare interstitial lung disease that rapidly progresses to respiratory failure or death. Several studies showed that myofibroblast plays an important role in the evolution of diffuse alveolar damage, which is the typical feature of acute interstitial pneumonia. However, no evidence exists whether alveolar epithelial cells are an additional source of myofibroblasts via epithelial-mesenchymal transition in acute interstitial pneumonia. Case presentation In this report, we present a case of acute interstitial pneumonia in a previously healthy 28-year-old non-smoking woman. Chest high-resolution computed tomography scan showed bilateral and diffusely ground-glass opacification. The biopsy was performed on the fifth day of her hospitalization, and results showed manifestation of acute exudative phase of diffuse alveolar damage characterized by hyaline membrane formation. On the basis of the preliminary diagnosis of acute interstitial pneumonia, high-dose glucocorticoid was used. However, this drug showed poor clinical response and could improve the patient’s symptoms only during the early phase. The patient eventually died of respiratory dysfunction. Histological findings in autopsy were consistent with the late form of acute interstitial pneumonia. Conclusions The results in this study revealed that alveolar epithelial cells underwent epithelial-mesenchymal transition and may be an important origin of myofibroblasts in the progression of acute interstitial pneumonia. Conducting research on the transformation of alveolar epithelial cells into myofibroblasts in the lung tissue of patients with acute interstitial pneumonia may be beneficial for the treatment of this disease. However, to our knowledge, no research has been conducted on this topic. PMID:24755111

The alveolar to arterial oxygen partial pressure difference is associated with pulmonary diffusing capacity in heart failure patients.

PubMed

Morosin, Marco; Vignati, Carlo; Novi, Angela; Salvioni, Elisabetta; Veglia, Fabrizio; Alimento, Marina; Merli, Guido; Sciomer, Susanna; Sinagra, Gianfranco; Agostoni, Piergiuseppe

2016-11-01

In chronic heart failure (HF), the alveolar-capillary membrane undergoes a remodeling process that negatively affects gas exchange. In case of alveolar-capillary gas diffusion impairment, arterial desaturation (SaO 2 ) is rarely observed in HF patients. At play are 3 factors: overall pulmonary diffusing capacity (assessed as lung diffusion for CO, DLCO), global O 2 consumption (VO 2 ) and alveolar (A) to arterial (a) pO 2 gradient (AaDO 2 ). In 100 consecutive stable HF patients, DLCO, resting respiratory gases and arterial blood gases were measured to determine VO 2, paO 2 , pAO 2 and AaDO 2 . DLCO was poorly but significantly related to AaDO 2 . The correlation improved after correcting AaDO 2 for VO 2 (p<0.001, r=0.49). Both VO 2 and AaDO 2 were independently associated with DLCO (p<0.001). Patients with reduced DLCO showed no differences as regards paO 2 and pAO 2 . AaDO 2 /VO 2 showed a higher gradient in patients with lower DLCO. AaDO 2 increase and VO 2 reduction allow preventing low SaO 2 in HF patients with reduced DLCO. Accordingly, we suggest considering AaDO 2 and VO 2 combined and reporting AaDO 2 /VO 2 . Copyright © 2016 Elsevier B.V. All rights reserved.

Hypoxia-inducible factors promote alveolar development and regeneration.

PubMed

Vadivel, Arul; Alphonse, Rajesh S; Etches, Nicholas; van Haaften, Timothy; Collins, Jennifer J P; O'Reilly, Megan; Eaton, Farah; Thébaud, Bernard

2014-01-01

Understanding how alveoli and the underlying capillary network develop and how these mechanisms are disrupted in disease states is critical for developing effective therapies for lung regeneration. Recent evidence suggests that lung angiogenesis promotes lung development and repair. Vascular endothelial growth factor (VEGF) preserves lung angiogenesis and alveolarization in experimental O2-induced arrested alveolar growth in newborn rats, but combined VEGF+angiopoietin 1 treatment is necessary to correct VEGF-induced vessel leakiness. Hypoxia-inducible factors (HIFs) are transcription factors that activate multiple O2-sensitive genes, including those encoding for angiogenic growth factors, but their role during postnatal lung growth is incompletely understood. By inducing the expression of a range of angiogenic factors in a coordinated fashion, HIF may orchestrate efficient and safe angiogenesis superior to VEGF. We hypothesized that HIF inhibition impairs alveolarization and that HIF activation regenerates irreversible O2-induced arrested alveolar growth. HIF inhibition by intratracheal dominant-negative adenovirus (dnHIF-1α)-mediated gene transfer or chetomin decreased lung HIF-1α, HIF-2α, and VEGF expression and led to air space enlargement and arrested lung vascular growth. In experimental O2-induced arrested alveolar growth in newborn rats, the characteristic features of air space enlargement and loss of lung capillaries were associated with decreased lung HIF-1α and HIF-2α expression. Intratracheal administration of Ad.HIF-1α restored HIF-1α, endothelial nitric oxide synthase, VEGF, VEGFR2, and Tie2 expression and preserved and rescued alveolar growth and lung capillary formation in this model. HIFs promote normal alveolar development and may be useful targets for alveolar regeneration.

Pulmonary Vascular Congestion: A Mechanism for Distal Lung Unit Dysfunction in Obesity.

PubMed

Oppenheimer, Beno W; Berger, Kenneth I; Ali, Saleem; Segal, Leopoldo N; Donnino, Robert; Katz, Stuart; Parikh, Manish; Goldring, Roberta M

2016-01-01

Obesity is characterized by increased systemic and pulmonary blood volumes (pulmonary vascular congestion). Concomitant abnormal alveolar membrane diffusion suggests subclinical interstitial edema. In this setting, functional abnormalities should encompass the entire distal lung including the airways. We hypothesize that in obesity: 1) pulmonary vascular congestion will affect the distal lung unit with concordant alveolar membrane and distal airway abnormalities; and 2) the degree of pulmonary congestion and membrane dysfunction will relate to the cardiac response. 54 non-smoking obese subjects underwent spirometry, impulse oscillometry (IOS), diffusion capacity (DLCO) with partition into membrane diffusion (DM) and capillary blood volume (VC), and cardiac MRI (n = 24). Alveolar-capillary membrane efficiency was assessed by calculation of DM/VC. Mean age was 45±12 years; mean BMI was 44.8±7 kg/m2. Vital capacity was 88±13% predicted with reduction in functional residual capacity (58±12% predicted). Despite normal DLCO (98±18% predicted), VC was elevated (135±31% predicted) while DM averaged 94±22% predicted. DM/VC varied from 0.4 to 1.4 with high values reflecting recruitment of alveolar membrane and low values indicating alveolar membrane dysfunction. The most abnormal IOS (R5 and X5) occurred in subjects with lowest DM/VC (r2 = 0.31, p<0.001; r2 = 0.34, p<0.001). Cardiac output and index (cardiac output / body surface area) were directly related to DM/VC (r2 = 0.41, p<0.001; r2 = 0.19, p = 0.03). Subjects with lower DM/VC demonstrated a cardiac output that remained in the normal range despite presence of obesity. Global dysfunction of the distal lung (alveolar membrane and distal airway) is associated with pulmonary vascular congestion and failure to achieve the high output state of obesity. Pulmonary vascular congestion and consequent fluid transudation and/or alterations in the structure of the alveolar capillary membrane may be considered often unrecognized causes of airway dysfunction in obesity.

In Vitro Investigation of Influences of Chitosan Nanoparticles on Fluorescein Permeation into Alveolar Macrophages.

PubMed

Chachuli, Siti Haziyah Mohd; Nawaz, Asif; Shah, Kifayatullah; Naharudin, Idanawati; Wong, Tin Wui

2016-06-01

Pulmonary infection namely tuberculosis is characterized by alveolar macrophages harboring a large microbe population. The chitosan nanoparticles exhibit fast extracellular drug release in aqueous biological milieu. This study investigated the matrix effects of chitosan nanoparticles on extracellular drug diffusion into macrophages. Oligo, low, medium and high molecular weight chitosan nanoparticles were prepared by nanospray drying technique. These nanoparticles were incubated with alveolar macrophages in vitro and had model drug sodium fluorescein added into the same cell culture. The diffusion characteristics of sodium fluorescein and nanoparticle behavior were investigated using fluorescence microscopy, scanning electron microscopy, differential scanning calorimetry and Fourier transform infrared spectroscopy techniques. The oligochitosan nanoparticles enabled macrophage membrane fluidization with the extent of sodium fluorescein entry into macrophages being directly governed by the nanoparticle loading. Using nanoparticles made of higher molecular weight chitosan, sodium fluorescein permeation into macrophages was delayed due to viscous chitosan diffusion barrier at membrane boundary. Macrophage-chitosan nanoparticle interaction at membrane interface dictates drug migration into cellular domains.

A compartment model of alveolar-capillary oxygen diffusion with ventilation-perfusion gradient and dynamics of air transport through the respiratory tract.

PubMed

Jaworski, Jacek; Redlarski, Grzegorz

2014-08-01

This paper presents a model of alveolar-capillary oxygen diffusion with dynamics of air transport through the respiratory tract. For this purpose electrical model representing the respiratory tract mechanics and differential equations representing oxygen membrane diffusion are combined. Relevant thermodynamic relations describing the mass of oxygen transported into the human body are proposed as the connection between these models, as well as the influence of ventilation-perfusion mismatch on the oxygen diffusion. The model is verified based on simulation results of varying exercise intensities and statistical calculations of the results obtained during various clinical trials. The benefit of the approach proposed is its application in simulation-based research aimed to generate quantitative data of normal and pathological conditions. Based on the model presented, taking into account many essential physiological processes and air transport dynamics, comprehensive and combined studies of the respiratory efficiency can be performed. The impact of physical exercise, precise changes in respiratory tract mechanics and alterations in breathing pattern can be analyzed together with the impact of various changes in alveolar-capillary oxygen diffusion. This may be useful in simulation of effects of many severe medical conditions and increased activity level. Copyright © 2014 Elsevier Ltd. All rights reserved.

Induced sputum deposition improves diagnostic yields of pulmonary alveolar proteinosis: A clinicopathological and methodological study of 17 cases.

PubMed

Huang, Ziling; Yi, Xianghua; Luo, Benfang; Zhu, Jian; Wu, Yunjin; Jiang, Wenxia; Chu, Haiqing; Yang, Zhongmin; Li, Shuai; Zhu, Hailong; Zhang, Suxia; Zhang, Lanjing; Zeng, Yu

2016-01-01

Pulmonary alveolar proteinosis (PAP) is a rare diffuse lung disease characterized by the accumulation of intra-alveolar lipoprotein-like surfactants. Lung core biopsy and bronchoalveolar lavage (BAL) fluid are currently the two major sources of sampling for diagnosis. In the present study, we assessed the value of induced sputum in diagnosing PAP by transmission electron microscopy and examined the PAP 2-year death rate in Asians. Transmission electron microscopy was performed on the samples from 17 patients with PAP, 13 patients with inflammatory lung diseases, and 13 healthy adults. The PAP patients were followed up for 3-156 months, and inflammatory lung diseases patients or healthy adults for 12-36 months. The ultrastructural features including diagnostic lamellar bodies of induced sputum deposition (ISD) samples were similar to that of the BAL fluid sediment. However, the rates of lamellar bodies were 73.7% in the ISD group, significantly higher than the spontaneous sputum deposition (SSD) group (42.1%, P < .0487) and similar to the BAL sediment (76.2%) and the lung biopsy (54.5%) groups. The overall 2-year death rate of our PAP patients was 17.6% (3/17), not statistically different from the healthy adults and patients with inflammatory diseases (0/13, P = .237 for both). ISD may be the preferred non-invasive sampling method for diagnosing PAP by electronic microscopy because of the higher diagnostic yield than SSD. The diagnostic yields of this noninvasive method were similar to that of lung core biopsy and BAL.

Serial Histopathological Examination of the Lungs of Mice Infected with Influenza A Virus PR8 Strain

PubMed Central

Fukushi, Masaya; Ito, Tateki; Oka, Teruaki; Kitazawa, Toshio; Miyoshi-Akiyama, Tohru; Kirikae, Teruo; Yamashita, Makoto; Kudo, Koichiro

2011-01-01

Avian influenza H5N1 and pandemic (H1N1) 2009 viruses are known to induce viral pneumonia and subsequent acute respiratory distress syndrome (ARDS) with diffuse alveolar damage (DAD). The mortality rate of ARDS/DAD is extremely high, at approximately 60%, and no effective treatment for ARDS/DAD has been established. We examined serial pathological changes in the lungs of mice infected with influenza virus to determine the progress from viral pneumonia to ARDS/DAD. Mice were intranasally infected with influenza A/Puerto Rico/8/34 (PR8) virus, and their lungs were examined both macro- and micro-pathologically every 2 days. We also evaluated general condition, survival rate, body weight, viral loads in lung, and surfactant proteins in serum. As a result, all infected mice died within 9 days postinfection. At 2 days postinfection, inflammation in alveolar septa, i.e., interstitial pneumonia, was observed around bronchioles. From 4 to 6 days postinfection, interstitial pneumonia with alveolar collapse expanded throughout the lungs. From 6 to 9 days postinfection, DAD with severe alveolar collapse was observed in the lungs of all of dying and dead mice. In contrast, DAD was not observed in the live infected-mice from 2 to 6 days postinfection, despite their poor general condition. In addition, histopathological analysis was performed in mice infected with a dose of PR8 virus which was 50% of the lethal dose for mice in the 20-day observation period. DAD with alveolar collapse was observed in all dead mice. However, in the surviving mice, instead of DAD, glandular metaplasia was broadly observed in their lungs. The present study indicates that DAD with severe alveolar collapse is associated with death in this mouse infection model of influenza virus. Inhibition of the development of DAD with alveolar collapse may decrease the mortality rate in severe viral pneumonia caused by influenza virus infection. PMID:21701593

Relationship between changes in alveolar surfactant levels and lung defence mechanisms.

PubMed

Pozzi, E; Luisetti, M; Spialtini, L; Coccia, P; Rossi, A; Donnini, M; Cetta, G; Salmona, M

1989-01-01

Pulmonary surfactant, besides its mechanical properties, is thought to be involved in lung defence mechanisms. We previously described that: (1) in healthy animals, surfactant synthesis stimulation with ambroxol was accompanied by alveolar macrophage activation and a shift of the alveolar elastase/antielastase balance towards increased antielastase activity, and (2) in bleomycin-treated rats alveolar phospholipidosis was obvious 14 days after drug administration, ambroxol protection reduced the phospholipid peak and the morphological apperance of lung fibrosis at the 14th day of the experiment. The present study found that: (1) in healthy rats, the ambroxol-induced increase of alveolar antielastase activity did not appear due to reactivation of alpha 1-antitrypsin normally oxidized in the alveolar milieu; (2) in bleomycin-induced pulmonary fibrosis, ambroxol protection reduced total long collagen content at day 28, and (3) in paraquat-induced pulmonary fibrosis, alveolar phospholipids were markedly reduced throughout the 21 days of the experiment. On increasing the dose of paraquat, ambroxol protection significantly reduced the animals' death rate.

Acute resolution of pulmonary alveolar infiltrates in 10 dogs with pulmonary hypertension treated with sildenafil citrate: 2005-2014.

PubMed

Kellihan, Heidi B; Waller, Kenneth R; Pinkos, Alyssa; Steinberg, Howard; Bates, Melissa L

2015-09-01

To describe clinical canine patients with naturally occurring pulmonary hypertension and radiographic pulmonary alveolar infiltrates before and after treatment with sildenafil. Ten client-owned dogs. A retrospective analysis of dogs with echocardiographically-determined pulmonary hypertension and pulmonary alveolar infiltrates on thoracic radiographs was performed before (PRE) and after (POST) sildenafil therapy. Clinical scores, pulmonary alveolar infiltrate scores and tricuspid regurgitation gradients were analyzed PRE and POST sildenafil. Pulmonary alveolar infiltrates associated with pulmonary hypertension developed in a diffusely patchy distribution (10/10). Sixty percent of dogs had a suspected diagnosis of interstitial pulmonary fibrosis as the etiology of pulmonary hypertension. Median PRE clinical score was 4 (range: 3-4) compared to POST score of 0 (0-2) (p = 0.005). Median alveolar infiltrate score PRE was 10 (5-12) compared to POST score of 4 (0-6) (p = 0.006). Median tricuspid regurgitation gradient PRE was 83 mmHg (57-196) compared to 55 mmHg POST (33-151) (p = 0.002). A subset of dogs with moderate to severe pulmonary hypertension present with diffuse, patchy alveolar infiltrates consistent with non-cardiogenic pulmonary edema. The typical clinical presentation is acute dyspnea and syncope, often in conjunction with heart murmurs suggestive of valvular insufficiency. This constellation of signs may lead to an initial misdiagnosis of congestive heart failure or pneumonia; however, these dogs clinically and radiographically improve with the initiation of sildenafil. Copyright © 2015 Elsevier B.V. All rights reserved.

Thrombin-induced contraction in alveolar epithelial cells probed by traction microscopy.

PubMed

Gavara, Núria; Sunyer, Raimon; Roca-Cusachs, Pere; Farré, Ramon; Rotger, Mar; Navajas, Daniel

2006-08-01

Contractile tension of alveolar epithelial cells plays a major role in the force balance that regulates the structural integrity of the alveolar barrier. The aim of this work was to study thrombin-induced contractile forces of alveolar epithelial cells. A549 alveolar epithelial cells were challenged with thrombin, and time course of contractile forces was measured by traction microscopy. The cells exhibited basal contraction with total force magnitude 55.0 +/- 12.0 nN (mean +/- SE, n = 12). Traction forces were exerted predominantly at the cell periphery and pointed to the cell center. Thrombin (1 U/ml) induced a fast and sustained 2.5-fold increase in traction forces, which maintained peripheral and centripetal distribution. Actin fluorescent staining revealed F-actin polymerization and enhancement of peripheral actin rim. Disruption of actin cytoskeleton with cytochalasin D (5 microM, 30 min) and inhibition of myosin light chain kinase with ML-7 (10 microM, 30 min) and Rho kinase with Y-27632 (10 microM, 30 min) markedly depressed basal contractile tone and abolished thrombin-induced cell contraction. Therefore, the contractile response of alveolar epithelial cells to the inflammatory agonist thrombin was mediated by actin cytoskeleton remodeling and actomyosin activation through myosin light chain kinase and Rho kinase signaling pathways. Thrombin-induced contractile tension might further impair alveolar epithelial barrier integrity in the injured lung.

Oral administration of aflatoxin G₁ induces chronic alveolar inflammation associated with lung tumorigenesis.

PubMed

Liu, Chunping; Shen, Haitao; Yi, Li; Shao, Peilu; Soulika, Athena M; Meng, Xinxing; Xing, Lingxiao; Yan, Xia; Zhang, Xianghong

2015-02-03

Our previous studies showed oral gavage of aflatoxin G₁ (AFG₁) induced lung adenocarcinoma in NIH mice. We recently found that a single intratracheal administration of AFG₁ caused chronic inflammatory changes in rat alveolar septum. Here, we examine whether oral gavage of AFG₁ induces chronic lung inflammation and how it contributes to carcinogenesis. We evaluated chronic lung inflammatory responses in Balb/c mice after oral gavage of AFG₁ for 1, 3 and 6 months. Inflammatory responses were heightened in the lung alveolar septum, 3 and 6 months after AFG₁ treatment, evidenced by increased macrophages and lymphocytes infiltration, up-regulation of NF-κB and p-STAT3, and cytokines production. High expression levels of superoxide dismutase (SOD-2) and hemoxygenase-1 (HO-1), two established markers of oxidative stress, were detected in alveolar epithelium of AFG₁-treated mice. Promoted alveolar type II cell (AT-II) proliferation in alveolar epithelium and angiogenesis, as well as increased COX-2 expression were also observed in lung tissues of AFG₁-treated mice. Furthermore, we prolonged survival of the mice in the above model for another 6 months to examine the contribution of AFG₁-induced chronic inflammation to lung tumorigenesis. Twelve months later, we observed that AFG₁ induced alveolar epithelial hyperplasia and adenocarcinoma in Balb/c mice. Up-regulation of NF-κB, p-STAT3, and COX-2 was also induced in lung adenocarcinoma, thus establishing a link between AFG₁-induced chronic inflammation and lung tumorigenesis. This is the first study to show that oral administration of AFG₁ could induce chronic lung inflammation, which may provide a pro-tumor microenvironment to contribute to lung tumorigenesis. Copyright © 2014. Published by Elsevier Ireland Ltd.

Tilmicosin reduces lipopolysaccharide-stimulated bovine alveolar macrophage prostaglandin E(2) production via a mechanism involving phospholipases.

PubMed

Lakritz, Jeffrey; Tyler, Jeff W; Marsh, Antoinette E; Romesburg-Cockrell, Mary; Smith, Kathy; Holle, Julie M

2002-01-01

Tilmicosin is a potent antimicrobial with broad-spectrum activity against the bacterial agents involved in the bovine respiratory disease complex. Recent studies indicate that in addition to being bactericidal, tilmicosin is capable of modulating inflammation in the lung. A series of experiments were designed to determine whether tilmicosin alters alveolar macrophage-prostaglandin E(2) (PGE(2)) production induced by Escherichia coli (O55:B5) lipopolysaccharide (LPS). Twenty-two healthy Holstein bull calves were used to study the effects of LPS-induced PGE(2) production of alveolar macrophages after in vivo or in vitro treatment with tilmicosin. In Experiment 1, tilmicosin was given by subcutaneous injection (15 mg/kg) twice, 48 hours apart, to four calves; four control calves received no treatment. Twenty-four hours after the second treatment, alveolar macrophages were stimulated with LPS in vitro. In Experiment 2, alveolar macrophages from five untreated calves were harvested and treated in vitro with tilmicosin, followed by LPS stimulation. In Experiment 3, the ability of in vitro tilmicosin treatment to alter the expression of LPS-induced cyclooxygenase-2 (COX-2) mRNA was evaluated. In Experiments 4 and 5, secretory phospholipase A(2) activity was examined in untreated calves. Treatment of calves with tilmicosin resulted in reduced LPS-induced alveolar macrophage PGE(2) production. Similar reductions in PGE(2) by LPS-stimulated alveolar macrophages after in vitro tilmicosin treatment were noted. This in vitro tilmicosin treatment was not associated with reduction of the expression of LPS-induced COX-2. Alveolar macrophage phospholipase A(2) activity induced by LPS was significantly reduced by prior tilmicosin treatment in vitro. Tilmicosin (in vivo and in vitro) appears to reduce the PGE(2) eicosanoid response of LPS-stimulated alveolar macrophages by reducing the in vitro substrate availability without altering in vitro COX-2 mRNA expression.

[A case of loxoprofen-induced pneumonitis pathologically resembling hypersensitivity pneumonitis].

PubMed

Tohyama, Masaki; Tamaki, Yuichiro; Toyama, Masato; Ishimine, Tomohiko; Miyazato, Akiko; Nakamoto, Atsushi; Miyara, Takayuki; Higa, Futoshi; Tateyama, Masao; Kawakami, Kazuyoshi; Nakamura, Hiroaki; Saito, Atsushi

2002-02-01

A 66-year-old woman was admitted to our hospital because of high fever, general fatigue, hypoxemia and liver dysfunction. Chest radiographs showed diffuse interstitial shadows in both lungs. We suspected drug-induced pneumonitis because of her history of drug administration for upper respiratory infection. Her symptoms and findings were markedly decreased by discontinuation of the drugs. Transbronchial lung biopsy specimens showed infiltration of eosinophils and lymphocytes to the alveolar septa, granuloma with Langhans' giant cells, and Masson bodies in a manner suggestive of hypersensitivity pneumonitis. Drug lymphocyte stimulation tests were negative except for loxoprofen. There was no recurrence of systemic or respiratory symptoms during overnight stays at home. On the basis of these findings, we arrived at a diagnosis of drug-induced pneumonitis caused by loxoprofen.

TRPA1 channels: expression in non-neuronal murine lung tissues and dispensability for hyperoxia-induced alveolar epithelial hyperplasia.

PubMed

Kannler, Martina; Lüling, Robin; Yildirim, Ali Önder; Gudermann, Thomas; Steinritz, Dirk; Dietrich, Alexander

2018-05-12

Transient receptor potential A1 (TRPA1) channels were originally characterized in neuronal tissues but also identified in lung epithelium by staining with fluorescently coupled TRPA1 antibodies. Its exact function in non-neuronal tissues, however, is elusive. TRPA1 is activated in vitro by hypoxia and hyperoxia and is therefore a promising TRP candidate for sensing hyperoxia in pulmonary epithelial cells and for inducing alveolar epithelial hyperplasia. Here, we isolated tracheal, bronchial, and alveolar epithelial cells and show low but detectable TRPA1 mRNA levels in all these cells as well as TRPA1 protein by Western blotting in alveolar type II (AT II) cells. We quantified changes in intracellular Ca 2+ ([Ca 2+ ] i ) levels induced by application of hyperoxic solutions in primary tracheal epithelial, bronchial epithelial, and AT II cells isolated from wild-type (WT) and TRPA1-deficient (TRPA1-/-) mouse lungs. In all cell types, we detected hyperoxia-induced rises in [Ca 2+ ] i levels, which were not significantly different in TRPA1-deficient cells compared to WT cells. We also tested TRPA1 function in a mouse model for hyperoxia-induced alveolar epithelial hyperplasia. A characteristic significant increase in thickening of alveolar tissues was detected in mouse lungs after exposure to hyperoxia, but not in normoxic WT and TRPA1-/- controls. Quantification of changes in lung morphology in hyperoxic WT and TRPA1-/- mice, however, again revealed no significant changes. Therefore, TRPA1 expression does neither appear to be a key player for hyperoxia-induced changes in [Ca 2+ ] i levels in primary lung epithelial cells, nor being essential for the development of hyperoxia-induced alveolar epithelial hyperplasia.

Oral administration of vitamin C prevents alveolar bone resorption induced by high dietary cholesterol in rats.

PubMed

Sanbe, Toshihiro; Tomofuji, Takaaki; Ekuni, Daisuke; Azuma, Tetsuji; Tamaki, Naofumi; Yamamoto, Tatsuo

2007-11-01

A high-cholesterol diet stimulates alveolar bone resorption, which may be induced via tissue oxidative damage. Vitamin C reduces tissue oxidative damage by neutralizing free radicals and scavenging hydroxyl radicals, and its antioxidant effect may offer the clinical benefit of preventing alveolar bone resorption in cases of hyperlipidemia. We examined whether vitamin C could suppress alveolar bone resorption in rats fed a high-cholesterol diet. In this 12-week study, rats were divided into four groups: a control group (fed a regular diet) and three experimental groups (fed a high-cholesterol diet supplemented with 0, 1, or 2 g/l vitamin C). Vitamin C was provided by adding it to the drinking water. The bone mineral density of the alveolar bone was analyzed by microcomputerized tomography. As an index of tissue oxidative damage, the 8-hydroxydeoxyguanosine level in the periodontal tissue was determined using a competitive enzyme-linked immunosorbent assay. Hyperlipidemia, induced by a high-cholesterol diet, decreased rat alveolar bone density and increased the number of tartrate-resistant acid phosphatase-positive osteoclasts. The expression of 8-hydroxydeoxyguanosine was upregulated in the periodontal tissues. Intake of vitamin C reduced the effect of a high-cholesterol diet on alveolar bone density and osteoclast differentiation and decreased periodontal 8-hydroxydeoxyguanosine expression. In the rat model, vitamin C suppressed alveolar bone resorption, induced by high dietary cholesterol, by decreasing the oxidative damage of periodontal tissue.

[Measurement of CO diffusion capacity (II): Standardization and quality criteria].

PubMed

Salcedo Posadas, A; Villa Asensi, J R; de Mir Messa, I; Sardón Prado, O; Larramona, H

2015-08-01

The diffusion capacity is the technique that measures the ability of the respiratory system for gas exchange, thus allowing a diagnosis of the malfunction of the alveolar-capillary unit. The most important parameter to assess is the CO diffusion capacity (DLCO). New methods are currently being used to measure the diffusion using nitric oxide (NO). There are other methods for measuring diffusion, although in this article the single breath technique is mainly referred to, as it is the most widely used and best standardized. Its complexity, its reference equations, differences in equipment, inter-patient variability and conditions in which the DLCO is performed, lead to a wide inter-laboratory variability, although its standardization makes this a more reliable and reproductive method. The practical aspects of the technique are analyzed, by specifying the recommendations to carry out a suitable procedure, the calibration routine, calculations and adjustments. Clinical applications are also discussed. An increase in the transfer of CO occurs in diseases in which there is an increased volume of blood in the pulmonary capillaries, such as in the polycythemia and pulmonary hemorrhage. There is a decrease in DLCO in patients with alveolar volume reduction or diffusion defects, either by altered alveolar-capillary membrane (interstitial diseases) or decreased volume of blood in the pulmonary capillaries (pulmonary embolism or primary pulmonary hypertension). Other causes of decreased or increased DLCO are also highlighted. Copyright © 2014 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.

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.

Sessile alveolar macrophages communicate with alveolar epithelium to modulate immunity

NASA Astrophysics Data System (ADS)

Westphalen, Kristin; Gusarova, Galina A.; Islam, Mohammad N.; Subramanian, Manikandan; Cohen, Taylor S.; Prince, Alice S.; Bhattacharya, Jahar

2014-02-01

The tissue-resident macrophages of barrier organs constitute the first line of defence against pathogens at the systemic interface with the ambient environment. In the lung, resident alveolar macrophages (AMs) provide a sentinel function against inhaled pathogens. Bacterial constituents ligate Toll-like receptors (TLRs) on AMs, causing AMs to secrete proinflammatory cytokines that activate alveolar epithelial receptors, leading to recruitment of neutrophils that engulf pathogens. Because the AM-induced response could itself cause tissue injury, it is unclear how AMs modulate the response to prevent injury. Here, using real-time alveolar imaging in situ, we show that a subset of AMs attached to the alveolar wall form connexin 43 (Cx43)-containing gap junction channels with the epithelium. During lipopolysaccharide-induced inflammation, the AMs remained sessile and attached to the alveoli, and they established intercommunication through synchronized Ca2+ waves, using the epithelium as the conducting pathway. The intercommunication was immunosuppressive, involving Ca2+-dependent activation of Akt, because AM-specific knockout of Cx43 enhanced alveolar neutrophil recruitment and secretion of proinflammatory cytokines in the bronchoalveolar lavage. A picture emerges of a novel immunomodulatory process in which a subset of alveolus-attached AMs intercommunicates immunosuppressive signals to reduce endotoxin-induced lung inflammation.

Follistatin-like 1 expression is decreased in the alveolar epithelium of hypoplastic rat lungs with nitrofen-induced congenital diaphragmatic hernia.

PubMed

Takahashi, Toshiaki; Zimmer, Julia; Friedmacher, Florian; Puri, Prem

2017-05-01

Pulmonary hypoplasia (PH), characterized by incomplete alveolar development, remains a major therapeutic challenge associated with congenital diaphragmatic hernia (CDH). Follistatin-like 1 (Fstl1) is a crucial regulator of alveolar formation and maturation, which is strongly expressed in distal airway epithelium. Fstl1-deficient mice exhibit reduced airspaces, impaired alveolar epithelial cell differentiation, and insufficient production of surfactant proteins similar to PH in human CDH. We hypothesized that pulmonary Fstl1 expression is decreased during alveolarization in the nitrofen-induced CDH model. Timed-pregnant rats received nitrofen or vehicle on gestational day 9 (D9). Fetal lungs were harvested on D18 and D21 and divided into control-/nitrofen-exposed specimens. Alveolarization was assessed using morphometric analysis techniques. Pulmonary gene expression of Fstl1 was determined by qRT-PCR. Immunofluorescence-double-staining for Fstl1 and alveolar epithelial marker surfactant protein C (SP-C) was performed to evaluate protein expression/localization. Radial alveolar count was significantly reduced in hypoplastic lungs of nitrofen-exposed fetuses with significant down regulation of Fstl1 mRNA expression on D18 and D21 compared to controls. Confocal-laser-scanning-microscopy revealed strikingly diminished Fstl1 immunofluorescence and SP-C expression in distal alveolar epithelium of nitrofen-exposed fetuses with CDH-associated PH on D18 and D21 compared to controls. Decreased expression of Fstl1 in alveolar epithelium may disrupt alveolarization and pulmonary surfactant production, thus contributing to the development of PH in the nitrofen-induced CDH model. 2b (Centre for Evidence-Based Medicine, Oxford). Copyright © 2017 Elsevier Inc. All rights reserved.

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

Frank, Evan A.; Birch, M. Eileen; Yadav, Jagjit S., E-mail: Jagjit.Yadav@uc.edu

Carbon nanotubes (CNTs) are rapidly emerging as high-priority occupational toxicants. CNT powders contain fibrous particles that aerosolize readily in places of manufacture and handling, posing an inhalation risk for workers. Studies using animal models indicate that lung exposure to CNTs causes prolonged inflammatory responses and diffuse alveolar injury. The mechanisms governing CNT-induced lung inflammation are not fully understood but have been suggested to involve alveolar macrophages (AMs). In the current study, we sought to systematically assess the effector role of AMs in vivo in the induction of lung inflammatory responses to CNT exposures and investigate their cell type-specific mechanisms. Multi-wallmore » CNTs characterized for various physicochemical attributes were used as the CNT type. Using an AM-specific depletion and repopulation approach in a mouse model, we unambiguously demonstrated that AMs are major effector cells necessary for the in vivo elaboration of CNT-induced lung inflammation. We further investigated in vitro AM responses and identified molecular targets which proved critical to pro-inflammatory responses in this model, namely MyD88 as well as MAPKs and Ca{sup 2} {sup +}/CamKII. We further demonstrated that MyD88 inhibition in donor AMs abrogated their capacity to reconstitute CNT-induced inflammation when adoptively transferred into AM-depleted mice. Taken together, this is the first in vivo demonstration that AMs act as critical effector cell types in CNT-induced lung inflammation and that MyD88 is required for this in vivo effector function. AMs and their cell type-specific mechanisms may therefore represent potential targets for future therapeutic intervention of CNT-related lung injury. - Highlights: • Demonstrated in vivo effector role of alveolar macrophages (AMs) in CNT toxicity • MyD88, MAPKs, and Ca{sup 2} {sup +}/CamKII are required for AM inflammatory responses in vitro. • MyD88 signaling is required for in vivo effector function of AMs. • MyD88 may be a potential target for intervention in CNT lung exposures.« less

Pigeon paramyxovirus type 1 from a fatal human case induces pneumonia in experimentally infected cynomolgus macaques (Macaca fascicularis).

PubMed

Kuiken, Thijs; Buijs, Pascal; van Run, Peter; van Amerongen, Geert; Koopmans, Marion; van den Hoogen, Bernadette

2017-11-21

Although avian paramyxovirus type 1 is known to cause mild transient conjunctivitis in human beings, there are two recent reports of fatal respiratory disease in immunocompromised human patients infected with the pigeon lineage of the virus (PPMV-1). In order to evaluate the potential of PPMV-1 to cause respiratory tract disease, we inoculated a PPMV-1 isolate (hPPMV-1/Netherlands/579/2003) from an immunocompromised human patient into three healthy cynomolgus macaques (Macaca fascicularis) and examined them by clinical, virological, and pathological assays. In all three macaques, PPMV-1 replication was restricted to the respiratory tract and caused pulmonary consolidation affecting up to 30% of the lung surface. Both alveolar and bronchiolar epithelial cells expressed viral antigen, which co-localized with areas of diffuse alveolar damage. The results of this study demonstrate that PPMV-1 is a primary respiratory pathogen in cynomolgus macaques, and support the conclusion that PPMV-1 may cause fatal respiratory disease in immunocompromised human patients.

Alveolar Macrophages Play a Key Role in Cockroach-Induced Allergic Inflammation via TNF-α Pathway

PubMed Central

Kim, Joo Young; Sohn, Jung Ho; Choi, Je-Min; Lee, Jae-Hyun; Hong, Chein-Soo; Lee, Joo-Shil; Park, Jung-Won

2012-01-01

The activity of the serine protease in the German cockroach allergen is important to the development of allergic disease. The protease-activated receptor (PAR)-2, which is expressed in numerous cell types in lung tissue, is known to mediate the cellular events caused by inhaled serine protease. Alveolar macrophages express PAR-2 and produce considerable amounts of tumor necrosis factor (TNF)-α. We determined whether the serine protease in German cockroach extract (GCE) enhances TNF-α production by alveolar macrophages through the PAR-2 pathway and whether the TNF-α production affects GCE-induced pulmonary inflammation. Effects of GCE on alveolar macrophages and TNF-α production were evaluated using in vitro MH-S and RAW264.6 cells and in vivo GCE-induced asthma models of BALB/c mice. GCE contained a large amount of serine protease. In the MH-S and RAW264.7 cells, GCE activated PAR-2 and thereby produced TNF-α. In the GCE-induced asthma model, intranasal administration of GCE increased airway hyperresponsiveness (AHR), inflammatory cell infiltration, productions of serum immunoglobulin E, interleukin (IL)-5, IL-13 and TNF-α production in alveolar macrophages. Blockade of serine proteases prevented the development of GCE induced allergic pathologies. TNF-α blockade also prevented the development of such asthma-like lesions. Depletion of alveolar macrophages reduced AHR and intracellular TNF-α level in pulmonary cell populations in the GCE-induced asthma model. These results suggest that serine protease from GCE affects asthma through an alveolar macrophage and TNF-α dependent manner, reflecting the close relation of innate and adaptive immune response in allergic asthma model. PMID:23094102

Transplantation of osteoporotic bone marrow stromal cells rejuvenated by the overexpression of SATB2 prevents alveolar bone loss in ovariectomized rats.

PubMed

Xu, Rongyao; Fu, Zongyun; Liu, Xue; Xiao, Tao; Zhang, Ping; Du, Yifei; Yuan, Hua; Cheng, Jie; Jiang, Hongbing

2016-11-01

Estrogen-deficient osteoporosis is an aging-related disease with high morbidity that not only significantly increases a woman's risk of fragility fracture but is also associated with tooth and bone loss in the supporting alveolar bone of the jaw. Emerging evidence suggests that the aging of bone marrow stromal cells (BMSCs) contributes to the development of osteoporosis. In this study, we aimed to investigate the role of the special AT-rich sequence-binding protein 2 (SATB2), a stemness and senescence regulator of craniofacial BMSCs, in rat ovariectomy-induced alveolar osteoporosis. We also sought to determine whether transplantation of SATB2-modified BMSCs could ameliorate estrogen deficient alveolar bone loss. Our data revealed that BMSCs from ovariectomy-induced alveolar bone exhibited typical senescence phenotypes such as diminished stemness and osteogenic capacity, increased expression of senescence or osteoclastic markers and enhanced adipogenic potential. These phenotypic changes are a result of SATB2-mediated senescence dysregulation as evidenced by nuclear γH2AX foci formation. Moreover, overexpression of SATB2 significantly alleviated the senescence of osteoporotic BMSCs in vitro. Importantly, transplantation of SATB2-modified BMSCs significantly attenuated ovariectomy-induced alveolar bone loss in vivo. Together, our results revealed that SATB2 is a critical regulator of alveolar BMSC senescence, and its overexpression decreases these senescent changes both in vitro and in vivo. SATB2-modified BMSC delivery could be a viable and promising therapeutic strategy for alveolar bone loss induced by estrogen-deficient osteoporosis. Copyright © 2016 Elsevier Inc. All rights reserved.

SARS-CoV replicates in primary human alveolar type II cell cultures but not in type I-like cells

PubMed Central

Mossel, Eric C.; Wang, Jieru; Jeffers, Scott; Edeen, Karen E.; Wang, Shuanglin; Cosgrove, Gregory P.; Funk, C. Joel; Manzer, Rizwan; Miura, Tanya A.; Pearson, Leonard D.; Holmes, Kathryn V.; Mason, Robert J.

2008-01-01

Severe acute respiratory syndrome (SARS) is a disease characterized by diffuse alveolar damage. We isolated alveolar type II cells and maintained them in a highly differentiated state. Type II cell cultures supported SARS-CoV replication as evidenced by RT-PCR detection of viral subgenomic RNA and an increase in virus titer. Virus titers were maximal by 24 hours and peaked at approximately 105 pfu/mL. Two cell types within the cultures were infected. One cell type was type II cells, which were positive for SP-A, SP-C, cytokeratin, a type II cell-specific monoclonal antibody, and Ep-CAM. The other cell type was composed of spindle-shaped cells that were positive for vimentin and collagen III and likely fibroblasts. Viral replication was not detected in type I-like cells or macrophages. Hence, differentiated adult human alveolar type II cells were infectible but alveolar type I-like cells and alveolar macrophages did not support productive infection. PMID:18022664

Inhibitory effects of Persicariae Rhizoma aqueous extracts on experimental periodontitis and alveolar bone loss in Sprague-Dawley rats

PubMed Central

Kang, Su Jin; Lee, Eun Kyung; Han, Chang Hyun; Lee, Bong Hyo; Lee, Young Joon; Ku, Sae Kwang

2016-01-01

Persicariae Rhizoma (PR) is the dried stem parts of Persicaria tinctoria H. Gross (Polygonaceae), and has been traditionally used as anti-inflammatory and detoxifying agent. In the present study, the effects of PR aqueous extracts on ligation-induced experimental periodontitis (EPD) and associated alveolar bone loss in rats were examined. Following the induction of EPD in rats, PR extracts were orally administered once a day for 10 days, and the changes and gains in body weight, alveolar bone loss and total aerobic bacterial counts of buccal gingiva were observed with histopathological analysis. In addition, anti-inflammatory effects were evaluated by monitoring myeloperoxidase (MPO) activities, and interleukin (IL)-1β and tumor necrosis factor (TNF)-α contents, and anti-oxidant effects were investigated by measuring inducible nitric oxide synthase (iNOS) activities and malondialdehyde (MDA) levels. Bacterial proliferation, periodontitis and associated alveolar bone loss induced by ligature placement were significantly and dose-dependently inhibited by the treatment with PR extracts. The inhibitory effects of 200 mg/kg PR were similar to those of 5 mg/kg indomethacin on ligation-induced periodontitis and associated alveolar bone losses in this study. The results suggest that PR effectively inhibits ligature placement-induced periodontitis and alveolar bone loss in rats via antibacterial, antioxidative and anti-inflammatory activities. PMID:27588077

Alendronate inhalation ameliorates elastase-induced pulmonary emphysema in mice by induction of apoptosis of alveolar macrophages.

PubMed

Ueno, Manabu; Maeno, Toshitaka; Nishimura, Satoshi; Ogata, Fusa; Masubuchi, Hiroaki; Hara, Kenichiro; Yamaguchi, Kouichi; Aoki, Fumiaki; Suga, Tatsuo; Nagai, Ryozo; Kurabayashi, Masahiko

2015-03-10

Alveolar macrophages play a crucial role in the pathogenesis of emphysema, for which there is currently no effective treatment. Bisphosphonates are widely used to treat osteoclast-mediated bone diseases. Here we show that delivery of the nitrogen-containing bisphosphonate alendronate via aerosol inhalation ameliorates elastase-induced emphysema in mice. Inhaled, but not orally ingested, alendronate inhibits airspace enlargement after elastase instillation, and induces apoptosis of macrophages in bronchoalveolar fluid via caspase-3- and mevalonate-dependent pathways. Cytometric analysis indicates that the F4/80(+)CD11b(high)CD11c(mild) population characterizing inflammatory macrophages, and the F4/80(+)CD11b(mild)CD11c(high) population defining resident alveolar macrophages take up substantial amounts of the bisphosphonate imaging agent OsteoSense680 after aerosol inhalation. We further show that alendronate inhibits macrophage migratory and phagocytotic activities and blunts the inflammatory response of alveolar macrophages by inhibiting nuclear factor-κB signalling. Given that the alendronate inhalation effectively induces apoptosis in both recruited and resident alveolar macrophages, we suggest this strategy may have therapeutic potential for the treatment of emphysema.

[Pulmonary pathology in fatal human influenza A (H1N1) infection].

PubMed

Duan, Xue-jing; Li, Yong; Gong, En-cong; Wang, Jue; Lü, Fu-dong; Zhang, He-qiu; Sun, Lin; Yue, Zhu-jun; Song, Chen-chao; Zhang, Shi-Jie; Li, Ning; Dai, Jie

2011-12-01

To study the pulmonary pathology in patients died of fatal human influenza A(H1N1) infection. Eight cases of fatal human influenza A (H1N1) infection, including 2 autopsy cases and 6 paramortem needle puncture biopsies, were enrolled into the study. Histologic examination, immunohistochemitry, flow cytometry and Western blotting were carried out. The major pathologic changes included necrotizing bronchiolitis with surrounding inflammation, diffuse alveolar damage and pulmonary hemorrhage. Influenza viral antigen expression was detected in the lung tissue by Western blotting. Immunohistochemical study demonstrated the presence of nuclear protein and hemagglutinin virus antigens in parts of trachea, bronchial epithelium and glands, alveolar epithelium, macrophages and endothelium. Flow cytometry showed that the apoptotic rate of type II pneumocytes (32.15%, 78.15%) was significantly higher than that of the controls (1.93%, 3.77%). Necrotizing bronchiolitis, diffuse alveolar damage and pulmonary hemorrhage followed by pulmonary fibrosis in late stage are the major pathologic changes in fatal human influenza A (H1N1) infection.

Rat coronaviruses infect rat alveolar type I epithelial cells and induce expression of CXC chemokines

PubMed Central

Miura, Tanya A.; Wang, Jieru; Holmes, Kathryn V.; Mason, Robert J.

2007-01-01

We analyzed the ability of two rat coronavirus (RCoV) strains, sialodacryoadenitis virus (SDAV) and Parker’s RCoV (RCoV-P), to infect rat alveolar type I cells and induce chemokine expression. Primary rat alveolar type II cells were transdifferentiated into the type I cell phenotype. Type I cells were productively infected with SDAV and RCoV-P, and both live virus and UV-inactivated virus induced mRNA and protein expression of three CXC chemokines: CINC-2, CINC-3, and LIX, which are neutrophil chemoattractants. Dual immunolabeling of type I cells for viral antigen and CXC chemokines showed that chemokines were expressed primarily by uninfected cells. Virus-induced chemokine expression was reduced by the IL-1 receptor antagonist, suggesting that IL-1 produced by infected cells induces uninfected cells to express chemokines. Primary cultures of alveolar epithelial cells are an important model for the early events in viral infection that lead to pulmonary inflammation. PMID:17804032

Salmeterol improves fluid clearance from alveolar-capillary membrane in COPD patients: a pilot study.

PubMed

Di Marco, Fabiano; Guazzi, Marco; Sferrazza Papa, Giuseppe Francesco; Vicenzi, Marco; Santus, Pierachille; Busatto, Paolo; Piffer, Federico; Blasi, Francesco; Centanni, Stefano

2012-02-01

The cardiovascular component associated with chronic obstructive pulmonary disease (COPD) plays a major role in disease prognosis, accounting for 25% of the deaths. Experimental and initial clinical data suggest that beta-adrenergic agonists accelerate fluid clearance from the alveolar airspace, with potentially positive effects on cardiogenic and noncardiogenic pulmonary oedema. This pilot study investigated the acute effects of the long-acting beta-2 agonist, salmeterol, on alveolar fluid clearance after rapid saline intravenous infusion by evaluating diffusive and mechanical lung properties. Ten COPD and 10 healthy subjects were treated with salmeterol or placebo 4 h before the patient's mechanical and diffusive lung properties were measured during four non consecutive days, just before and after a rapid saline infusion, or during a similar period without an infusion. In both COPD and healthy subjects, rapid saline infusion with placebo or salmeterol premedication lead to a significant decrease in diffusion capacity for carbon monoxide (DLCO) and forced expiratory volume in 1 s (FEV1). Nonetheless, salmeterol pretreatment lead to a significantly reduced gas exchange impairment caused by saline infusion (-64% of DLCO reduction compared with placebo), whereas it did not affect changes in FEV1. In the control setting with no infusion, we found no significant change in either DLCO or mechanical properties of the lung. Salmeterol appears to provide a protective effect, not related to bronchodilation, against an acute alveolar fluid clearance challenge secondary to lung fluid overload in COPD patients. Copyright © 2012 Elsevier Ltd. All rights reserved.

Breakdown of lung framework and an increase in pores of Kohn as initial events of emphysema and a cause of reduction in diffusing capacity.

PubMed

Yoshikawa, Akira; Sato, Shuntaro; Tanaka, Tomonori; Hashisako, Mikiko; Kashima, Yukio; Tsuchiya, Tomoshi; Yamasaki, Naoya; Nagayasu, Takeshi; Yamamoto, Hiroshi; Fukuoka, Junya

2016-01-01

Pulmonary emphysema is the pathological prototype of chronic obstructive pulmonary disease and is also associated with other lung diseases. We considered that observation with different approaches may provide new insights for the pathogenesis of emphysema. We reviewed tissue blocks of the lungs of 25 cases with/without emphysema and applied a three-dimensional observation method to the blocks. Based on the three-dimensional characteristics of the alveolar structure, we considered one face of the alveolar polyhedron as a structural unit of alveoli and called it a framework unit (FU). We categorized FUs based on their morphological characteristics and counted their number to evaluate the destructive changes in alveoli. We also evaluated the number and the area of pores of Kohn in FUs. We performed linear regression analysis to estimate the effect of these data on pulmonary function tests. In multivariable regression analysis, a decrease in the number of FUs without an alveolar wall led to a significant decrease in the diffusing capacity of the lung for carbon monoxide (DLCO) and DLCO per unit alveolar volume, and an increase in the area of pores of Kohn had a significant effect on an increase in residual capacity. A breakdown in the lung framework and an increase in pores of Kohn are associated with a decrease in DLCO and DLCO per unit alveolar volume with/without emphysema.

Alveolar Thin Layer Flows and Surfactant Dynamics

NASA Astrophysics Data System (ADS)

Roumie, Ahmad; Jbaily, Abdulrahman; Szeri, Andrew J.

2017-11-01

Pulmonary surfactants play a vital role in everyday respiration. They regulate surface tension in the lungs by diffusing through the hypophase, a liquid layer that lines the interior surface of the alveoli, and adsorbing to the existing air-fluid interface. This decreases the equilibrium surface tension value by as much as a factor of 3, minimizing breathing effort and preventing lung collapse at the end of exhalation. Given that the hypophase thickness h lies within the range 0.1 μm < h <0.5 μm , and that the average alveolar radius R is 100 μm , for some purposes the hypophase may usefully be modeled as a fluid layer on a flat sheet representing the alveolar wall. Moreover, because of the large aspect ratio, the lubrication approximation can be applied. The aim of the present work is to study the interaction between the straining of the alveolar wall and the fluid flow in the hypophase. The analysis is governed by the relative magnitudes of the time scales of surfactant diffusion, adsorption, desorption, viscous dissipation and sheet straining. Cases of particular interest include non-uniform surfactant concentration at the interface, leading to Marangoni flows and a non-uniform hypophase thickness profile. The analytical formulation and numerical simulations are presented. This work is motivated by a need to understand alveolar deformation during breathing, and to do so in a way that derives from improved understanding of the fluid mechanics of the problem.

Linking lung function to structural damage of alveolar epithelium in ventilator-induced lung injury.

PubMed

Hamlington, Katharine L; Smith, Bradford J; Dunn, Celia M; Charlebois, Chantel M; Roy, Gregory S; Bates, Jason H T

2018-05-06

Understanding how the mechanisms of ventilator-induced lung injury (VILI), namely atelectrauma and volutrauma, contribute to the failure of the blood-gas barrier and subsequent intrusion of edematous fluid into the airspace is essential for the design of mechanical ventilation strategies that minimize VILI. We ventilated mice with different combinations of tidal volume and positive end-expiratory pressure (PEEP) and linked degradation in lung function measurements to injury of the alveolar epithelium observed via scanning electron microscopy. Ventilating with both high inspiratory plateau pressure and zero PEEP was necessary to cause derangements in lung function as well as visually apparent physical damage to the alveolar epithelium of initially healthy mice. In particular, the epithelial injury was tightly associated with indicators of alveolar collapse. These results support the hypothesis that mechanical damage to the epithelium during VILI is at least partially attributed to atelectrauma-induced damage of alveolar type I epithelial cells. Copyright © 2018. Published by Elsevier B.V.

Bayesian inference of the lung alveolar spatial model for the identification of alveolar mechanics associated with acute respiratory distress syndrome

NASA Astrophysics Data System (ADS)

Christley, Scott; Emr, Bryanna; Ghosh, Auyon; Satalin, Josh; Gatto, Louis; Vodovotz, Yoram; Nieman, Gary F.; An, Gary

2013-06-01

Acute respiratory distress syndrome (ARDS) is acute lung failure secondary to severe systemic inflammation, resulting in a derangement of alveolar mechanics (i.e. the dynamic change in alveolar size and shape during tidal ventilation), leading to alveolar instability that can cause further damage to the pulmonary parenchyma. Mechanical ventilation is a mainstay in the treatment of ARDS, but may induce mechano-physical stresses on unstable alveoli, which can paradoxically propagate the cellular and molecular processes exacerbating ARDS pathology. This phenomenon is called ventilator induced lung injury (VILI), and plays a significant role in morbidity and mortality associated with ARDS. In order to identify optimal ventilation strategies to limit VILI and treat ARDS, it is necessary to understand the complex interplay between biological and physical mechanisms of VILI, first at the alveolar level, and then in aggregate at the whole-lung level. Since there is no current consensus about the underlying dynamics of alveolar mechanics, as an initial step we investigate the ventilatory dynamics of an alveolar sac (AS) with the lung alveolar spatial model (LASM), a 3D spatial biomechanical representation of the AS and its interaction with airflow pressure and the surface tension effects of pulmonary surfactant. We use the LASM to identify the mechanical ramifications of alveolar dynamics associated with ARDS. Using graphical processing unit parallel algorithms, we perform Bayesian inference on the model parameters using experimental data from rat lung under control and Tween-induced ARDS conditions. Our results provide two plausible models that recapitulate two fundamental hypotheses about volume change at the alveolar level: (1) increase in alveolar size through isotropic volume change, or (2) minimal change in AS radius with primary expansion of the mouth of the AS, with the implication that the majority of change in lung volume during the respiratory cycle occurs in the alveolar ducts. These two model solutions correspond to significantly different mechanical properties of the tissue, and we discuss the implications of these different properties and the requirements for new experimental data to discriminate between the hypotheses.

Disruption of THY-1 signaling in alveolar lipofibroblasts in experimentally induced congenital diaphragmatic hernia.

PubMed

Friedmacher, Florian; Hofmann, Alejandro Daniel; Takahashi, Hiromizu; Takahashi, Toshiaki; Gosemann, Jan-Hendrik; Puri, Prem

2014-02-01

Pulmonary hypoplasia (PH), characterized by alveolar immaturity, remains the main cause of neonatal mortality and long-term morbidity in infants with congenital diaphragmatic hernia (CDH). Lipid-containing interstitial fibroblasts (LIFs) are critically important for normal alveolar development. Thymocyte antigen 1 (Thy-1) is a highly expressed cell-surface protein in this specific subset of lung fibroblasts, which plays a key role in fetal alveolarization by coordinating the differentiation and lipid homeostasis of alveolar LIFs. Thy-1 increases the lipid content of LIFs by upregulation of adipocyte differentiation-related protein (ADRP), a lipogenic molecular marker characterizing pulmonary LIFs. Thy-1 (-/-) mice further show impaired alveolar development with reduced proliferation of pulmonary LIFs, resulting in a PH-similar phenotype. We hypothesized that pulmonary Thy-1 signaling is disrupted in experimentally induced CDH, which may has an adverse effect on the lipid content of alveolar LIFs. Timed-pregnant Sprague-Dawley rats were treated with either 100 mg nitrofen or vehicle on embryonic day 9.5 (E9.5). Fetuses were killed on E21.5, and lungs were divided into controls (n = 14) and CDH-associated PH (n = 14). Pulmonary gene expression levels of Thy-1 and ADRP were assessed by quantitative real-time PCR. ADRP immunohistochemistry and oil-red-O staining were used to localize alveolar LIF expression and lipid droplets. Immunofluorescence double staining for Thy-1 and oil-red-O was performed to evaluate Thy-1 expression and lipid content in alveolar LIFs. Radial alveolar count was significantly reduced in CDH-associated PH with significant downregulation of pulmonary Thy-1 and ADRP mRNA expression compared to controls. ADRP immunoreactivity and lipid droplets were markedly diminished in alveolar interstitial cells, which coincided with decreased alveolar LIF expression in CDH-associated PH compared to controls. Confocal laser scanning microscopy confirmed markedly decreased Thy-1 expression and lipid content in alveolar LIFs of CDH-associated PH compared to controls. Our study provides strong evidence that disruption of pulmonary Thy-1 signaling results in reduced lipid droplets in alveolar LIFs and may thus contribute to PH in the nitrofen-induced CDH model. Treatment modalities aimed at increasing lipid content in alveolar LIFs may therefore have a therapeutic potential in attenuating CDH-associated PH.

Transport of gases between the environment and alveoli – theoretical foundations

PubMed Central

Butler, James P.; Tsuda, Akira

2015-01-01

The transport of oxygen and carbon dioxide in the gas phase from the ambient environment to and from the alveolar gas/blood interface is accomplished through the tracheobronchial tree, and involves mechanisms of bulk or convective transport and diffusive net transport. The geometry of the airway tree and the fluid dynamics of these two transport processes combine in such a way that promotes a classical fractionation of ventilation into dead space and alveolar ventilation respectively. This simple picture continues to capture much of the essence of gas phase transport. On the other hand, a more detailed look at the interaction of convection and diffusion leads to significant new issues, many of which remain open questions. These are associated with parallel and serial inhomogeneities especially within the distal acinar units, velocity profiles in distal airways and terminal spaces subject to moving boundary conditions, and the serial transport of respiratory gases within the complex acinar architecture. This chapter focuses specifically on the theoretical foundations of gas transport, addressing two broad areas. The first deals with the reasons why the classical picture of alveolar and dead space ventilation is so successful; the second examines the underlying assumptions within current approximations to convective and diffusive transport, and how they interact to effect net gas exchange. PMID:23733643

Critical role of the axonal guidance cue EphrinB2 in lung growth, angiogenesis, and repair.

PubMed

Vadivel, Arul; van Haaften, Tim; Alphonse, Rajesh S; Rey-Parra, Gloria-Juliana; Ionescu, Lavinia; Haromy, Al; Eaton, Farah; Michelakis, Evangelos; Thébaud, Bernard

2012-03-01

Lung diseases characterized by alveolar damage currently lack efficient treatments. The mechanisms contributing to normal and impaired alveolar growth and repair are incompletely understood. Axonal guidance cues (AGC) are molecules that guide the outgrowth of axons to their targets. Among these AGCs, members of the Ephrin family also promote angiogenesis, cell migration, and organogenesis outside the nervous system. The role of Ephrins during alveolar growth and repair is unknown. We hypothesized that EphrinB2 promotes alveolar development and repair. We used in vitro and in vivo manipulation of EphrinB2 signaling to assess the role of this AGC during normal and impaired lung development. In vivo EphrinB2 knockdown using intranasal siRNA during the postnatal stage of alveolar development in rats arrested alveolar and vascular growth. In a model of O(2)-induced arrested alveolar growth in newborn rats, air space enlargement, loss of lung capillaries, and pulmonary hypertension were associated with decreased lung EphrinB2 and receptor EphB4 expression. In vitro, EphrinB2 preserved alveolar epithelial cell viability in O(2), decreased O(2)-induced alveolar epithelial cell apoptosis, and accelerated alveolar epithelial cell wound healing, maintained lung microvascular endothelial cell viability, and proliferation and vascular network formation. In vivo, treatment with intranasal EphrinB2 decreased alveolar epithelial and endothelial cell apoptosis, preserved alveolar and vascular growth in hyperoxic rats, and attenuated pulmonary hypertension. The AGC EphrinB2 may be a new therapeutic target for lung repair and pulmonary hypertension.

Epigallocatechin gallate (EGCG) suppresses lipopolysaccharide-induced inflammatory bone resorption, and protects against alveolar bone loss in mice.

PubMed

Tominari, Tsukasa; Matsumoto, Chiho; Watanabe, Kenta; Hirata, Michiko; Grundler, Florian M W; Miyaura, Chisato; Inada, Masaki

2015-01-01

Epigallocatechin gallate (EGCG), a major polyphenol in green tea, possesses antioxidant properties and regulates various cell functions. Here, we examined the function of EGCG in inflammatory bone resorption. In calvarial organ cultures, lipopolysaccharide (LPS)-induced bone resorption was clearly suppressed by EGCG. In osteoblasts, EGCG suppressed the LPS-induced expression of COX-2 and mPGES-1 mRNAs, as well as prostaglandin E2 production, and also suppressed RANKL expression, which is essential for osteoclast differentiation. LPS-induced bone resorption of mandibular alveolar bones was attenuated by EGCG in vitro, and the loss of mouse alveolar bone mass was inhibited by the catechin in vivo.

Changes in cytokine and nitric oxide secretion by rat alveolar macrophages after oral administration of bacterial extracts.

PubMed Central

Broug-Holub, E; Persoons, J H; Schornagel, K; Kraal, G

1995-01-01

Oral administration of the bacterial immunomodulator Broncho-Vaxom (OM-85), a lysate of eight bacteria strains commonly causing respiratory disease, has been shown to enhance the host defence of the respiratory tract. In this study we examined the effect of orally administered (in vivo) OM-85 on stimulus-induced cytokine and nitric oxide secretion by rat alveolar macrophages in vitro. The results show that alveolar macrophages isolated from OM-85-treated rats secreted significantly more nitric oxide, tumour necrosis factor-alpha (TNF-alpha) and IL-1 beta upon in vitro stimulation with lipopolysaccharide (LPS), whereas, in contrast, LPS-induced IL-6 secretion was significantly lower. The observed effects of in vivo OM-85 treatment on stimulus-induced cytokine secretion in vitro are not due to a direct effect of OM-85 on the cells, because in vitro incubation of alveolar macrophages with OM-85 did not result in altered activity, nor did direct intratracheal instillation of OM-85 in the lungs of rats result in altered alveolar macrophage activity in vitro. It is hypothesized that oral administration of OM-85 leads to priming of alveolar macrophages in such a way that immune responses are non-specifically enhanced upon stimulation. The therapeutic action of OM-85 may therefore result from an enhanced clearance of infectious bacteria from the respiratory tract due to increased alveolar macrophage activity. PMID:7648713

Expression of cyclin D{sub 1} during endotoxin-induced aleveolar type II cell hyperplasia in rat lung and the detection of apoptotic cells during the remodeling process

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

Tesfaigzi, J.; Wood, M.B.; Johnson, N.F.

Our studies have shown that endotoxin intratracheally instilled into the rat lung induces proliferation of alveolar type II cells. In that study, the alveolar type II cells. In that study, the alveolar type II cell hyperplasia occurred 2 d after instillation of endotoxin and persisted for a further 2 d. After hyperplasia, the lung remodeled and returned to a normal state within 24-48 h. Understanding the mechanisms involved in the remodeling process of this transient hyperplasia may be useful to identify molecular changes that are altered in neoplasia. The purpose of the present study was to corroborate induction of epithelialmore » cell hyperplasia by endotoxin and to delineate mechanisms involved in tissue remodeling after endotoxin-induced alveolar type II cell hyperplasia. In conclusion, immonostaining with cyclin D1 and cytokeratin shows that endotoxin induced epithelial cell proliferation and resulted in hyperplasia in the lung which persisted through 4 d post-instillation.« less

Survival in a case of diffuse alveolar hemorrhage due to Strongyloides stercoralis hyperinfection.

PubMed

Steinhaus, Daniel A; Gainor, Justin F; Vernovsky, Inna; Winsett, Julie; Beer, Dennis J

2012-01-01

Strongyloides stercoralis is an intestinal nematode endemic to tropical and sub-tropical regions. Although infection is typically asymptomatic or self-limited, immunocompromised individuals can develop a severe form of disease marked by hyperinfection. Pulmonary involvement accompanies hyperinfection in a majority of cases, though manifestations range from asymptomatic infiltrates to diffuse alveolar hemorrhage (DAH) and respiratory failure. When complicated by DAH, the hyperinfection syndrome is usually fatal. We report a case of a 65-year-old Guatemalan woman with chronic inflammatory demyelinating polyneuropathy (CIDP) treated with chronic steroids who presented with Escherichia coli urosepsis. She was initially treated with antibiotics and corticosteroids. She subsequently developed DAH due to disseminated strongyloidiasis. She was treated with oral and subcutaneous ivermectin and had complete recovery.

Nonuniformity of diffusing capacity from small alveolar gas samples is increased in smokers.

PubMed

Cotton, D J; Mink, J T; Graham, B L

1998-01-01

Although centrilobular emphysema, and small airway, interstitial and alveoli inflammation can be detected pathologically in the lungs of smokers with relatively well preserved lung function, these changes are difficult to assess using available physiological tests. Because submaximal single breath washout (SBWSM) manoeuvres improve the detection of abnormalities in ventilation inhomogeneity in the lung periphery in smokers compared with traditional vital capacity manoeuvres, SBWSM manoeuvres were used in this study to measure temporal differences in diffusing capacity using a rapid response carbon monoxide analyzer. To determine whether abnormalities in the lung periphery can be detected in smokers with normal forced expired volumes in 1 s using the three-equation diffusing capacity (DLcoSB-3EQ) among small alveolar gas samples and whether the abnormalities correlate with increases in peripheral ventilation inhomogeneity. Cross-sectional study in 21 smokers and 21 nonsmokers all with normal forced exhaled flow rates. Both smokers and nonsmokers performed SBWSM manoeuvres consisting of slow inhalation of test gas from functional residual capacity to one-half inspiratory capacity with either 0 or 10 s of breath holding and slow exhalation to residual volume (RV). They also performed conventional vital capacity single breath (SBWVC) manoeuvres consisting of slow inhalation of test gas from RV to total lung capacity and, without breath holding, slow exhalation to RV. DLcoSB-3EQ was calculated from the total alveolar gas sample. DLcoSB-3EQ was also calculated from four equal sequential, simulated aliquots of the total alveolar gas sample. DLcoSB-3EQ values from the four alveolar samples were normalized by expressing each as a percentge of DLcoSB-3EQ from the entire alveolar gas sample. An index of variation (DI) among the small-sample DLcoSB-3EQ values was correlated with the normalized phase III helium slope (Sn) and the mixing efficiency (Emix). For SBWSM, DI was increased in smokers at 0 s of breath holding compared with nonsmokers, and correlated with age, smoking pack-years and Sn. The decrease in DI with breath holding was greater in smokers and correlated with the change in Sn with breath holding. For SBWVC manoeuvres, there were no differences due to smoking in Sn or Emix, but DI was increased in smokers and correlated with age and smoking pack-years, but not with Sn. For SBWSM manoeuvres the increase in DI in smokers correlated with breath hold time-dependent increases in Sn, suggesting that the changes in DI reflected the same structural alterations that caused increases in peripheral ventilation inhomogeneity. For SBWVC manoeuvres, the increase in DI in smokers was not associated with changes in ventilation inhomogeneity, suggesting that the effect of smoking on DI during this manoeuvre was due to smoke-related changes in alveolar capillary diffusion, rather than due solely to alterations in the distribution of ventilation.

Basal and induced NO formation in the pharyngo-oral tract influences estimates of alveolar NO levels.

PubMed

Malinovschi, Andrei; Janson, Christer; Holm, Lena; Nordvall, Lennart; Alving, Kjell

2009-02-01

The present study analyzed how models currently used to distinguish alveolar from bronchial contribution to exhaled nitric oxide (NO) are affected by manipulation of NO formation in the pharyngo-oral tract. Exhaled NO was measured at multiple flow rates in 15 healthy subjects in two experiments: 1) measurements at baseline and 5 min after chlorhexidine (CHX) mouthwash and 2) measurements at baseline, 60 min after ingestion of 10 mg NaNO(3)/kg body wt, and 5 min after CHX mouthwash. Alveolar NO concentration (Calv(NO)) and bronchial flux (J'aw(NO)) were calculated by using the slope-intercept model with or without adjustment for trumpet shape of airways and axial diffusion (TMAD). Salivary nitrate and nitrite were measured in the second experiment. Calv(NO) [median (range)] was reduced from 1.16 ppb (0.77, 1.96) at baseline to 0.84 ppb (0.57, 1.48) 5 min after CHX mouthwash (P < 0.001). The TMAD-adjusted Calv(NO) value after CHX mouthwash was 0.50 ppb (0, 0.85). The nitrate load increased J'aw(NO) from 32.2 nl/min (12.2, 60.3) to 57.1 nl/min (22.0, 119) in all subjects and Calv(NO) from 1.47 ppb (0.73, 1.95) to 1.87 ppb (10.85, 7.20) in subjects with high nitrate turnover (>10-fold increase of salivary nitrite after nitrate load). CHX mouthwash reduced Calv(NO) levels to 1.15 ppb (0.72, 2.07) in these subjects with high nitrate turnover. All these results remained consistent after TMAD adjustment. We conclude that estimated alveolar NO concentration is affected by pharyngo-oral tract production of NO in healthy subjects, with a decrease after CHX mouthwash. Moreover, unknown ingestion of dietary nitrate could significantly increase estimated alveolar NO in subjects with high nitrate turnover, and this might be falsely interpreted as a sign of peripheral inflammation. These findings were robust for TMAD.

Preventive Effects of Drinking Hydrogen-Rich Water on Gingival Oxidative Stress and Alveolar Bone Resorption in Rats Fed a High-Fat Diet

PubMed Central

Yoneda, Toshiki; Tomofuji, Takaaki; Kunitomo, Muneyoshi; Ekuni, Daisuke; Irie, Koichiro; Azuma, Tetsuji; Machida, Tatsuya; Miyai, Hisataka; Fujimori, Kouhei; Morita, Manabu

2017-01-01

Obesity induces gingival oxidative stress, which is involved in the progression of alveolar bone resorption. The antioxidant effect of hydrogen-rich water may attenuate gingival oxidative stress and prevent alveolar bone resorption in cases of obesity. We examined whether hydrogen-rich water could suppress gingival oxidative stress and alveolar bone resorption in obese rats fed a high-fat diet. Male Fischer 344 rats (n = 18) were divided into three groups of six rats each: a control group (fed a regular diet and drinking distilled water) and two experimental groups (fed a high-fat diet and drinking distilled water or hydrogen-rich water). The level of 8-hydroxydeoxyguanosine was determined to evaluate oxidative stress. The bone mineral density of the alveolar bone was analyzed by micro-computerized tomography. Obese rats, induced by a high-fat diet, showed a higher gingival level of 8-hydroxydeoxyguanosine and a lower level of alveolar bone density compared to the control group. Drinking hydrogen-rich water suppressed body weight gain, lowered gingival level of 8-hydroxydeoxyguanosine, and reduced alveolar bone resorption in rats on a high-fat diet. The results indicate that hydrogen-rich water could suppress gingival oxidative stress and alveolar bone resorption by limiting obesity. PMID:28098768

Preventive Effects of Drinking Hydrogen-Rich Water on Gingival Oxidative Stress and Alveolar Bone Resorption in Rats Fed a High-Fat Diet.

PubMed

Yoneda, Toshiki; Tomofuji, Takaaki; Kunitomo, Muneyoshi; Ekuni, Daisuke; Irie, Koichiro; Azuma, Tetsuji; Machida, Tatsuya; Miyai, Hisataka; Fujimori, Kouhei; Morita, Manabu

2017-01-13

Obesity induces gingival oxidative stress, which is involved in the progression of alveolar bone resorption. The antioxidant effect of hydrogen-rich water may attenuate gingival oxidative stress and prevent alveolar bone resorption in cases of obesity. We examined whether hydrogen-rich water could suppress gingival oxidative stress and alveolar bone resorption in obese rats fed a high-fat diet. Male Fischer 344 rats ( n = 18) were divided into three groups of six rats each: a control group (fed a regular diet and drinking distilled water) and two experimental groups (fed a high-fat diet and drinking distilled water or hydrogen-rich water). The level of 8-hydroxydeoxyguanosine was determined to evaluate oxidative stress. The bone mineral density of the alveolar bone was analyzed by micro-computerized tomography. Obese rats, induced by a high-fat diet, showed a higher gingival level of 8-hydroxydeoxyguanosine and a lower level of alveolar bone density compared to the control group. Drinking hydrogen-rich water suppressed body weight gain, lowered gingival level of 8-hydroxydeoxyguanosine, and reduced alveolar bone resorption in rats on a high-fat diet. The results indicate that hydrogen-rich water could suppress gingival oxidative stress and alveolar bone resorption by limiting obesity.

Lung injury via oxidative stress in mice induced by inhalation exposure to rocket kerosene

PubMed Central

Xu, Bingxin; Li, Chenglin; Wang, Jianying; Wu, Jihua; Si, Shaoyan; Liu, Zhiguo; Li, Jianzhong; Zhang, Jianzhong; Cui, Yan

2015-01-01

Rocket kerosene (RK) is a new rocket propellant. Toxicity occurs if a high level of RK is inhaled. To study the toxicity of RK in lung and the mechanisms of RK-induced lung jury, a total of 72 male ICR mice (1.5 months, adult) were randomly assigned to the RK exposure group (RKEG) and normal control group (NCG). Mice were whole-body exposed to room air or aerosol of 18000 mg/m3 RK for 4 hours. Histopathological analysis was performed to evaluate the pulmonary lesions. Oxidative stress was assessed by assay of MDA, SOD, GSH-PX and TAOC. Inflammatory response was estimated by detecting inflammatory cell counts, TNF-α and IL-6 protein levels in serum. The results showed that after 2 to 6 hours of RK exposure, pulmonary vascular dilatation, congestion and edematous widening of the alveolar septum were noted. After 12 to 24 hours post-exposure, diffuse hemorrhage in alveolar space were found, along with the progressive pulmonary vascular dilatation and edematous widening of alveolar septum. During 3 to 7 days of RK-exposure, inflammatory cells were scattered in the lung tissue. The pathological alterations of the lung were alleviated after 14 days post-exposure, and showed significant improvement after 21 days post-exposure. After 30 days of RK exposure, the pathological changes in the lung tissue were nearly recovered except the local thickening of the alveolar wall. Compared with NCG, RK inhalation produced a significant increase of MDA levels and a significant decrease of SOD, GSH-Px and TAOC activity in the lung after 2 hours post-exposure (P < 0.05). There were significant increases of TNF-α and IL-6 protein levels in serum of mice in RKEG after 2, 6 and 12 hours and 1, 4 and 7 days post-exposure compared with NCG (P < 0.05). TNF-α protein levels had a sharp increase after 4 days of exposure. IL-6 protein level was increased at early phase of experiment and then gradually decreased along with the prolonged course of exposure. Considering that the RK-induced lung injury was through the oxidative stress, inhibition of oxidative stress after RK exposure may be urgently needed. PMID:26191256

Lung injury via oxidative stress in mice induced by inhalation exposure to rocket kerosene.

PubMed

Xu, Bingxin; Li, Chenglin; Wang, Jianying; Wu, Jihua; Si, Shaoyan; Liu, Zhiguo; Li, Jianzhong; Zhang, Jianzhong; Cui, Yan

2015-01-01

Rocket kerosene (RK) is a new rocket propellant. Toxicity occurs if a high level of RK is inhaled. To study the toxicity of RK in lung and the mechanisms of RK-induced lung jury, a total of 72 male ICR mice (1.5 months, adult) were randomly assigned to the RK exposure group (RKEG) and normal control group (NCG). Mice were whole-body exposed to room air or aerosol of 18000 mg/m3 RK for 4 hours. Histopathological analysis was performed to evaluate the pulmonary lesions. Oxidative stress was assessed by assay of MDA, SOD, GSH-PX and TAOC. Inflammatory response was estimated by detecting inflammatory cell counts, TNF-α and IL-6 protein levels in serum. The results showed that after 2 to 6 hours of RK exposure, pulmonary vascular dilatation, congestion and edematous widening of the alveolar septum were noted. After 12 to 24 hours post-exposure, diffuse hemorrhage in alveolar space were found, along with the progressive pulmonary vascular dilatation and edematous widening of alveolar septum. During 3 to 7 days of RK-exposure, inflammatory cells were scattered in the lung tissue. The pathological alterations of the lung were alleviated after 14 days post-exposure, and showed significant improvement after 21 days post-exposure. After 30 days of RK exposure, the pathological changes in the lung tissue were nearly recovered except the local thickening of the alveolar wall. Compared with NCG, RK inhalation produced a significant increase of MDA levels and a significant decrease of SOD, GSH-Px and TAOC activity in the lung after 2 hours post-exposure (P<0.05). There were significant increases of TNF-α and IL-6 protein levels in serum of mice in RKEG after 2, 6 and 12 hours and 1, 4 and 7 days post-exposure compared with NCG (P<0.05). TNF-α protein levels had a sharp increase after 4 days of exposure. IL-6 protein level was increased at early phase of experiment and then gradually decreased along with the prolonged course of exposure. Considering that the RK-induced lung injury was through the oxidative stress, inhibition of oxidative stress after RK exposure may be urgently needed.

Pulmonary NO and C18O2 uptake during pressure-induced lung expansion in rabbits.

PubMed

Heller, Hartmut; Schuster, Klaus-Dieter

2007-01-01

In artificially ventilated animals we investigated the dependence of the pulmonary diffusing capacities of nitric oxide (NO) and doubly 18O-labeled carbon dioxide (DLNO, DLC18O2) on lung expansion with respect to ventilator-driven increases in intrapulmonary pressure. For this purpose we applied computerized single-breath experiments to 11 anesthetized paralyzed rabbits (weight 2.8-3.8 kg) at various alveolar volumes (45-72 ml) by studying the almost entire inspiratory limb of the respective pressure/volume curves (intrapulmonary pressure: 6-27 cmH2O). The animals were ventilated with room air, employing a computerized ventilatory servo-system that we designed to maintain mechanical ventilation and to execute the particular lung function tests automatically. Each single-breath maneuver was started from residual volume (13.5+/-2 ml, mean+/-SD) by inflating the rabbit lungs with 35-55 ml indicator gas mixture containing 0.05% NO in N2 or 0.9% C18O2 in N2. Alveolar partial pressures of NO and C18O2 were measured by respiratory mass spectrometry. Values of DLNO and DLC18O2 ranged between 1.55 and 2.49 ml/(mmHg min) and 11.7 and 16.6 ml/(mmHg min), respectively. Linear regression analyses yielded a significant increase in DLNO with simultaneous increase in alveolar volume (P<0.005) and intrapulmonary pressure (P<0.023) whereas DLC18O2 was not improved. Our results suggest that the ventilator-driven lung expansion impaired the C18O2 blood uptake conductance, finally compensating for the beneficial effect of the increase in alveolar volume on DLC18O2 values.

DIFFERENTIAL GENE EXPRESSION BY CHAPEL HILL FINE PARTICLES IN HUMAN ALVEOLAR MACHROPHAGES

EPA Science Inventory

Pollutant particles (PM) induce systemic and lung inflammation. Alveolar macrophages (AM) are one of the lung cells directly exposed to PM that may initiate these responses. In this study, we determined the gene expression profile induced by Chapel Hill fine particles (PM2.5) in ...

[The clinicopathological features of acute fibrinous and organizing pneumonia].

PubMed

Qiu, Yu-ying; Miao, Li-yun; Cai, Hou-rong; Xiao, Yong-long; Ye, Qing; Meng, Fan-qing; Feng, An-ning

2013-06-01

To improve understanding of the clinical, radiological and pathological characteristics of acute fibrinous and organizing pneumonia (AFOP). The clinical data of 5 AFOP patients were retrospectively analyzed. AFOP was diagnosed via percutaneous lung biopsy guided by chest computerized tomography (CT) in the Affiliated Drum Tower Hospital of Nanjing University Medical School during March 2011 to June 2012. The clinical, radiological and pathological characteristics of those patients were summarized. Among the 5 patients, 2 were male and 3 were female, aging 43-61 years. They were all subacute onset. The main clinical manifestations were dyspnea, productive cough, fever and chest pain with hypoxemia via blood gas analysis. Bilateral infiltrates with diffuse and pathy distribution were the predominant features in chest HRCT. The pathological examination revealed slightly widened alveolar septa, 1ymphocyte and plasma cell infiltration and the presence of intra-alveolar fibrin in the form of fibrin "balls" (organization) within the alveolar spaces. No neutrophil, and eosinophil infiltration and hyaline membrane formation were detected, which was different from other well-recognized histologic patterns of acute lung injury, such as diffuse alveolar damage, cryptogenic organizing pneumonia and eosinophilic pneumonia. All patients were treated by corticosteroids and showed significant clinical and radiological improvement. AFOP has nospecific features, and its diagnosis depends on pathological examination. Treatment with corticosteroids is optimal. However, whether it is a unique interstitial disease needs to be further clinically investigated.

Effects of positive end-expiratory pressure titration and recruitment maneuver on lung inflammation and hyperinflation in experimental acid aspiration-induced lung injury.

PubMed

Ambrosio, Aline M; Luo, Rubin; Fantoni, Denise T; Gutierres, Claudia; Lu, Qin; Gu, Wen-Jie; Otsuki, Denise A; Malbouisson, Luiz M S; Auler, Jose O C; Rouby, Jean-Jacques

2012-12-01

In acute lung injury positive end-expiratory pressure (PEEP) and recruitment maneuver are proposed to optimize arterial oxygenation. The aim of the study was to evaluate the impact of such a strategy on lung histological inflammation and hyperinflation in pigs with acid aspiration-induced lung injury. Forty-seven pigs were randomly allocated in seven groups: (1) controls spontaneously breathing; (2) without lung injury, PEEP 5 cm H2O; (3) without lung injury, PEEP titration; (4) without lung injury, PEEP titration + recruitment maneuver; (5) with lung injury, PEEP 5 cm H2O; (6) with lung injury, PEEP titration; and (7) with lung injury, PEEP titration + recruitment maneuver. Acute lung injury was induced by intratracheal instillation of hydrochloric acid. PEEP titration was performed by incremental and decremental PEEP from 5 to 20 cm H2O for optimizing arterial oxygenation. Three recruitment maneuvers (pressure of 40 cm H2O maintained for 20 s) were applied to the assigned groups at each PEEP level. Proportion of lung inflammation, hemorrhage, edema, and alveolar wall disruption were recorded on each histological field. Mean alveolar area was measured in the aerated lung regions. Acid aspiration increased mean alveolar area and produced alveolar wall disruption, lung edema, alveolar hemorrhage, and lung inflammation. PEEP titration significantly improved arterial oxygenation but simultaneously increased lung inflammation in juxta-diaphragmatic lung regions. Recruitment maneuver during PEEP titration did not induce additional increase in lung inflammation and alveolar hyperinflation. In a porcine model of acid aspiration-induced lung injury, PEEP titration aimed at optimizing arterial oxygenation, substantially increased lung inflammation. Recruitment maneuvers further improved arterial oxygenation without additional effects on inflammation and hyperinflation.

[Intra-alveolar hemorrhage: rare presentation of fat pulmonary embolism].

PubMed

Ketata, W; Msaad, S; Bahloul, N; Marouen, F; Ayoub, A

2010-11-01

Fat embolism syndrome is a severe complication of long bone fractures, corresponding to the obstruction of small vessels by microdroplets of fat, originating from medulla ossium. Pulmonary involvement, present in 90% cases, makes the severity of the disease. We report the case of a 22-year-old man who presented, two days after industrial accident causing an opened tibial fracture, acute dyspnea with hemoptysis. Angio-CT-scan didn't show any proximal vascular obstruction, but parenchymal sections showed diffuse, bilateral and multifocal hyperdensities predominating at the periphery. Broncho-alveolar lavage brought a hemorrhagic liquid, with a high macrophage content and lipid inclusions in macrophages. Exams for the etiologic diagnosis of intra-alveolar hemorrhage were negative: renal function, 24-hour proteinuria, antinuclear antibodies, antineutrophil cytoplasmic antibodies. The diagnosis of intra-alveolar hemorrhage secondary to fat embolism was established. The outcome was spontaneously favorable. The occurrence of intra-alveolar hemorrhage in the course fat embolism is rarely reported. Its pathogenic mechanisms are not understood. It is mandatory to eliminate the other causes of alveolar hemorrhage before holding the diagnosis of fat embolism. Treatment is only symptomatic, based on respiratory reanimation. Copyright © 2010 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Alveolar hemorrhage associated with warfarin therapy: a case report and literature review.

PubMed

Erdogan, Dogan; Kocaman, Orhan; Oflaz, Huseyin; Goren, Taner

2004-04-01

A 75-year-old man was admitted to our clinic with the complaints of palpitation, fever, severe dyspnea, dizziness and bloody sputum associated with coughing. Chest radiographs revealed that the lungs were bilaterally infiltrated. A high resolution computed tomographic study of the thorax disclosed diffuse alveolar hemorrhage, of which presence was proved by histopathological study of bronchoalveolar lavage material. The hemorrhage occured at 8th day of 5 mg daily warfarin therapy, which was given for frequent atrial fibrillation attacks was controlled by fresh frozen plasma and vitamin K. Alveolar hemorrhage is difficult to diagnose and has high mortality if the treatment was not started as soon as possible. This is the first report of alveolar hemorrhage caused by 5 mg daily warfarin therapy. We propose that the patient's age, nutritional status, used drugs should be taken into consideration for true management of patients with atrial fibrillation.

Diffuse alveolar hemorrhage due to metastatic angiosarcoma of the lung: A case report

PubMed Central

PAN, ZHIJIE; AN, ZHOU; LI, YANYUAN; ZHOU, JIANYING

2015-01-01

Angiosarcoma is a rare, heterogeneous malignant tumor that derives from endothelial cells, and it has aggressive characteristics with a marked tendency for distant metastasis. Diffuse alveolar hemorrhage (DAH) is a catastrophic clinical syndrome, however, it is rare as the presentation of pulmonary angiosarcoma. To increase awareness with regard to angiosarcoma and DAH, the current study presents a case of angiosarcoma that originated from the subcutaneous soft tissue of the mastoid process, but was subject to a delayed diagnosis and rapid invasion into the brain and lung. The metastatic angiosarcoma of the lung presented with DAH as the initial manifestation. The pathological examination of a biopsy of the subcutaneous mass and pulmonary lesions confirmed the diagnosis of angiosarcoma. The patient succumbed to respiratory failure at 1 month post-diagnosis. PMID:26788222

Acute fibrinous and organising pneumonia.

PubMed

Guimarães, Catarina; Sanches, Inês; Ferreira, Catarina

2012-03-20

Acute fibrinous and organising pneumonia (AFOP) was recently described as an unusual pattern of diffuse lung disease. Particular characteristics make the differential diagnosis with the well recognised clinical patterns of diffuse alveolar damage, cryptogenic organising pneumonia or eosinophilic pneumonia. The lack of hyaline membranes, the presence of intra-alveolar fibrin, absence of noticeable eosinophils and patchy distribution suggests that AFOP define a distinct histological pattern. The authors describe the case of a woman diagnosed with AFOP after surgical lung biopsy, in association with primary biliary cirrhosis. The patient presented dyspnoea, fatigue, dry cough and thoracic pain. The CT scan showed bilateral patchy infiltrates predominantly in the lower lobes. Flexible bronchoscopy and subsidiary techniques were inconclusive and biopsy through video-assisted thoracoscopic surgery led to anatomopathological diagnosis of AFOP. The patient is having a good clinical response to prednisone.

Alveolar type II cell transplantation restores pulmonary surfactant protein levels in lung fibrosis.

PubMed

Guillamat-Prats, Raquel; Gay-Jordi, Gemma; Xaubet, Antoni; Peinado, Victor I; Serrano-Mollar, Anna

2014-07-01

Alveolar Type II cell transplantation has been proposed as a cell therapy for the treatment of idiopathic pulmonary fibrosis. Its long-term benefits include repair of lung fibrosis, but its success partly depends on the restoration of lung homeostasis. Our aim was to evaluate surfactant protein restoration after alveolar Type II cell transplantation in an experimental model of bleomycin-induced lung fibrosis in rats. Lung fibrosis was induced by intratracheal instillation of bleomycin. Alveolar Type II cells were obtained from healthy animals and transplanted 14 days after bleomycin was administered. Furthermore, one group transplanted with alveolar macrophages and another group treated with surfactant were established to evaluate the specificity of the alveolar Type II cell transplantation. The animals were euthanized at 21 days after bleomycin instillation. Lung fibrosis was confirmed by a histologic study and an evaluation of the hydroxyproline content. Changes in surfactant proteins were evaluated by mRNA expression, Western blot and immunofluorescence studies. The group with alveolar Type II cell transplantation was the only one to show a reduction in the degree of lung fibrosis and a complete recovery to normal levels of surfactant proteins. One of the mechanisms involved in the beneficial effect of alveolar Type II cell transplantation is restoration of lung surfactant protein levels, which is required for proper respiratory function. Copyright © 2014 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Emodin suppresses TGF-β1-induced epithelial-mesenchymal transition in alveolar epithelial cells through Notch signaling pathway

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

Gao, Rundi; Chen, Ruilin; Cao, Yu

Pulmonary fibrosis is characterized by the destruction of lung tissue architecture and the formation of fibrous foci, currently has no satisfactory treatment. Emodin is a component of Chinese herb that has been reported to be medicament on pancreatic fibrosis and liver fibrosis. However, its role in pulmonary fibrosis has not been established yet. In the present study, we investigated the hypothesis that Emodin plays an inhibitory role in TGF-β1 induced epithelial-mesenchymal transition (EMT) of alveolar epithelial cell, and Emodin exerts its effect through the Notch signaling pathway. Emodin inhibits the proliferation of Rat alveolar type II epithelial cells RLE-6TN inmore » a concentration-dependent manner; reduces the expression of Collagen I, α-SMA and Vimentin, promotes the expression of E-cadherin. Moreover, Emodin could regulate the expression patterns of the Notch signaling pathway-related factors and reduce the Notch-1 nucleus translocation. Knockdown of Notch-1 enhances the inhibitory effect of Emodin on TGF-β1-induced EMT in RLE-6TN cells. In conclusion, the data of the present study suggests that Emodin suppresses TGF-β1-induced EMT in alveolar epithelial cells through Notch signaling pathway and shows the potential to be effective in the treatment of pulmonary fibrosis. - Highlights: • Emodin inhibits TGF-β1-induced EMT in alveolar epithelial cells. • Emodin regulates the expression patterns of the Notch signaling pathway-related factors. • Emodin inhibits TGF-β1-induced Notch-1 nucleus translocation and activation.« less

YC-1 potentiates cAMP-induced CREB activation and nitric oxide production in alveolar macrophages.

PubMed

Hwang, Tsong-Long; Tang, Ming-Chi; Kuo, Liang-Mou; Chang, Wen-De; Chung, Pei-Jen; Chang, Ya-Wen; Fang, Yao-Ching

2012-04-15

Alveolar macrophages play significant roles in the pathogenesis of several inflammatory lung diseases. Increases in exhaled nitric oxide (NO) are well documented to reflect disease severity in the airway. In this study, we investigated the effect of 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1), a known activator of soluble guanylyl cyclase, on prostaglandin (PG)E₁ (a stable PGE₂ analogue) and forskolin (a adenylate cyclase activator) induced NO production and inducible NO synthase (iNOS) expression in rat alveolar macrophages (NR8383). YC-1 did not directly cause NO production or iNOS expression, but drastically potentiated PGE₁- or forskolin-induced NO production and iNOS expression in NR8383 alveolar macrophages. Combination treatment with YC-1 and PGE₁ significantly increased phosphorylation of the cAMP response element-binding protein (CREB), but not nuclear factor (NF)-κB activation. The combined effect on NO production, iNOS expression, and CREB phosphorylation was reversed by a protein kinase (PK)A inhibitor (H89), suggesting that the potentiating functions were mediated through a cAMP/PKA signaling pathway. Consistent with this, cAMP analogues, but not the cGMP analogue, caused NO release, iNOS expression, and CREB activation. YC-1 treatment induced an increase in PGE₁-induced cAMP formation, which occurred through the inhibition of cAMP-specific phosphodiesterase (PDE) activity. Furthermore, the combination of rolipram (an inhibitor of PDE4), but not milronone (an inhibitor of PDE3), and PGE₁ also triggered NO production and iNOS expression. In summary, YC-1 potentiates PGE₁-induced NO production and iNOS expression in alveolar macrophages through inhibition of cAMP PDE activity and activation of the cAMP/PKA/CREB signaling pathway. Copyright © 2012 Elsevier Inc. All rights reserved.

Generation of Alveolar Epithelial Spheroids via Isolated Progenitor Cells from Human Pluripotent Stem Cells

PubMed Central

Gotoh, Shimpei; Ito, Isao; Nagasaki, Tadao; Yamamoto, Yuki; Konishi, Satoshi; Korogi, Yohei; Matsumoto, Hisako; Muro, Shigeo; Hirai, Toyohiro; Funato, Michinori; Mae, Shin-Ichi; Toyoda, Taro; Sato-Otsubo, Aiko; Ogawa, Seishi; Osafune, Kenji; Mishima, Michiaki

2014-01-01

Summary No methods for isolating induced alveolar epithelial progenitor cells (AEPCs) from human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) have been reported. Based on a study of the stepwise induction of alveolar epithelial cells (AECs), we identified carboxypeptidase M (CPM) as a surface marker of NKX2-1+ “ventralized” anterior foregut endoderm cells (VAFECs) in vitro and in fetal human and murine lungs. Using SFTPC-GFP reporter hPSCs and a 3D coculture system with fetal human lung fibroblasts, we showed that CPM+ cells isolated from VAFECs differentiate into AECs, demonstrating that CPM is a marker of AEPCs. Moreover, 3D coculture differentiation of CPM+ cells formed spheroids with lamellar-body-like structures and an increased expression of surfactant proteins compared with 2D differentiation. Methods to induce and isolate AEPCs using CPM and consequently generate alveolar epithelial spheroids would aid human pulmonary disease modeling and regenerative medicine. PMID:25241738

Involvement of Cot/Tp12 in bone loss during periodontitis.

PubMed

Ohnishi, T; Okamoto, A; Kakimoto, K; Bandow, K; Chiba, N; Matsuguchi, T

2010-02-01

Periodontitis causes resorption of alveolar bone, in which RANKL induces osteoclastogenesis. The binding of lipopolysaccharide to Toll-like receptors causes phosphorylation of Cot/Tp12 to activate the MAPK cascade. Previous in vitro studies showed that Cot/Tp12 was essential for the induction of RANKL expression by lipopolysaccharide. In this study, we examined whether Cot/Tp12 deficiency reduced the progression of alveolar bone loss and osteoclastogenesis during experimental periodontitis. We found that the extent of alveolar bone loss and osteoclastogenesis induced by ligature-induced periodontitis was decreased in Cot/Tp12-deficient mice. In addition, reduction of RANKL expression was observed in periodontal tissues of Cot/Tp12-deficient mice with experimental periodontitis. Furthermore, we found that Cot/Tp12 was involved in the induction of TNF-alpha mRNA expression in gingiva of mice with experimental periodontitis. Our observations suggested that Cot/Tp12 is essential for the progression of alveolar bone loss and osteoclastogenesis in periodontal tissue during experimental periodontitis mediated through increased RANKL expression.

An Unusual Consolidation: Lobar Pulmonary Hemorrhage Due to Antithrombotic Therapy.

PubMed

D'Amore, Katrina; Traficante, David; McGovern, Terrance; Propersi, Marco; Barnes, Stacey

2017-11-01

Alveolar hemorrhage is a rare yet devastating clinical entity if not identified and treated aggressively. Exceedingly rare are the cases of anticoagulant-induced alveolar hemorrhage with very few cases described in the current literature. The nonspecific presentation of an alveolar hemorrhage makes its diagnosis and appropriate treatment difficult in the emergency department. We report a case of a patient on warfarin for atrial fibrillation who was initially misdiagnosed as having community-acquired pneumonia, but subsequently was identified to have a fatal alveolar hemorrhage.

Activated alveolar macrophage and lymphocyte alveolitis in extrathoracic sarcoidosis without radiological mediastinopulmonary involvement

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

Wallaert, B.; Ramon, P.; Fournier, E.C.

1986-01-01

Cellular characteristics of BAL were investigated in 18 patients with proved extrathoracic sarcoidosis (that is, sarcoidosis that affected the skin, eyes, parotid glands, stomach, nose, kidneys, or meninges) without clinical or radiological mediastinopulmonary involvement. Computed tomography of the thorax was performed on five patients: four patients were normal, and one had enlarged lymph nodes (these enlargements were not detectable on the patient's chest roentgenogram). The results of pulmonary function tests were normal in all patients. The total BAL cell count did not differ significantly between controls and patients. Abnormal percentages of alveolar lymphocytes (from 18 to 87%) were noted inmore » 15 out of 18 patients. SACE levels were normal in 15 patients. No pulmonary gallium uptake was detected. The chemiluminescence of AM's, whether spontaneous or PMA induced, was increased in five out of seven patients. The percentages of T3+ lymphocytes in sarcoidosis patients did not significantly differ from those in controls. The T4+:T8+ ratio was normal in four patients and slightly increased in one. Follow-up of patients showed that alveolar lymphocytosis is as lasting as extrathoracic involvement. Our data demonstrate increased percentages of lymphocytes and activated AM's in the BAL of patients with extrathoracic sarcoidosis. This may be due to the initial involvement of the respiratory tract in extrathoracic sarcoidosis or to the diffusion of activated macrophages and lymphocytes from an extrathoracic site into the lung.« less

[Fatal alveolar haemorrhage following a "bang" of cannabis].

PubMed

Grassin, F; André, M; Rallec, B; Combes, E; Vinsonneau, U; Paleiron, N

2011-09-01

The new methods of cannabis consumption (home made water pipe or "bang") may be responsible for fatal respiratory complications. We present a case, with fatal outcome, of a man of 19 years with no previous history other than an addiction to cannabis using "bang". He was admitted to intensive care with acute dyspnoea. A CT scan showed bilateral, diffuse alveolar shadowing. He was anaemic with an Hb of 9.3g/l. Bronchoalveolar lavage revealed massive alveolar haemorrhage. Investigations for infection and immunological disorder were negative and toxicology was negative except for cannabis. Antibiotic treatment was given and favourable progress allowed early discharge. Death occurred 15 days later due to alveolar haemorrhage following a further "bang" of cannabis. Autopsy showed toxic alveolar haemorrhage. The probable mechanism is pulmonary damage due to acid anhydrides released by the incomplete combustion of cannabis in contact with plastic. These acids have a double effect on the lungs: a direct toxicity with severe inflammation of the mucosa leading to alveolar haemorrhage and subsequently the acid anhydrides may lead to the syndrome of intra-alveolar haemorrhage and anaemia described in occupational lung diseases by Herbert in Oxford in 1979. It manifests itself by haemoptysis and intravascular haemolysis. We draw attention to the extremely serious potential consequences of new methods of using cannabis, particularly the use of "bang" in homemade plastic materials. Copyright © 2011 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Proteinase-activated receptor 4 stimulation-induced epithelial-mesenchymal transition in alveolar epithelial cells

PubMed Central

Ando, Seijitsu; Otani, Hitomi; Yagi, Yasuhiro; Kawai, Kenzo; Araki, Hiromasa; Fukuhara, Shirou; Inagaki, Chiyoko

2007-01-01

Background Proteinase-activated receptors (PARs; PAR1–4) that can be activated by serine proteinases such as thrombin and neutrophil catepsin G are known to contribute to the pathogenesis of various pulmonary diseases including fibrosis. Among these PARs, especially PAR4, a newly identified subtype, is highly expressed in the lung. Here, we examined whether PAR4 stimulation plays a role in the formation of fibrotic response in the lung, through alveolar epithelial-mesenchymal transition (EMT) which contributes to the increase in myofibroblast population. Methods EMT was assessed by measuring the changes in each specific cell markers, E-cadherin for epithelial cell, α-smooth muscle actin (α-SMA) for myofibroblast, using primary cultured mouse alveolar epithelial cells and human lung carcinoma-derived alveolar epithelial cell line (A549 cells). Results Stimulation of PAR with thrombin (1 U/ml) or a synthetic PAR4 agonist peptide (AYPGKF-NH2, 100 μM) for 72 h induced morphological changes from cobblestone-like structure to elongated shape in primary cultured alveolar epithelial cells and A549 cells. In immunocytochemical analyses of these cells, such PAR4 stimulation decreased E-cadherin-like immunoreactivity and increased α-SMA-like immunoreactivity, as observed with a typical EMT-inducer, tumor growth factor-β (TGF-β). Western blot analyses of PAR4-stimulated A549 cells also showed similar changes in expression of these EMT-related marker proteins. Such PAR4-mediated changes were attenuated by inhibitors of epidermal growth factor receptor (EGFR) kinase and Src. PAR4-mediated morphological changes in primary cultured alveolar epithelial cells were reduced in the presence of these inhibitors. PAR4 stimulation increased tyrosine phosphorylated EGFR or tyrosine phosphorylated Src level in A549 cells, and the former response being inhibited by Src inhibitor. Conclusion PAR4 stimulation of alveolar epithelial cells induced epithelial-mesenchymal transition (EMT) as monitored by cell shapes, and epithelial or myofibroblast marker at least partly through EGFR transactivation via receptor-linked Src activation. PMID:17433115

The severe pathogenicity of alveolar macrophage-depleted ferrets infected with 2009 pandemic H1N1 influenza virus.

PubMed

Kim, Heui Man; Kang, Young Myong; Ku, Keun Bon; Park, Eun Hye; Yum, Jung; Kim, Jeong Cheol; Jin, Seo Yeon; Lee, Joo Sub; Kim, Hyun Soo; Seo, Sang Heui

2013-09-01

The in vivo role of alveolar macrophages in the infections with 2009 pandemic H1N1 influenza virus is not as yet known. Ferret study shows that alveolar macrophages are critical for lowering the risk of severe outcomes in 2009 pandemic H1N1 influenza virus infections. Up to 40% of the infected ferrets depleted of alveolar macrophages died, with elevated body temperature and major loss of body weight in contrast to infected ferrets not depleted of alveolar macrophages. The higher viral titers in the lungs were detected in infected ferrets depleted of alveolar macrophages than infected ferrets not depleted of alveolar macrophages 5 days after infection. The inflammatory chemokines were induced at greater levels in the lungs of infected ferrets depleted of alveolar macrophages than in those of infected ferrets not depleted of alveolar macrophages. Our study implies that alveolar macrophages are important for controlling the infections of 2009 pandemic H1N1 influenza virus. © 2013 Elsevier Inc. All rights reserved.

Overexpression of IL-38 protein in anticancer drug-induced lung injury and acute exacerbation of idiopathic pulmonary fibrosis.

PubMed

Tominaga, Masaki; Okamoto, Masaki; Kawayama, Tomotaka; Matsuoka, Masanobu; Kaieda, Shinjiro; Sakazaki, Yuki; Kinoshita, Takashi; Mori, Daisuke; Inoue, Akira; Hoshino, Tomoaki

2017-09-01

Interleukin (IL)-38, a member of the IL-1 family, shows high homology to IL-1 receptor antagonist (IL-1Ra) and IL-36 receptor antagonist (IL-36Ra). Its function in interstitial lung disease (ILD) is still unknown. To determine the expression pattern of IL-38 mRNA, a panel of cDNAs derived from various tissues was analyzed by quantitative real-time PCR. Immunohistochemical reactivity with anti-human IL-38 monoclonal antibody (clone H127C) was evaluated semi-quantitatively in lung tissue samples from 12 patients with idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP), 5 with acute exacerbation of IPF, and 10 with anticancer drug-induced ILD (bleomycin in 5 and epidermal growth factor receptor-tyrosine kinase inhibitor in 5). Control lung tissues were obtained from areas of normal lung in 22 lung cancer patients who underwent extirpation surgery. IL-38 transcripts were strongly expressed in the lung, spleen, synoviocytes, and peripheral blood mononuclear cells, and at a lower level in pancreas and muscle. IL-38 protein was not strongly expressed in normal pulmonary alveolar tissues in all 22 control lungs. In contrast, IL-38 was overexpressed in the lungs of 4 of 5 (80%) patients with acute IPF exacerbation and 100% (10/10) of the patients with drug-induced ILD. IL-38 overexpression was limited to hyperplastic type II pneumocytes, which are considered to reflect regenerative change following diffuse alveolar damage in ILD. IL-38 may play an important role in acute and/or chronic inflammation in anticancer drug-induced lung injury and acute exacerbation of IPF. Copyright © 2017 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

The relationship between alveolar oxygen tension and the single-breath carbon monoxide diffusing capacity.

PubMed

Kanner, R E; Crapo, R O

1986-04-01

The effects of alveolar oxygen tension (PAO2) on the single-breath carbon monoxide diffusing capacity (DLCO) were quantified and a factor was derived to accommodate for differences in PAO2 over commonly encountered altitudes and/or varying concentrations of oxygen in the test gas mixture (FIO2) We performed duplicate measurements of DLCO in 7 normal subjects with 6 different oxygen fractions (0.176, 0.196, 0.211, 0.22, 0.25, and 0.27). The PAO2 for each test was measured as the PO2 in the alveolar gas sample bag. DLCO varied inversely with PAO2 and changed by 0.35% for each mmHg change in PAO2 (r = -0.62, p less than 0.001). At an FIO2 of 0.25, PAO2 varied between subjects and was highly correlated with each subject's residual volume to total lung capacity ratio (r = -0.84, p less than 0.001). We suggest that laboratories can adjust the measured DLCO when PAO2 is not congruent to 120 mmHg by the following formula: DLCO (corrected = DLCO (measured) x [1.0 + 0.0035 (PAO2 - 120)].

[Measures to be taken in adults with bronchiolitis].

PubMed

De Crémoux, Hubert

2003-02-22

The majority of bronchial and interstitial diseases of the adult are accompanied by bronchiolar inflammation, but over time the use of the term "bronchiolitis" has been limited to a few specific affections. Bronchiolitis with predominantly alveolar involvement Some "bronchiolites" emphasize the problem of an interstitial pneumopathy, since the disease predominantly involves the alveolar spaces. Only a few bronchiolites are severely damaging: bronchiolitis obliterans with organizing pneumonia and interstitial pneumopathy with respiratory bronchiolitis. These predominantly alveolar affections reveal the clinical (crepitant rales), radiographic (multiple or even diffuse opacities), and functional aspects (restrictive ventilation problems). Brochiolitis with obstructive airway problems In this case the disease predominantly involves the bronchioles and spares the alveolar tissue. The term "bronchiolitis" is in this case perfectly justified. The clinical picture is evocative with obstructed airway and a clear pulmonary parenchyma on the thoracic x-ray. These affections belong to the obstructive broncho-pneumopathy group. The prototype is brochiolitis obliterans, the anatomic correlation of which is generally constrictive bronchiolitis obliterans. Occasionally primitive, it frequently complicates the progression of many morbid states (transplants, collagenosis, inhaled or ingested toxic substances.). Diffuse panbronchiolitis Other "bronchiolites" deviate from this framework and are accompanied by marked lesions of other respiratory tracts (membrane bronchioles, cartilage bronchi, mucosa, ear nose and throat). The prototype is panbronchiolitis, described in the Far East. It is exceptional in Europe, where similar but nosologically different clinical aspects are observed during various diseases: cystic fibrosis, Young's syndrome, hypogammaglobulinemia, bone marrow transplant, context of HIV or haemorrhagic recto-colitis.

Formation of reactive oxygen species in lung alveolar cells: effect of vitamin E deficiency.

PubMed

Sabat, Robert; Guthmann, Florian; Rüstow, Bernd

2008-01-01

Reactive oxygen species (ROS) play an important role in the pathogenesis of numerous pulmonary diseases. Various mainly membrane-bound ROS-generating processes exist in alveolar cells. Vitamin E (vit. E) is the most important lipophilic antioxidant. However, the significance of vit. E levels in alveolar cells for the regulation of ROS generation has not been investigated so far. We demonstrated here that feeding rats with vit. E-depleted nourishment for 5 weeks reduced the concentration of vit. E in alveolar type II cell preparations to one-fifth the amount of control animals. This reduction of vit. E levels was associated with an approximately threefold increase in ROS generation in type II pneumocytes, lymphocytes, and macrophages. The contribution of individual processes of ROS formation in control animals differed strongly among these three cell types. However, vit. E deficiency induced predominantly nonmitochondrial ROS formation in alveolar cells. Expression and NAD(P)H-oxidase activity in alveolar type II cell preparations was not affected by vit. E deficiency. Moreover, protein kinase C (PKC) also did not seem to be responsible for vit. E deficiency-induced ROS generation in alveolar cells. Alimentary vit. E supplementation for 2 days corrected the cellular vit. E concentration but failed to normalize ROS generation in alveolar cells. These data let us assume that alimentary vit. E deficiency caused a preferentially nonmitochondria-mediated increase of ROS formation in type II pneumocytes, macrophages, and lymphocytes. However, the short-term supplementation of vit. E does not reverse these effects.

Butyrfentanyl overdose resulting in diffuse alveolar hemorrhage.

PubMed

Cole, Jon B; Dunbar, John F; McIntire, Sarah A; Regelmann, Warren E; Slusher, Tina M

2015-03-01

Butyrfentanyl is a potent short-acting opioid and a fentanyl analog with uncertain clinical effects. A review of the literature reveals no human case reports of butyrfentanyl overdose. As the use of analog and synthetic drugs continues to increase, clinicians are often faced with tremendous uncertainty when they encounter patients exposed to these synthetic drugs. We describe, to our knowledge, the first case of a butyrfentanyl overdose that resulted in clinically significant hemoptysis, acute lung injury, hypoxic respiratory failure, and diffuse alveolar hemorrhage. Complicating this case was a false-positive urine drug screen for fentanyl. Clinicians who encounter fentanyl exposures should be aware they may in fact be dealing with butyrfentanyl. As little is known of butyrfentanyl and our patient suffered a significant pulmonary hemorrhage, those who encounter butyrfentanyl exposures should monitor for hemorrhagic complications. Copyright © 2015 by the American Academy of Pediatrics.

Critical Determinants of Uptake and Translocation of Nanoparticles by the Human Pulmonary Alveolar Epithelium

PubMed Central

2015-01-01

The ability to manipulate the size and surface properties of nanomaterials makes them a promising vector for improving drug delivery and efficacy. Inhalation is a desirable route of administration as nanomaterials preferentially deposit in the alveolar region, a large surface area for drug absorption. However, as yet, the mechanisms by which particles translocate across the alveolar epithelial layer are poorly understood. Here we show that human alveolar type I epithelial cells internalize nanoparticles, whereas alveolar type II epithelial cells do not, and that nanoparticles translocate across the epithelial monolayer but are unable to penetrate the tight junctions between cells, ruling out paracellular translocation. Furthermore, using siRNA, we demonstrate that 50 nm nanoparticles enter largely by passive diffusion and are found in the cytoplasm, whereas 100 nm nanoparticles enter primarily via clathrin- and also caveolin-mediated endocytosis and are found in endosomes. Functionalization of nanoparticles increases their uptake and enhances binding of surfactant which further promotes uptake. Thus, we demonstrate that uptake and translocation across the pulmonary epithelium is controlled by alveolar type I epithelial cells, and furthermore, we highlight a number of factors that should be considered when designing new nanomedicines in order to improve drug delivery to the lung. PMID:25360809

Hypoxia increases transepithelial electrical conductance and reduces occludin at the plasma membrane in alveolar epithelial cells via PKC-ζ and PP2A pathway

PubMed Central

Caraballo, Juan Carlos; Yshii, Cecilia; Butti, Maria L.; Westphal, Whitney; Borcherding, Jennifer A.; Allamargot, Chantal

2011-01-01

During pulmonary edema, the alveolar space is exposed to a hypoxic environment. The integrity of the alveolar epithelial barrier is required for the reabsorption of alveolar fluid. Tight junctions (TJ) maintain the integrity of this barrier. We set out to determine whether hypoxia creates a dysfunctional alveolar epithelial barrier, evidenced by an increase in transepithelial electrical conductance (Gt), due to a decrease in the abundance of TJ proteins at the plasma membrane. Alveolar epithelial cells (AEC) exposed to mild hypoxia (Po2 = 50 mmHg) for 30 and 60 min decreased occludin abundance at the plasma membrane and significantly increased Gt. Other cell adhesion molecules such as E-cadherin and claudins were not affected by hypoxia. AEC exposed to hypoxia increased superoxide, but not hydrogen peroxide (H2O2). Overexpression of superoxide dismutase 1 (SOD1) but not SOD2 prevented the hypoxia-induced Gt increase and occludin reduction in AEC. Also, overexpression of catalase had a similar effect as SOD1, despite not detecting any increase in H2O2 during hypoxia. Blocking PKC-ζ and protein phosphatase 2A (PP2A) prevented the hypoxia-induced occludin reduction at the plasma membrane and increase in Gt. In summary, we show that superoxide, PKC-ζ, and PP2A are involved in the hypoxia-induced increase in Gt and occludin reduction at the plasma membrane in AEC. PMID:21257729

Diffusion Lung Imaging with Hyperpolarized Gas MRI

PubMed Central

Yablonskiy, Dmitriy A; Sukstanskii, Alexander L; Quirk, James D

2015-01-01

Lung imaging using conventional 1H MRI presents great challenges due to low density of lung tissue, lung motion and very fast lung tissue transverse relaxation (typical T2* is about 1-2 ms). MRI with hyperpolarized gases (3He and 129Xe) provides a valuable alternative due to a very strong signal originated from inhaled gas residing in the lung airspaces and relatively slow gas T2* relaxation (typical T2* is about 20-30 ms). Though in vivo human experiments should be done very fast – usually during a single breath-hold. In this review we describe the recent developments in diffusion lung MRI with hyperpolarized gases. We show that a combination of modeling results of gas diffusion in lung airspaces and diffusion measurements with variable diffusion-sensitizing gradients allows extracting quantitative information on the lung microstructure at the alveolar level. This approach, called in vivo lung morphometry, allows from a less than 15-second MRI scan, providing quantitative values and spatial distributions of the same physiological parameters as are measured by means of the “standard” invasive stereology (mean linear intercept, surface-to-volume ratio, density of alveoli, etc.). Besides, the approach makes it possible to evaluate some advanced Weibel parameters characterizing lung microstructure - average radii of alveolar sacs and ducts, as well as the depth of their alveolar sleeves. Such measurements, providing in vivo information on the integrity of pulmonary acinar airways and their changes in different diseases, are of great importance and interest to a broad range of physiologists and clinicians. We also discuss a new type of experiments that are based on the in vivo lung morphometry technique combined with quantitative CT measurements as well as with the Gradient Echo MRI measurements of hyperpolarized gas transverse relaxation in the lung airspaces. Such experiments provide additional information on the blood vessel volume fraction, specific gas volume, the length of acinar airways, and allows evaluation of lung parenchymal and non-parenchymal tissue. PMID:26676342

Effects of Phosphodiesterase 4 Inhibition on Alveolarization and Hyperoxia Toxicity in Newborn Rats

PubMed Central

Méhats, Céline; Franco-Montoya, Marie-Laure; Boucherat, Olivier; Lopez, Emmanuel; Schmitz, Thomas; Zana, Elodie; Evain-Brion, Danièle; Bourbon, Jacques; Delacourt, Christophe; Jarreau, Pierre-Henri

2008-01-01

Background Prolonged neonatal exposure to hyperoxia is associated with high mortality, leukocyte influx in airspaces, and impaired alveolarization. Inhibitors of type 4 phosphodiesterases are potent anti-inflammatory drugs now proposed for lung disorders. The current study was undertaken to determine the effects of the prototypal phosphodiesterase-4 inhibitor rolipram on alveolar development and on hyperoxia-induced lung injury. Methodology/Findings Rat pups were placed under hyperoxia (FiO2>95%) or room air from birth, and received rolipram or its diluent daily until sacrifice. Mortality rate, weight gain and parameters of lung morphometry were recorded on day 10. Differential cell count and cytokine levels in bronchoalveolar lavage and cytokine mRNA levels in whole lung were recorded on day 6. Rolipram diminished weight gain either under air or hyperoxia. Hyperoxia induced huge mortality rate reaching 70% at day 10, which was prevented by rolipram. Leukocyte influx in bronchoalveolar lavage under hyperoxia was significantly diminished by rolipram. Hyperoxia increased transcript and protein levels of IL-6, MCP1, and osteopontin; rolipram inhibited the increase of these proteins. Alveolarization was impaired by hyperoxia and was not restored by rolipram. Under room air, rolipram-treated pups had significant decrease of Radial Alveolar Count. Conclusions Although inhibition of phosphodiesterases 4 prevented mortality and lung inflammation induced by hyperoxia, it had no effect on alveolarization impairment, which might be accounted for by the aggressiveness of the model. The less complex structure of immature lungs of rolipram-treated pups as compared with diluent-treated pups under room air may be explained by the profound effect of PDE4 inhibition on weight gain that interfered with normal alveolarization. PMID:18941502

Impact and safety of open lung biopsy in patients with acute respiratory distress syndrome (ARDS).

PubMed

Ortiz, G; Garay, M; Mendoza, D; Cardinal-Fernández, P

2018-02-28

Acute respiratory distress syndrome (ARDS) is an inflammatory lung disorder, and its pathological hallmark is diffuse alveolar damage (DAD). Given that open lung biopsy (OLB) can sometimes result in severe side effects, it is rarely performed in patients with ARDS. The aims of this study were to describe: (a) the rate of treatment change associated with the histological result; and (b) the incidence of side effects induced by OLB. A retrospective, single-center, descriptive observational study was carried out in Hospital Santa Clara (Bogotá, Colombia) from February 2007 to January 2014. Critically ill patients over 18 years of age, undergoing invasive mechanical ventilation, diagnosed with ARDS of unknown etiology, and with OLB performed at the bedside. ARDS was diagnosed according to the Berlin definition. DAD was defined by the presence of a hyaline membrane plus at least one of the following: intra-alveolar edema, alveolar type I cell necrosis, alveolar type II cell (cuboidal cells) proliferation progressively covering the denuded alveolar-capillary membrane, interstitial proliferation of fibroblasts and myofibroblasts, or organizing interstitial fibrosis. The rate of treatment change (RTC) was established according to whether the OLB pathology report resulted in: a) the prescription or discontinuation of an antimicrobial; b) the indication of new procedures; c) medical interconsultation; or d) limitation of therapeutic effort. Patients were followed-up until death or hospital discharge. This study was approved by the Ethics Committee. A total of 32 OLBs were performed during the study period; 17 were ruled out as they did not involve ARDS, and 15 were considered for further analysis. A histological diagnosis was reached in 14 of the 15 patients (12 DAD, one case of bronchiolitis obliterans organizing pneumonia and one case of Wegener's granulomatosis with alveolar hemorrhage). The RTC rate was 0.73. The most frequent intervention was discontinuation of antimicrobial or corticosteroid treatment. No deaths but four side effects (3 airway leaks and one hemothorax) were associated with the OLB procedure. All were resolved before ICU discharge. The information provided by OLB performed at the bedside in ARDS patients of unknown etiology could be relevant, as it may optimize treatment. The risk associated with OLB seems to be acceptable. Copyright © 2018 Elsevier España, S.L.U. y SEMICYUC. All rights reserved.

Physiology in Medicine: Understanding dynamic alveolar physiology to minimize ventilator-induced lung injury.

PubMed

Nieman, Gary F; Satalin, Josh; Kollisch-Singule, Michaela; Andrews, Penny; Aiash, Hani; Habashi, Nader M; Gatto, Louis A

2017-06-01

Acute respiratory distress syndrome (ARDS) remains a serious clinical problem with the main treatment being supportive in the form of mechanical ventilation. However, mechanical ventilation can be a double-edged sword: if set improperly, it can exacerbate the tissue damage caused by ARDS; this is known as ventilator-induced lung injury (VILI). To minimize VILI, we must understand the pathophysiologic mechanisms of tissue damage at the alveolar level. In this Physiology in Medicine paper, the dynamic physiology of alveolar inflation and deflation during mechanical ventilation will be reviewed. In addition, the pathophysiologic mechanisms of VILI will be reviewed, and this knowledge will be used to suggest an optimal mechanical breath profile (MB P : all airway pressures, volumes, flows, rates, and the duration that they are applied at both inspiration and expiration) necessary to minimize VILI. Our review suggests that the current protective ventilation strategy, known as the "open lung strategy," would be the optimal lung-protective approach. However, the viscoelastic behavior of dynamic alveolar inflation and deflation has not yet been incorporated into protective mechanical ventilation strategies. Using our knowledge of dynamic alveolar mechanics (i.e., the dynamic change in alveolar and alveolar duct size and shape during tidal ventilation) to modify the MB P so as to minimize VILI will reduce the morbidity and mortality associated with ARDS. Copyright © 2017 the American Physiological Society.

The protective effect of Rhizoma Dioscoreae extract against alveolar bone loss in ovariectomized rats via regulating Wnt and p38 MAPK signaling.

PubMed

Zhang, Zhiguo; Xiang, Lihua; Bai, Dong; Wang, Wenlai; Li, Yan; Pan, Jinghua; Liu, Hong; Wang, Shaojun; Xiao, Gary Guishan; Ju, Dahong

2014-12-12

The aim of this study was to evaluate the osteoprotective effect of aqueous Rhizoma Dioscoreae extract (RDE) on the alveolar bone of rats with ovariectomy-induced bone loss. Female Wistar rats were subjected to either ovariectomy or a sham operation (SHAM). The ovariectomized (OVX) rats were treated with vehicle (OVX) or RDE by oral gavage or with 17β-estradiol (E2) subcutaneously. After treatments, the bone mineral density (BMD), the three-dimensional bone architecture of the alveolar bone and the plasma biomarkers of bone turnover were analyzed to assess bone metabolism, and the histomorphometry of the alveolar bone was observed. Microarrays were used to evaluate gene expression profiles in alveolar bone from RDE-treated and OVX rats. The differential expression of genes was further analyzed using Ingenuity Pathway Analysis (IPA). The key findings were verified using real-time quantitative RT-PCR (qRT-PCR). Our results showed that RDE inhibited alveolar bone loss in OVX rats. Compared to the OVX rats, the RDE-treated rats showed upregulated expression levels of 207 genes and downregulated expression levels of 176 genes in the alveolar bone. The IPA showed that several genes had the potential to code for proteins that were involved in the Wnt/β-catenin signaling pathway (Wnt7a, Fzd2, Tcf3, Spp1, Frzb, Sfrp2 and Sfrp4) and the p38 MAPK signaling pathway (Il1rn and Mapk14). These experiments revealed that RDE could inhibit ovariectomy-induced alveolar bone loss in rats. The mechanism of this anti-osteopenic effect in alveolar bone may be involved in the reduced abnormal bone remodeling, which is associated with the modulation of the Wnt/β-catenin and the p38 MAPK signaling pathways via gene regulation.

YC-1 potentiates cAMP-induced CREB activation and nitric oxide production in alveolar macrophages

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

Hwang, Tsong-Long, E-mail: htl@mail.cgu.edu.tw; Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Kweishan, Taoyuan, Taiwan; Tang, Ming-Chi

2012-04-15

Alveolar macrophages play significant roles in the pathogenesis of several inflammatory lung diseases. Increases in exhaled nitric oxide (NO) are well documented to reflect disease severity in the airway. In this study, we investigated the effect of 3-(5′-hydroxymethyl-2′-furyl)-1-benzyl indazole (YC-1), a known activator of soluble guanylyl cyclase, on prostaglandin (PG)E{sub 1} (a stable PGE{sub 2} analogue) and forskolin (a adenylate cyclase activator) induced NO production and inducible NO synthase (iNOS) expression in rat alveolar macrophages (NR8383). YC-1 did not directly cause NO production or iNOS expression, but drastically potentiated PGE{sub 1}- or forskolin-induced NO production and iNOS expression in NR8383more » alveolar macrophages. Combination treatment with YC-1 and PGE{sub 1} significantly increased phosphorylation of the cAMP response element-binding protein (CREB), but not nuclear factor (NF)-κB activation. The combined effect on NO production, iNOS expression, and CREB phosphorylation was reversed by a protein kinase (PK)A inhibitor (H89), suggesting that the potentiating functions were mediated through a cAMP/PKA signaling pathway. Consistent with this, cAMP analogues, but not the cGMP analogue, caused NO release, iNOS expression, and CREB activation. YC-1 treatment induced an increase in PGE{sub 1}-induced cAMP formation, which occurred through the inhibition of cAMP-specific phosphodiesterase (PDE) activity. Furthermore, the combination of rolipram (an inhibitor of PDE4), but not milronone (an inhibitor of PDE3), and PGE{sub 1} also triggered NO production and iNOS expression. In summary, YC-1 potentiates PGE{sub 1}-induced NO production and iNOS expression in alveolar macrophages through inhibition of cAMP PDE activity and activation of the cAMP/PKA/CREB signaling pathway. Highlights: ► YC-1 potentiated PGE1-induced iNOS expression in alveolar macrophages. ► The combination of YC-1 and PGE1 increased CREB but not NFκB activation. ► The combined effects were reversed by H89. ► The combination of rolipram and PGE1 triggered NO production and iNOS expression. ► Effect of YC-1 occurred through inhibition of cAMP-specific PDE.« less

Unsteady Oxygen Transfer in Space-Filling Models of the Pulmonary Acinus

NASA Astrophysics Data System (ADS)

Hofemeier, Philipp; Shachar-Berman, Lihi; Filoche, Marcel; Sznitman, Josue

2014-11-01

Diffusional screening in the pulmonary acinus is a well-known physical phenomenon that results from the depletion of fresh oxygen in proximal acinar generations diffusing through the alveolar wall membranes and effectively creating a gradient in the oxygen partial pressure along the acinar airways. Until present, most studies have focused on steady-state oxygen diffusion in generic sub-acinar structures and discarded convective oxygen transport due to low Peclet numbers in this region. Such studies, however, fall typically short in capturing the complex morphology of acinar airways as well as the oscillatory nature of convecive acinar breathing. Here, we revisit this problem and solve the convective-diffusive transport equations in breathing 3D acinar structures, underlining the significance of convective flows in proximal acinar generations as well as recirculating alveolar flow patterns. In particular, to assess diffusional screening, we monitor time-dependent efficiencies of the acinus under cyclic breathing motion. Our study emphasizes the necessity of capturing both a dynamically breathing and anatomically-realistic model of the sub-acinus to characterize unsteady oxygen transport across the acinar walls.

Effects of inspiratory pause on CO2 elimination and arterial PCO2 in acute lung injury

PubMed Central

Devaquet, Jérôme; Jonson, Björn; Niklason, Lisbet; Si Larbi, Anne-Gaëlle; Uttman, Leif; Aboab, Jérôme; Brochard, Laurent

2008-01-01

A high respiratory rate associated with the use of small tidal volumes, recommended for acute lung injury (ALI), shortens time for gas diffusion in the alveoli. This may decrease CO2 elimination. We hypothesized that a post-inspiratory pause could enhance CO2 elimination and reduce PaCO2 by reducing dead space in ALI. In 15 mechanically ventilated patients with ALI and hypercapnia, a 20% post-inspiratory pause (Tp20) was applied during a period of 30 min between two ventilation periods without post-inspiratory pause (Tp0). Other parameters were kept unchanged. The single breath test for CO2 was recorded every 5 minutes to measure tidal CO2 elimination (VtCO2), airway dead space (VDaw) and slope of the alveolar plateau. PaO2, PaCO2, physiological and alveolar dead space (VDphys, VDalv) were determined at the end of each 30 minute period. The post-inspiratory pause, 0.7±0.2 s, induced on average less than 0.5 cm H2O of intrinsic PEEP. During Tp20, VtCO2 increased immediately by 28±10% (14±5 ml per breath compared to 11±4 for Tp0) and then decreased without reaching the initial value within 30 minutes. The addition of a post-inspiratory pause decreased significantly VDaw by 14% and VDphys by 11% with no change in VDalv. During Tp20, the slope of alveolar plateau initially fell to 65±10 % of baseline value and continued to decrease. Tp20 induced a 10±3% decrease in PaCO2 at 30 minutes (from 55±10 to 49±9 mmHg, p<0.001) with no significant variation in PaO2. Post-inspiratory pause has a significant influence on CO2 elimination when small tidal volumes are used during mechanical ventilation for ALI. PMID:18801962

Diffuse Alveolar Damage: A Common Phenomenon in Progressive Interstitial Lung Disorders

PubMed Central

Kaarteenaho, Riitta; Kinnula, Vuokko L.

2011-01-01

It has become obvious that several interstitial lung diseases, and even viral lung infections, can progress rapidly, and exhibit similar features in their lung morphology. The final histopathological feature, common in these lung disorders, is diffuse alveolar damage (DAD). The histopathology of DAD is considered to represent end stage phenomenon in acutely behaving interstitial pneumonias, such as acute interstitial pneumonia (AIP) and acute exacerbations of idiopathic pulmonary fibrosis (IPF). Acute worsening and DAD may occur also in patients with nonspecific interstitial pneumonias (NSIPs), and even in severe viral lung infections where there is DAD histopathology in the lung. A better understanding of the mechanisms underlying the DAD reaction is needed to clarify the treatment for these serious lung diseases. There is an urgent need for international efforts for studying DAD-associated lung diseases, since the prognosis of these patients has been and is still dismal. PMID:21637367

Noninvasive quantification of alveolar morphometry in elderly never- and ex-smokers

PubMed Central

Paulin, Gregory A; Ouriadov, Alexei; Lessard, Eric; Sheikh, Khadija; McCormack, David G; Parraga, Grace

2015-01-01

Diffusion-weighted magnetic resonance imaging (MRI) provides a way to generate in vivo lung images with contrast sensitive to the molecular displacement of inhaled gas at subcellular length scales. Here, we aimed to evaluate hyperpolarized 3He MRI estimates of the alveolar dimensions in 38 healthy elderly never-smokers (73 ± 6 years, 15 males) and 21 elderly ex-smokers (70 ± 10 years, 14 males) with (n = 8, 77 ± 6 years) and without emphysema (n = 13, 65 ± 10 years). The ex-smoker and never-smoker subgroups were significantly different for FEV1/FVC (P = 0.0001) and DLCO (P = 0.009); while ex-smokers with emphysema reported significantly diminished FEV1/FVC (P = 0.02) and a trend toward lower DLCO (P = 0.05) than ex-smokers without emphysema. MRI apparent diffusion coefficients (ADC) and CT measurements of emphysema (relative area–CT density histogram, RA950) were significantly different (P = 0.001 and P = 0.007) for never-smoker and ex-smoker subgroups. In never-smokers, the MRI estimate of mean linear intercept (260 ± 27 μm) was significantly elevated as compared to the results previously reported in younger never-smokers (210 ± 30 μm), and trended smaller than in the age-matched ex-smokers (320 ± 72 μm, P = 0.06) evaluated here. Never-smokers also reported significantly smaller internal (220 ± 24 μm, P = 0.01) acinar radius but greater alveolar sheath thickness (120 ± 4 μm, P < 0.0001) than ex-smokers. Never-smokers were also significantly different than ex-smokers without emphysema for alveolar sheath thickness but not ADC, while ex-smokers with emphysema reported significantly different ADC but not alveolar sheath thickness compared to ex-smokers without CT evidence of emphysema. Differences in alveolar measurements in never- and ex-smokers demonstrate the sensitivity of MRI measurements to the different effects of smoking and aging on acinar morphometry. PMID:26462748

Fatal acute pulmonary injury associated with everolimus.

PubMed

Depuydt, Pieter; Nollet, Joke; Benoit, Dominique; Praet, Marleen; Caes, Frank

2012-03-01

To report a case of fatal alveolar hemorrhage associated with the use of everolimus in a patient who underwent a solid organ transplant. In a 71-year-old cardiac transplant patient, cyclosporine was replaced with everolimus because of worsening renal function. Over the following weeks, the patient developed nonproductive cough and increasing dyspnea. His condition deteriorated to acute respiratory failure with hemoptysis, requiring hospital admission. Bilateral patchy alveolar infiltrates were apparent on chest X-ray and computed tomography. Cardiac failure was ruled out and empiric antimicrobial therapy was initiated. Additional extensive workup could not document opportunistic infection. Everolimus was discontinued and high-dose corticosteroid therapy was initiated. Despite this, the patient required invasive mechanical ventilation and died because of refractory massive hemoptysis. Autopsy revealed diffuse alveolar hemorrhage. Everolimus is a mammalian target of rapamycin inhibitor approved for use as an immunosuppressant and antineoplastic agent. Its main advantage over calcineurin inhibitors (tacrolimus and cyclosporine) is a distinct safety profile. Although it has become clear that everolimus induces pulmonary toxicity more frequently than initially thought, most published cases thus far represented mild and reversible disease, and none was fatal. Here, we report a case of pulmonary toxicity developing over weeks following the introduction of everolimus, in which a fatal outcome could not be prevented by drug withdrawal and corticosteroid treatment. The association of everolimus and this syndrome was probable according to the Naranjo probability scale. This case indicates that with the increasing use of everolimus, clinicians should be aware of the rare, but life-threatening manifestation of pulmonary toxicity.

Estimation of changes in alveolar-arterial oxygen gradient induced by hypoxia.

PubMed

Hoffstein, V; Duguid, N; Zamel, N; Rebuck, A S

1984-11-01

The alveolar-arterial oxygen tension difference provides a useful clinical indication of ventilation-blood flow mismatching in the lungs. In some clinical situations involving alveolar hypoxia (e.g., patients with chronic obstructive lung disease flying in commercial aircraft or normal humans at high altitudes) it would be useful to know this tension difference to predict the likely arterial PO2 under such potentially stressful conditions. Such estimates would require multiple arterial punctures performed under a variety of trying circumstances, conditions usually far distant from a suitable analytic facility. Consequently, we induced controlled hypoxia in 23 healthy humans and calculated changes in the alveolar-arterial oxygen tension difference during the hypoxic challenge test. We plotted this difference as a function of the alveolar oxygen tension over a range from 35 to 110 mm Hg. In addition to a series of control studies in which multiple arterial blood samples were obtained, we calculated arterial PO2 by converting the arterial oxyhemoglobin saturation (measured with an ear oximeter) into partial pressure of oxygen. During hypoxic procedures in which levels of oxygenation fell on the steep section of the oxyhemoglobin dissociation curve, fixing PCO2 at constant predetermined levels allowed accurate predictions of arterial PO2. We were able to demonstrate that the alveolar-arterial oxygen tension difference narrowed with decreasing alveolar oxygen tension, and that measurement with an ear oximeter provided data that allowed a reasonable estimate of the tension difference during hypoxic conditions.

Protective effect of Rhizoma Dioscoreae extract against alveolar bone loss in ovariectomized rats via regulation of IL-6/STAT3 signaling.

PubMed

Zhang, Zhi-Guo; Chen, Yan-Jing; Xiang, Li-Hua; Pan, Jing-Hua; Wang, Zhen; Xiao, Gary Guishan; Ju, Da-Hong

2017-11-01

The aim of the present study was to assess the effectiveness of Rhizoma Dioscoreae extract (RDE) on preventing rat alveolar bone loss induced by ovariectomy (OVX), and to determine the role of interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in this effect. Female Wistar rats were subjected to OVX or sham surgery. The rats that had undergone OVX were treated with RDE (RDE group), vehicle (OVX group) or 17β-estradiol subcutaneous injection (E2 group). Subsequently, bone metabolic activity was assessed by analyzing 3-D alveolar bone construction, bone mineral density, as well as the plasma biomarkers of bone turnover. The gene expression of alveolar bone in the OVX and RDE groups was evaluated by IL-6/STAT3 signaling pathway polymerase chain reaction (PCR) arrays, and differentially expressed genes were determined through reverse transcription-quantitative PCR. The inhibitory effect of RDE on alveolar bone loss in the OVX group was demonstrated in the study. In comparison with the OVX group, the RDE group exhibited 19 downregulated genes and 1 upregulated gene associated with the IL-6/STAT3 signaling pathway in alveolar bone. Thus, RDE was shown to relieve OVX-induced alveolar bone loss in rats, an effect which was likely associated with decreased abnormal bone remodeling via regulation of the IL-6/STAT3 signaling pathway.

Emodin suppresses TGF-β1-induced epithelial-mesenchymal transition in alveolar epithelial cells through Notch signaling pathway.

PubMed

Gao, Rundi; Chen, Ruilin; Cao, Yu; Wang, Yuan; Song, Kang; Zhang, Ya; Yang, Junchao

2017-03-01

Pulmonary fibrosis is characterized by the destruction of lung tissue architecture and the formation of fibrous foci, currently has no satisfactory treatment. Emodin is a component of Chinese herb that has been reported to be medicament on pancreatic fibrosis and liver fibrosis. However, its role in pulmonary fibrosis has not been established yet. In the present study, we investigated the hypothesis that Emodin plays an inhibitory role in TGF-β1 induced epithelial-mesenchymal transition (EMT) of alveolar epithelial cell, and Emodin exerts its effect through the Notch signaling pathway. Emodin inhibits the proliferation of Rat alveolar type II epithelial cells RLE-6TN in a concentration-dependent manner; reduces the expression of Collagen I, α-SMA and Vimentin, promotes the expression of E-cadherin. Moreover, Emodin could regulate the expression patterns of the Notch signaling pathway-related factors and reduce the Notch-1 nucleus translocation. Knockdown of Notch-1 enhances the inhibitory effect of Emodin on TGF-β1-induced EMT in RLE-6TN cells. In conclusion, the data of the present study suggests that Emodin suppresses TGF-β1-induced EMT in alveolar epithelial cells through Notch signaling pathway and shows the potential to be effective in the treatment of pulmonary fibrosis. Copyright © 2016 Elsevier Inc. All rights reserved.

A disseminated alveolar rhabdomyosarcoma in a 9-year-old boy disclosed by chromosomal translocation (2;13) (q35;q14)

PubMed

Brichard, B; Ninane, J; Gosseye, S; Verellen-Dumoulin, C; Vermylen, C; Rodhain, J; Cornu, G

1991-01-01

A 9-year-old boy presented with a small subcutaneous tumor of the trunk and diffuse bone marrow involvement. The first histological diagnosis given was undifferentiated malignancy possibly of neural crest origin and chemotherapy was started immediately using vincristine, cyclophosphamide, cisplatin, and teniposide (OPEC). Complete response was achieved after four courses of chemotherapy. Histological slides were then reviewed and the final diagnosis of alveolar rhabdomyosarcoma (RMS) was retained. Moreover, chromosome analysis of malignant cells in the bone marrow revealed a translocation involving chromosomes 2 and 13:t(2;13) (q35;q14). This specific karyotype finding has been recently reported in a few cases and could be specific for alveolar RMS. The patient had a relapse 7 months after diagnosis and died 4 months later.

Alveolar macrophage development in mice requires L-plastin for cellular localization in alveoli.

PubMed

Todd, Elizabeth M; Zhou, Julie Y; Szasz, Taylor P; Deady, Lauren E; D'Angelo, June A; Cheung, Matthew D; Kim, Alfred H J; Morley, Sharon Celeste

2016-12-15

Alveolar macrophages are lung-resident sentinel cells that develop perinatally and protect against pulmonary infection. Molecular mechanisms controlling alveolar macrophage generation have not been fully defined. Here, we show that the actin-bundling protein L-plastin (LPL) is required for the perinatal development of alveolar macrophages. Mice expressing a conditional allele of LPL (CD11c.Cre pos -LPL fl/fl ) exhibited significant reductions in alveolar macrophages and failed to effectively clear pulmonary pneumococcal infection, showing that immunodeficiency results from reduced alveolar macrophage numbers. We next identified the phase of alveolar macrophage development requiring LPL. In mice, fetal monocytes arrive in the lungs during a late fetal stage, maturing to alveolar macrophages through a prealveolar macrophage intermediate. LPL was required for the transition from prealveolar macrophages to mature alveolar macrophages. The transition from prealveolar macrophage to alveolar macrophage requires the upregulation of the transcription factor peroxisome proliferator-activated receptor-γ (PPAR-γ), which is induced by exposure to granulocyte-macrophage colony-stimulating factor (GM-CSF). Despite abundant lung GM-CSF and intact GM-CSF receptor signaling, PPAR-γ was not sufficiently upregulated in developing alveolar macrophages in LPL -/- pups, suggesting that precursor cells were not correctly localized to the alveoli, where GM-CSF is produced. We found that LPL supports 2 actin-based processes essential for correct localization of alveolar macrophage precursors: (1) transmigration into the alveoli, and (2) engraftment in the alveoli. We thus identify a molecular pathway governing neonatal alveolar macrophage development and show that genetic disruption of alveolar macrophage development results in immunodeficiency. © 2016 by The American Society of Hematology.

Chloride transport-driven alveolar fluid secretion is a major contributor to cardiogenic lung edema

PubMed Central

Solymosi, Esther A.; Kaestle-Gembardt, Stefanie M.; Vadász, István; Wang, Liming; Neye, Nils; Chupin, Cécile Julie Adrienne; Rozowsky, Simon; Ruehl, Ramona; Tabuchi, Arata; Schulz, Holger; Kapus, Andras; Morty, Rory E.; Kuebler, Wolfgang M.

2013-01-01

Alveolar fluid clearance driven by active epithelial Na+ and secondary Cl− absorption counteracts edema formation in the intact lung. Recently, we showed that impairment of alveolar fluid clearance because of inhibition of epithelial Na+ channels (ENaCs) promotes cardiogenic lung edema. Concomitantly, we observed a reversal of alveolar fluid clearance, suggesting that reversed transepithelial ion transport may promote lung edema by driving active alveolar fluid secretion. We, therefore, hypothesized that alveolar ion and fluid secretion may constitute a pathomechanism in lung edema and aimed to identify underlying molecular pathways. In isolated perfused lungs, alveolar fluid clearance and secretion were determined by a double-indicator dilution technique. Transepithelial Cl− secretion and alveolar Cl− influx were quantified by radionuclide tracing and alveolar Cl− imaging, respectively. Elevated hydrostatic pressure induced ouabain-sensitive alveolar fluid secretion that coincided with transepithelial Cl− secretion and alveolar Cl− influx. Inhibition of either cystic fibrosis transmembrane conductance regulator (CFTR) or Na+-K+-Cl− cotransporters (NKCC) blocked alveolar fluid secretion, and lungs of CFTR−/− mice were protected from hydrostatic edema. Inhibition of ENaC by amiloride reproduced alveolar fluid and Cl− secretion that were again CFTR-, NKCC-, and Na+-K+-ATPase–dependent. Our findings show a reversal of transepithelial Cl− and fluid flux from absorptive to secretory mode at hydrostatic stress. Alveolar Cl− and fluid secretion are triggered by ENaC inhibition and mediated by NKCC and CFTR. Our results characterize an innovative mechanism of cardiogenic edema formation and identify NKCC1 as a unique therapeutic target in cardiogenic lung edema. PMID:23645634

Cigarette Smoking Decreases Global MicroRNA Expression in Human Alveolar Macrophages

PubMed Central

Graff, Joel W.; Powers, Linda S.; Dickson, Anne M.; Kim, Jongkwang; Reisetter, Anna C.; Hassan, Ihab H.; Kremens, Karol; Gross, Thomas J.

2012-01-01

Human alveolar macrophages are critical components of the innate immune system. Cigarette smoking-induced changes in alveolar macrophage gene expression are linked to reduced resistance to pulmonary infections and to the development of emphysema/COPD. We hypothesized that microRNAs (miRNAs) could control, in part, the unique messenger RNA (mRNA) expression profiles found in alveolar macrophages of cigarette smokers. Activation of macrophages with different stimuli in vitro leads to a diverse range of M1 (inflammatory) and M2 (anti-inflammatory) polarized phenotypes that are thought to mimic activated macrophages in distinct tissue environments. Microarray mRNA data indicated that smoking promoted an “inverse” M1 mRNA expression program, defined by decreased expression of M1-induced transcripts and increased expression of M1-repressed transcripts with few changes in M2-regulated transcripts. RT-PCR arrays identified altered expression of many miRNAs in alveolar macrophages of smokers and a decrease in global miRNA abundance. Stratification of human subjects suggested that the magnitude of the global decrease in miRNA abundance was associated with smoking history. We found that many of the miRNAs with reduced expression in alveolar macrophages of smokers were predicted to target mRNAs upregulated in alveolar macrophages of smokers. For example, miR-452 is predicted to target the transcript encoding MMP12, an important effector of smoking-related diseases. Experimental antagonism of miR-452 in differentiated monocytic cells resulted in increased expression of MMP12. The comprehensive mRNA and miRNA expression profiles described here provide insight into gene expression regulation that may underlie the adverse effects cigarette smoking has on alveolar macrophages. PMID:22952876

Curcumin Modulates the Inflammatory Response and Inhibits Subsequent Fibrosis in a Mouse Model of Viral-induced Acute Respiratory Distress Syndrome

PubMed Central

Liu, Guangliang; Wang, Ruixue; London, Steven D.; London, Lucille

2013-01-01

Acute Respiratory Distress Syndrome (ARDS) is a clinical syndrome characterized by diffuse alveolar damage usually secondary to an intense host inflammatory response of the lung to a pulmonary or extrapulmonary infectious or non-infectious insult often leading to the development of intra-alveolar and interstitial fibrosis. Curcumin, the principal curcumoid of the popular Indian spice turmeric, has been demonstrated as an anti-oxidant and anti-inflammatory agent in a broad spectrum of diseases. Using our well-established model of reovirus 1/L-induced acute viral pneumonia, which displays many of the characteristics of the human ALI/ARDS, we evaluated the anti-inflammatory and anti-fibrotic effects of curcumin. Female CBA/J mice were treated with curcumin (50 mg/kg) 5 days prior to intranasal inoculation with 107 pfu reovirus 1/L and daily, thereafter. Mice were evaluated for key features associated with ALI/ARDS. Administration of curcumin significantly modulated inflammation and fibrosis, as revealed by histological and biochemical analysis. The expression of IL-6, IL-10, IFNγ, and MCP-1, key chemokines/cytokines implicated in the development of ALI/ARDS, from both the inflammatory infiltrate and whole lung tissue were modulated by curcumin potentially through a reduction in the phosphorylated form of NFκB p65. While the expression of TGFß1 was not modulated by curcumin, TGFß Receptor II, which is required for TGFß signaling, was significantly reduced. In addition, curcumin also significantly inhibited the expression of α-smooth muscle actin and Tenascin-C, key markers of myofibroblast activation. This data strongly supports a role for curcumin in modulating the pathogenesis of viral-induced ALI/ARDS in a pre-clinical model potentially manifested through the alteration of inflammation and myofibroblast differentiation. PMID:23437361

The Mitochondrial Cardiolipin Remodeling Enzyme Lysocardiolipin Acyltransferase Is a Novel Target in Pulmonary Fibrosis

PubMed Central

Huang, Long Shuang; Mathew, Biji; Zhao, Yutong; Noth, Imre; Reddy, Sekhar P.; Harijith, Anantha; Usatyuk, Peter V.; Berdyshev, Evgeny V.; Kaminski, Naftali; Zhou, Tong; Zhang, Wei; Zhang, Yanmin; Rehman, Jalees; Kotha, Sainath R.; Gurney, Travis O.; Parinandi, Narasimham L.; Lussier, Yves A.; Garcia, Joe G. N.

2014-01-01

Rationale: Lysocardiolipin acyltransferase (LYCAT), a cardiolipin-remodeling enzyme regulating the 18:2 linoleic acid pattern of mammalian mitochondrial cardiolipin, is necessary for maintaining normal mitochondrial function and vascular development. We hypothesized that modulation of LYCAT expression in lung epithelium regulates development of pulmonary fibrosis. Objectives: To define a role for LYCAT in human and murine models of pulmonary fibrosis. Methods: We analyzed the correlation of LYCAT expression in peripheral blood mononuclear cells (PBMCs) with the outcomes of pulmonary functions and overall survival, and used the murine models to establish the role of LYCAT in fibrogenesis. We studied the LYCAT action on cardiolipin remodeling, mitochondrial reactive oxygen species generation, and apoptosis of alveolar epithelial cells under bleomycin challenge. Measurements and Main Results: LYCAT expression was significantly altered in PBMCs and lung tissues from patients with idiopathic pulmonary fibrosis (IPF), which was confirmed in two preclinical murine models of IPF, bleomycin- and radiation-induced pulmonary fibrosis. LYCAT mRNA expression in PBMCs directly and significantly correlated with carbon monoxide diffusion capacity, pulmonary function outcomes, and overall survival. In both bleomycin- and radiation-induced pulmonary fibrosis murine models, hLYCAT overexpression reduced several indices of lung fibrosis, whereas down-regulation of native LYCAT expression by siRNA accentuated fibrogenesis. In vitro studies demonstrated that LYCAT modulated bleomycin-induced cardiolipin remodeling, mitochondrial membrane potential, reactive oxygen species generation, and apoptosis of alveolar epithelial cells, potential mechanisms of LYCAT-mediated lung protection. Conclusions: This study is the first to identify modulation of LYCAT expression in fibrotic lungs and offers a novel therapeutic approach for ameliorating lung inflammation and pulmonary fibrosis. PMID:24779708

Curcumin modulates the inflammatory response and inhibits subsequent fibrosis in a mouse model of viral-induced acute respiratory distress syndrome.

PubMed

Avasarala, Sreedevi; Zhang, Fangfang; Liu, Guangliang; Wang, Ruixue; London, Steven D; London, Lucille

2013-01-01

Acute Respiratory Distress Syndrome (ARDS) is a clinical syndrome characterized by diffuse alveolar damage usually secondary to an intense host inflammatory response of the lung to a pulmonary or extrapulmonary infectious or non-infectious insult often leading to the development of intra-alveolar and interstitial fibrosis. Curcumin, the principal curcumoid of the popular Indian spice turmeric, has been demonstrated as an anti-oxidant and anti-inflammatory agent in a broad spectrum of diseases. Using our well-established model of reovirus 1/L-induced acute viral pneumonia, which displays many of the characteristics of the human ALI/ARDS, we evaluated the anti-inflammatory and anti-fibrotic effects of curcumin. Female CBA/J mice were treated with curcumin (50 mg/kg) 5 days prior to intranasal inoculation with 10(7)pfu reovirus 1/L and daily, thereafter. Mice were evaluated for key features associated with ALI/ARDS. Administration of curcumin significantly modulated inflammation and fibrosis, as revealed by histological and biochemical analysis. The expression of IL-6, IL-10, IFNγ, and MCP-1, key chemokines/cytokines implicated in the development of ALI/ARDS, from both the inflammatory infiltrate and whole lung tissue were modulated by curcumin potentially through a reduction in the phosphorylated form of NFκB p65. While the expression of TGFß1 was not modulated by curcumin, TGFß Receptor II, which is required for TGFß signaling, was significantly reduced. In addition, curcumin also significantly inhibited the expression of α-smooth muscle actin and Tenascin-C, key markers of myofibroblast activation. This data strongly supports a role for curcumin in modulating the pathogenesis of viral-induced ALI/ARDS in a pre-clinical model potentially manifested through the alteration of inflammation and myofibroblast differentiation.

The Use of High-Frequency Percussive Ventilation for Whole-Lung Lavage: A Case Report.

PubMed

Kinthala, Sudhakar; Liang, Mark; Khusid, Felix; Harrison, Sebron

2018-04-23

Whole-lung lavage (WLL) remains the gold standard in the treatment of pulmonary alveolar proteinosis. However, anesthetic management during WLL can be challenging because of the risk of intraoperative hypoxemia and various cardiorespiratory complications of 1-lung ventilation. Here, we describe a novel strategy involving the application of high-frequency percussive ventilation using a volumetric diffusive respirator (VDR-4) during WLL in a 47-year-old woman with pulmonary alveolar proteinosis. Our observations suggest that high-frequency percussive ventilation is a potentially effective ventilation strategy during WLL that may reduce the risk of hypoxemia and facilitate lavage.

NADPH Oxidase Contributes to Resistance against Aggregatibacter actinomycetemcomitans-Induced Periodontitis in Mice.

PubMed

Bast, Antje; Kubis, Helen; Holtfreter, Birte; Ribback, Silvia; Martin, Heiner; Schreiner, Helen C; Dominik, Malte J; Breitbach, Katrin; Dombrowski, Frank; Kocher, Thomas; Steinmetz, Ivo

2017-02-01

Aggregatibacter actinomycetemcomitans is a Gram-negative commensal bacterium of the oral cavity which has been associated with the pathogenesis of periodontitis with severe alveolar bone destruction. The role of host factors such as reactive oxygen and nitrogen intermediates in periodontal A. actinomycetemcomitans infection and progression to periodontitis is still ill-defined. Therefore, this study aimed to analyze the role of NADPH oxidase and inducible nitric oxide synthase (iNOS) in a murine model of A. actinomycetemcomitans-induced periodontitis. NADPH oxidase-deficient (gp91 phox knockout [KO]), iNOS-deficient (iNOS KO), and C57BL/6 wild-type mice were orally infected with A. actinomycetemcomitans and analyzed for bacterial colonization at various time points. Alveolar bone mineral density and alveolar bone volume were quantified by three-dimensional micro-computed tomography, and the degree of tissue inflammation was calculated by histological analyses. At 5 weeks after infection, A. actinomycetemcomitans persisted at significantly higher levels in the murine oral cavities of infected gp91 phox KO mice than in those of iNOS KO and C57BL/6 mice. Concomitantly, alveolar bone mineral density was significantly lower in all three infected groups than in uninfected controls, but with the highest loss of bone density in infected gp91 phox KO mice. Only infected gp91 phox KO mice revealed significant loss of alveolar bone volume and enhanced inflammatory cell infiltration, as well as an increased number of osteoclasts. Our results indicate that NADPH oxidase is important to control A. actinomycetemcomitans infection in the murine oral cavity and to prevent subsequent alveolar bone destruction and osteoclastogenesis. Copyright © 2017 American Society for Microbiology.

NADPH Oxidase Contributes to Resistance against Aggregatibacter actinomycetemcomitans-Induced Periodontitis in Mice

PubMed Central

Bast, Antje; Kubis, Helen; Holtfreter, Birte; Ribback, Silvia; Martin, Heiner; Schreiner, Helen C.; Dominik, Malte J.; Breitbach, Katrin; Dombrowski, Frank; Kocher, Thomas

2016-01-01

ABSTRACT Aggregatibacter actinomycetemcomitans is a Gram-negative commensal bacterium of the oral cavity which has been associated with the pathogenesis of periodontitis with severe alveolar bone destruction. The role of host factors such as reactive oxygen and nitrogen intermediates in periodontal A. actinomycetemcomitans infection and progression to periodontitis is still ill-defined. Therefore, this study aimed to analyze the role of NADPH oxidase and inducible nitric oxide synthase (iNOS) in a murine model of A. actinomycetemcomitans-induced periodontitis. NADPH oxidase-deficient (gp91phox knockout [KO]), iNOS-deficient (iNOS KO), and C57BL/6 wild-type mice were orally infected with A. actinomycetemcomitans and analyzed for bacterial colonization at various time points. Alveolar bone mineral density and alveolar bone volume were quantified by three-dimensional micro-computed tomography, and the degree of tissue inflammation was calculated by histological analyses. At 5 weeks after infection, A. actinomycetemcomitans persisted at significantly higher levels in the murine oral cavities of infected gp91phox KO mice than in those of iNOS KO and C57BL/6 mice. Concomitantly, alveolar bone mineral density was significantly lower in all three infected groups than in uninfected controls, but with the highest loss of bone density in infected gp91phox KO mice. Only infected gp91phox KO mice revealed significant loss of alveolar bone volume and enhanced inflammatory cell infiltration, as well as an increased number of osteoclasts. Our results indicate that NADPH oxidase is important to control A. actinomycetemcomitans infection in the murine oral cavity and to prevent subsequent alveolar bone destruction and osteoclastogenesis. PMID:27849181

Intravenous S-Ketamine Does Not Inhibit Alveolar Fluid Clearance in a Septic Rat Model

PubMed Central

Weber, Nina C.; van der Sluijs, Koen; Hackl, Florian; Hotz, Lorenz; Dahan, Albert; Hollmann, Markus W.; Berger, Marc M.

2014-01-01

We previously demonstrated that intratracheally administered S-ketamine inhibits alveolar fluid clearance (AFC), whereas an intravenous (IV) bolus injection had no effect. The aim of the present study was to characterize whether continuous IV infusion of S-ketamine, yielding clinically relevant plasma concentrations, inhibits AFC and whether its effect is enhanced in acute lung injury (ALI) which might favor the appearance of IV S-ketamine at the alveolar surface. AFC was measured in fluid-instilled rat lungs. S-ketamine was administered IV over 6 h (loading dose: 20 mg/kg, followed by 20 mg/kg/h), or intratracheally by addition to the instillate (75 µg/ml). ALI was induced by IV lipopolysaccharide (LPS; 7 mg/kg). Interleukin (IL)-6 and cytokine-induced neutrophil chemoattractant (CINC)-3 were measured by ELISA in plasma and bronchoalveolar lavage fluid. Isolated rat alveolar type-II cells were exposed to S-ketamine (75 µg/ml) and/or LPS (1 mg/ml) for 6 h, and transepithelial ion transport was measured as short circuit current (ISC). AFC was 27±5% (mean±SD) over 60 min in control rats and was unaffected by IV S-ketamine. Tracheal S-ketamine reduced AFC to 18±9%. In LPS-treated rats, AFC decreased to 16±6%. This effect was not enhanced by IV S-ketamine. LPS increased IL-6 and CINC-3 in plasma and bronchoalveolar lavage fluid. In alveolar type-II cells, S-ketamine reduced ISC by 37% via a decrease in amiloride-inhibitable sodium transport. Continuous administration of IV S-ketamine does not affect rat AFC even in endotoxin-induced ALI. Tracheal application with direct exposure of alveolar epithelial cells to S-ketamine decreases AFC by inhibition of amiloride-inhibitable sodium transport. PMID:25386677

MIF induces osteoclast differentiation and contributes to progression of periodontal disease in mice.

PubMed

Madeira, Mila Fernandes Moreira; Queiroz-Junior, Celso Martins; Costa, Graciela Mitre; Santos, Patrícia Campi; Silveira, Elcia Maria; Garlet, Gustavo Pompermaier; Cisalpino, Patrícia Silva; Teixeira, Mauro Martins; Silva, Tarcília Aparecida; Souza, Daniele da Glória

2012-02-01

Periodontal disease (PD) is a chronic inflammatory and alveolar bone destructive disease triggered by microorganisms from the oral biofilm. Oral inoculation of mice with the periodontopathogen Aggregatibacter actinomycetemcomitans (Aa) induces marked alveolar bone loss and local production of inflammatory mediators, including Macrophage Migration Inhibitory Factor (MIF). The role of MIF for alveolar bone resorption during PD is not known. In the present study, experimental PD was induced in BALB/c wild-type mice (WT) and MIF knockout mice (MIF⁻/⁻) through oral inoculation of Aa. Despite enhanced number of bacteria, MIF⁻/⁻ mice had reduced infiltration of TRAP-positive cells and reduced alveolar bone loss. This was associated with decreased neutrophil accumulation and increased levels of IL-10 in periodontal tissues. TNF-α production was similar in both groups. In vitro, LPS from Aa enhanced osteoclastic activity in a MIF-dependent manner. In conclusion, MIF has role in controlling bacterial growth in the context of PD but contributes more significantly to the progression of bone loss during PD by directly affecting differentiation and activity of osteoclasts. Copyright © 2011 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

Persistent structural adaptation in the lungs of guinea pigs raised at high altitude.

PubMed

Ravikumar, Priya; Bellotto, Dennis J; Hsia, Connie C W

2015-03-01

Laboratory guinea pigs raised at high altitude (HA, 3800 m) for up to 6 mo exhibit enhanced alveolar growth and remodeling (Hsia et al., 2005. Resp. Physiol. Neurobiol. 147, 105-115). To determine whether initial HA-induced structural enhancement persists following return to intermediate altitude (IA), we raised weanling guinea pigs at (a) HA for 11-12 mo, (b) IA (1200 m) for 11-12 mo, and (c) HA for 4 mo followed by IA for 7-8 mo (HA-to-IA). Morphometric analysis was performed under light and electron microscopy. Body weight and lung volume were similar among groups. Prolonged HA residence increased alveolar epithelium and interstitium volumes while reducing alveolar-capillary blood volume. The HA-induced gains in type-1 epithelium volume and alveolar surface area were no longer present following return to IA whereas volume increases in type-2 epithelium and interstitium and the reduction in alveolar duct volume persisted. Results demonstrate persistent augmentation of some but not all aspects of lung structure throughout prolonged HA residence, with partial reversibility following re-acclimatization to IA. Copyright © 2014 Elsevier B.V. All rights reserved.

The Protective Effect of Rhizoma Dioscoreae Extract against Alveolar Bone Loss in Ovariectomized Rats via Regulating Wnt and p38 MAPK Signaling

PubMed Central

Zhang, Zhiguo; Xiang, Lihua; Bai, Dong; Wang, Wenlai; Li, Yan; Pan, Jinghua; Liu, Hong; Wang, Shaojun; Xiao, Gary Guishan; Ju, Dahong

2014-01-01

Aim: The aim of this study was to evaluate the osteoprotective effect of aqueous Rhizoma Dioscoreae extract (RDE) on the alveolar bone of rats with ovariectomy-induced bone loss. Methods: Female Wistar rats were subjected to either ovariectomy or a sham operation (SHAM). The ovariectomized (OVX) rats were treated with vehicle (OVX) or RDE by oral gavage or with 17β-estradiol (E2) subcutaneously. After treatments, the bone mineral density (BMD), the three-dimensional bone architecture of the alveolar bone and the plasma biomarkers of bone turnover were analyzed to assess bone metabolism, and the histomorphometry of the alveolar bone was observed. Microarrays were used to evaluate gene expression profiles in alveolar bone from RDE-treated and OVX rats. The differential expression of genes was further analyzed using Ingenuity Pathway Analysis (IPA). The key findings were verified using real-time quantitative RT-PCR (qRT-PCR). Results: Our results showed that RDE inhibited alveolar bone loss in OVX rats. Compared to the OVX rats, the RDE-treated rats showed upregulated expression levels of 207 genes and downregulated expression levels of 176 genes in the alveolar bone. The IPA showed that several genes had the potential to code for proteins that were involved in the Wnt/β-catenin signaling pathway (Wnt7a, Fzd2, Tcf3, Spp1, Frzb, Sfrp2 and Sfrp4) and the p38 MAPK signaling pathway (Il1rn and Mapk14). Conclusion: These experiments revealed that RDE could inhibit ovariectomy-induced alveolar bone loss in rats. The mechanism of this anti-osteopenic effect in alveolar bone may be involved in the reduced abnormal bone remodeling, which is associated with the modulation of the Wnt/β-catenin and the p38 MAPK signaling pathways via gene regulation. PMID:25514564

The effect of an inhibitor of gut serotonin (LP533401) during the induction of periodontal disease.

PubMed

Lima, G M G; Corazza, B J M; Moraes, R M; de Oliveira, F E; de Oliveira, L D; Franco, G C N; Perrien, D S; Elefteriou, F; Anbinder, A L

2016-10-01

LP533401 is an inhibitor of tryptophan hydroxylase 1, which regulates serotonin production in the gut. Previous work indicates that LP533401 has an anabolic effect in bone. Thus, we hypothesized that inhibition of gut serotonin production may modulate the host response in periodontal disease. In this study, we aimed to analyze the effects of LP533401 in a rat periodontitis model to evaluate the role of gut serotonin in periodontitis pathophysiology. Twenty-four rats were divided into three groups: treated group (T: ligature-induced periodontal disease and LP533401, 25 mg/kg/d) by gavage; ligature group (L: ligature-induced periodontal disease only); and control group (C: without ligature-induced periodontal disease). After 28 d, radiographic alveolar bone support was measured on digital radiographs, and alveolar bone volume fraction, tissue mineral density and trabeculae characteristics were quantified by microcomputed tomography in the right hemi-mandible. Left hemi-mandibles were decalcified and alveolar bone loss, attachment loss and area of collagen in the gingiva were histologically analyzed. Significant difference between the L and C groups was found, confirming that periodontal disease was induced. We observed no difference between the T and L groups regarding alveolar bone destruction and area of collagen. LP533401 (25 mg/kg/d) for 28 d does not prevent bone loss and does not modulate host response in a rat model of induced periodontal disease. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Ghrelin ameliorates the human alveolar epithelial A549 cell apoptosis induced by lipopolysaccharide

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

Huang, Chunrong; Zheng, Haichong; He, Wanmei

Ghrelin is a gastric acyl-peptide that plays an inhibitory role in cell apoptosis. Herein we investigate the protective effects of ghrelin in LPS-induced apoptosis of human alveolar epithelial A549 cells, along with the possible molecular mechanisms. LPS exposure impaired cell viability and increased apoptosis of A549 cells significantly in concentration- and time-dependent manners embodied in increased Bax and cleaved caspase-3 production, coupled with decreased Bcl-2 levels. Simultaneously, LPS remarkably decreased the expression of phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) and extracellular signal-regulated kinas (ERK) in A549 cells. However, ghrelin'pretreatment ameliorated LPS-caused alterations in the ratio of Bax/Bcl-2 and cleaved caspase-3 expression, whereas activatedmore » the PI3K/Akt and ERK signaling. These results demonstrate that ghrelin lightens LPS-induced apoptosis of human alveolar epithelial cells partly through activating the PI3K/Akt and ERK pathway and thereby might benefit alleviating septic ALI. -- Graphical abstract: Ghrelin ameliorates the human alveolar epithelial A549 cells apoptosis induced by lipopolysaccharide partly through activating the PI3K/Akt and ERK pathway. Display Omitted -- Highlights: •It has been observed that LPS insult significantly increased apoptosis in A549 cells. •Both Akt and ERK signaling are critical adapter molecules to mediate the ghrelin-mediated proliferative effect. •Ghrelin may have a therapeutic effect in the prevention of LPS-induced apoptosis.« less

All-trans retinoic acid results in irregular repair of septa and fails to inhibit proinflammatory macrophages.

PubMed

Seifart, C; Muyal, J P; Plagens, A; Yildirim, A Ö; Kohse, K; Grau, V; Sandu, S; Reinke, C; Tschernig, T; Vogelmeier, C; Fehrenbach, H

2011-08-01

All-trans retinoic acid (ATRA) is controversially discussed in emphysema therapy. We re-evaluated ATRA in the elastase model and hypothesised that beneficial effects should be reflected by increased alveolar surface area, elastin expression and downregulation of inflammatory mediators and matrix metalloproteinases (MMPs). Emphysema was induced by porcine pancreatic elastase versus saline in Sprague-Dawley rats. On days 26-37, rats received daily intraperitoneal injections with ATRA (500 μg · kg(-1) body weight) versus olive oil. Lungs were removed at day 38. Rat alveolar epithelial L2 cells were incubated with/without elastase followed by ATRA- or vehicle-treatment, respectively. ATRA only partially ameliorated structural defects. Alveolar walls exhibited irregular architecture: increased arithmetic mean thickness, reduction in surface coverage by alveolar epithelial cells type II. ATRA only partially restored reduced soluble elastin. It tended to increase the ratio of ED1(+):ED2(+) macrophages. Bronchoalveolar lavage (BAL) cells exhibited a proinflammatory state and high expression of interleukin-1β, cytokine-induced neutrophil chemoattractant-1, tumour necrosis factor-α, nuclear factor-κB, MMP-2, MMP-9, MMP-12, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 in emphysema, with ATRA exerting only few effects. MMP-7 was highly induced by ATRA in healthy but not in emphysematous lungs. ATRA reduced both MMP-2 and TIMP-1 activity in BAL fluid of emphysematous lungs. ATRA-therapy may bear the risk of unwanted side-effects on alveolar septal architecture in emphysematous lungs.

Inhibition of Prolyl Hydroxylase Attenuates Fas Ligand-Induced Apoptosis and Lung Injury in Mice.

PubMed

Nagamine, Yusuke; Tojo, Kentaro; Yazawa, Takuya; Takaki, Shunsuke; Baba, Yasuko; Goto, Takahisa; Kurahashi, Kiyoyasu

2016-12-01

Alveolar epithelial injury and increased alveolar permeability are hallmarks of acute respiratory distress syndrome. Apoptosis of lung epithelial cells via the Fas/Fas ligand (FasL) pathway plays a critical role in alveolar epithelial injury. Activation of hypoxia-inducible factor (HIF)-1 by inhibition of prolyl hydroxylase domain proteins (PHDs) is a possible therapeutic approach to attenuate apoptosis and organ injury. Here, we investigated whether treatment with dimethyloxalylglycine (DMOG), an inhibitor of PHDs, could attenuate Fas/FasL-dependent apoptosis in lung epithelial cells and lung injury. DMOG increased HIF-1α protein expression in vitro in MLE-12 cells, a murine alveolar epithelial cell line. Treatment of MLE-12 cells with DMOG significantly suppressed cell surface expression of Fas and attenuated FasL-induced caspase-3 activation and apoptotic cell death. Inhibition of the HIF-1 pathway by echinomycin or small interfering RNA transfection abolished these antiapoptotic effects of DMOG. Moreover, intraperitoneal injection of DMOG in mice increased HIF-1α expression and decreased Fas expression in lung tissues. DMOG treatment significantly attenuated caspase-3 activation, apoptotic cell death in lung tissue, and the increase in alveolar permeability in mice instilled intratracheally with FasL. In addition, inflammatory responses and histopathological changes were also significantly attenuated by DMOG treatment. In conclusion, inhibition of PHDs protects lung epithelial cells from Fas/FasL-dependent apoptosis through HIF-1 activation and attenuates lung injury in mice.

Melanocortin agonism as a viable strategy to control alveolar bone loss induced by oral infection.

PubMed

Madeira, Mila F M; Queiroz-Junior, Celso M; Montero-Melendez, Trinidad; Werneck, Silvia M C; Corrêa, Jôice D; Soriani, Frederico M; Garlet, Gustavo P; Souza, Daniele G; Teixeira, Mauro M; Silva, Tarcilia A; Perretti, Mauro

2016-12-01

Alveolar bone loss is a result of an aggressive form of periodontal disease (PD) associated with Aggregatibacter actinomycetemcomitans (Aa) infection. PD is often observed with other systemic inflammatory conditions, including arthritis. Melanocortin peptides activate specific receptors to exert antiarthritic properties, avoiding excessing inflammation and modulating macrophage function. Recent work has indicated that melanocortin can control osteoclast development and function, but whether such protection takes place in infection-induced alveolar bone loss has not been investigated. The purpose of this study was to evaluate the role of melanocortin in Aa-induced PD. Mice were orally infected with Aa and treated with the melanocortin analog DTrp 8 -γMSH or vehicle daily for 30 d. Then, periodontal tissue was collected and analyzed. Aa-infected mice treated with DTrp 8 -γMSH presented decreased alveolar bone loss and a lower degree of neutrophil infiltration in the periodontium than vehicle-treated animals; these actions were associated with reduced periodontal levels of TNF-α, IFN-γ, and IL-17A. In vitro experiments with cells differentiated into osteoclasts showed that osteoclast formation and resorptive activity were attenuated after treatment with DTrp 8 -γMSH. Thus, melanocortin agonism could represent an innovative way to tame overexuberant inflammation and, at the same time, preserve bone physiology, as seen after Aa infection.-Madeira, M. F. M., Queiroz-Junior, C. M., Montero-Melendez, T., Werneck, S. M. C., Corrêa, J. D., Soriani, F. M., Garlet, G. P., Souza, D. G., Teixeira, M. M., Silva, T. A., Perretti, M. Melanocortin agonism as a viable strategy to control alveolar bone loss induced by oral infection. © FASEB.

iNOS-Derived Nitric Oxide Stimulates Osteoclast Activity and Alveolar Bone Loss in Ligature-Induced Periodontitis in Rats

PubMed Central

Herrera, Bruno S.; Martins-Porto, Rodrigo; Maia-Dantas, Aline; Campi, Paula; Spolidorio, Luis C.; Costa, Soraia K.P.; Van Dyke, Thomas E.; Gyurko, Robert; Muscara, Marcelo N.

2012-01-01

Background Inflammatory stimuli activate inducible nitric oxide synthase (iNOS) in a variety of cell types, including osteoclasts (OC) and osteoblasts, resulting in sustained NO production. In this study, we evaluate the alveolar bone loss in rats with periodontitis under long-term iNOS inhibition, and the differentiation and activity of OC from iNOS-knockout (KO) mice in vitro. Methods Oral aminoguanidine (an iNOS inhibitor) or water treatment was started 2 weeks before induction of periodontitis. Rats were sacrificed 3, 7, or 14 days after ligature placement, and alveolar bone loss was evaluated. In vitro OC culture experiments were also performed to study the differentiation of freshly isolated bone marrow cells from both iNOS KO and wild-type C57BL/6 mice. OC were counted 6 days later after tartrate-resistant acid phosphatase staining (a marker of osteoclast identity), and bone resorption activity was assessed by counting the number of resorption pits on dentin disks. Results Rats with ligature showed progressive and significant alveolar bone loss compared to sham animals, and aminoguanidine treatment significantly inhibited ligature-induced bone loss at 7 and 14 days after the induction. In comparison to bone marrow cells from wild-type mice, cells from iNOS KO mice showed decreased OC growth and the resulting OC covered a smaller culture dish area and generated fewer resorption pit counts. Conclusion Our results demonstrate that iNOS inhibition prevents alveolar bone loss in a rat model of ligature-induced periodontitis, thus confirming that iNOS-derived NO plays a crucial role in the pathogenesis of periodontitis, probably by stimulating OC differentiation and activity. PMID:21417589

Lungs in Heart Failure

PubMed Central

Apostolo, Anna; Giusti, Giuliano; Gargiulo, Paola; Bussotti, Maurizio; Agostoni, Piergiuseppe

2012-01-01

Lung function abnormalities both at rest and during exercise are frequently observed in patients with chronic heart failure, also in the absence of respiratory disease. Alterations of respiratory mechanics and of gas exchange capacity are strictly related to heart failure. Severe heart failure patients often show a restrictive respiratory pattern, secondary to heart enlargement and increased lung fluids, and impairment of alveolar-capillary gas diffusion, mainly due to an increased resistance to molecular diffusion across the alveolar capillary membrane. Reduced gas diffusion contributes to exercise intolerance and to a worse prognosis. Cardiopulmonary exercise test is considered the “gold standard” when studying the cardiovascular, pulmonary, and metabolic adaptations to exercise in cardiac patients. During exercise, hyperventilation and consequent reduction of ventilation efficiency are often observed in heart failure patients, resulting in an increased slope of ventilation/carbon dioxide (VE/VCO2) relationship. Ventilatory efficiency is as strong prognostic and an important stratification marker. This paper describes the pulmonary abnormalities at rest and during exercise in the patients with heart failure, highlighting the principal diagnostic tools for evaluation of lungs function, the possible pharmacological interventions, and the parameters that could be useful in prognostic assessment of heart failure patients. PMID:23365739

Acyloxyacyl hydrolase promotes the resolution of lipopolysaccharide-induced acute lung injury

PubMed Central

Tang, Zihui; Yang, Qian; Qian, Guojun; Qian, Jing; Zeng, Wenjiao; Gu, Jie; Chu, Tianqing; Zhu, Ning; Zhang, Wenhong; Yan, Dapeng; He, Rui; Chu, Yiwei

2017-01-01

Pulmonary infection is the most common risk factor for acute lung injury (ALI). Innate immune responses induced by Microbe-Associated Molecular Pattern (MAMP) molecules are essential for lung defense but can lead to tissue injury. Little is known about how MAMP molecules are degraded in the lung or how MAMP degradation/inactivation helps prevent or ameliorate the harmful inflammation that produces ALI. Acyloxyacyl hydrolase (AOAH) is a host lipase that inactivates Gram-negative bacterial endotoxin (lipopolysaccharide, or LPS). We report here that alveolar macrophages increase AOAH expression upon exposure to LPS and that Aoah+/+ mice recover more rapidly than do Aoah-/- mice from ALI induced by nasally instilled LPS or Klebsiella pneumoniae. Aoah-/- mouse lungs had more prolonged leukocyte infiltration, greater pro- and anti-inflammatory cytokine expression, and longer-lasting alveolar barrier damage. We also describe evidence that the persistently bioactive LPS in Aoah-/- alveoli can stimulate alveolar macrophages directly and epithelial cells indirectly to produce chemoattractants that recruit neutrophils to the lung and may prevent their clearance. Distinct from the prolonged tolerance observed in LPS-exposed Aoah-/- peritoneal macrophages, alveolar macrophages that lacked AOAH maintained or increased their responses to bioactive LPS and sustained inflammation. Inactivation of LPS by AOAH is a previously unappreciated mechanism for promoting resolution of pulmonary inflammation/injury induced by Gram-negative bacterial infection. PMID:28622363

Morpho-histological assessment of the periodontal support structures under the action of excessive occlusal forces and under the influence of nicotine.

PubMed

Ispas, Ana; Mihu, Carmen Mihaela; Crăciun, Antarinia Maria; Constantiniuc, Mariana

2018-01-01

Smoking and occlusal trauma are two factors that can interfere with bone homeostasis. The aim of this study was to evaluate the histocellular changes occurring in the periodontal ligament and alveolar bone during the action of excessive occlusal forces, and to assess the influence of nicotine on the alveolar bone loss in teeth subjected to occlusal trauma. Fifty-six Wistar rats were randomized into seven groups (n=8). Animals were exposed to nicotine and occlusal trauma for 7, 14 and 30 days. Three groups were exposed to occlusal trauma alone, another three groups were exposed to occlusal trauma and nicotine, and one group was not exposed to any treatment. Periodontal lesions induced in the first stage (7-14 days) manifested by a moderate increase of the periodontal space, a multiplication, thickening and elongation of periodontal fibers, as well as their condensation in the middle area of the periradicular space. Regarding bone changes induced by occlusal trauma, groups 5 and 7 (occlusal trauma and nicotine administration) had higher bone losses compared to groups 1, 2, 3, 4 and 6. This study demonstrated that nicotine significantly affected the alveolar bone. The induced occlusal trauma caused obvious tissue damage. At the same time, it was found that nicotine enhanced alveolar bone resorption, increased tooth mobility and induced an exacerbation of inflammatory processes.

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.

Genistein suppresses Prevotella intermedia lipopolysaccharide-induced inflammatory response in macrophages and attenuates alveolar bone loss in ligature-induced periodontitis.

PubMed

Choi, Eun-Young; Bae, Seung Han; Ha, Min Hee; Choe, So-Hui; Hyeon, Jin-Yi; Choi, Jeom-Il; Choi, In Soon; Kim, Sung-Jo

2016-02-01

Genistein is a major isoflavone subclass of flavonoids found in soybean and a potent tyrosine kinase inhibitor. The present study aimed to assess the effect of genistein on the production of proinflammatory mediators in murine macrophages stimulated with lipopolysaccharide (LPS) isolated from Prevotella intermedia, a pathogen associated with different forms of periodontal disease, and to evaluate its possible influence on alveolar bone loss in ligature-induced periodontitis using micro-computed tomography (micro-CT) analysis as well. LPS was isolated from P. intermedia ATCC 25611 by using the standard hot phenol-water method. Culture supernatants were analyzed for nitric oxide (NO) and interleukin-6 (IL-6). Inducible NO synthase (iNOS) protein expression was evaluated by immunoblot analysis. Real-time PCR was carried out to measure iNOS and IL-6 mRNA expression. In addition, effect of genistein on alveolar bone loss was evaluated in a rat model of experimental periodontitis using micro-CT analysis. Genistein significantly attenuated P. intermedia LPS-induced production of iNOS-derived NO and IL-6 with attendant decrease in their mRNA expression in RAW264.7 cells. In addition, when genistein was administered to rats, decreases in alveolar bone height and bone volume fraction induced by ligature placement were significantly inhibited. Genistein administration also prevented ligature-induced alterations in the microstructural parameters of trabecular bone, including trabecular thickness, trabecular separation, bone mineral density and structure model index. While additional studies are required, we suggest that genistein could be utilized for the therapy of human periodontitis in the future. Copyright © 2015 Elsevier Ltd. All rights reserved.

Mycobacterium tuberculosis infection causes different levels of apoptosis and necrosis in human macrophages and alveolar epithelial cells.

PubMed

Danelishvili, Lia; McGarvey, Jeffery; Li, Yong-Jun; Bermudez, Luiz E

2003-09-01

Mycobacterium tuberculosis interacts with macrophages and epithelial cells in the alveolar space of the lung, where it is able to invade and replicate in both cell types. M. tuberculosis-associated cytotoxicity to these cells has been well documented, but the mechanisms of host cell death are not well understood. We examined the induction of apoptosis and necrosis of human macrophages (U937) and type II alveolar epithelial cells (A549) by virulent (H37Rv) and attenuated (H37Ra) M. tuberculosis strains. Apoptosis was determined by both enzyme-linked immunosorbent assay (ELISA) and TdT-mediated dUTP nick end labelling (TUNEL) assay, whereas necrosis was evaluated by the release of lactate dehydrogenase (LDH). Both virulent and attenuated M. tuberculosis induced apoptosis in macrophages; however, the attenuated strain resulted in significantly more apoptosis than the virulent strain after 5 days of infection. In contrast, cytotoxicity of alveolar cells was the result of necrosis, but not apoptosis. Although infection with M. tuberculosis strains resulted in apoptosis of 14% of the cells on the monolayer, cell death associated with necrosis was observed in 59% of alveolar epithelial cells after 5 days of infection. Infection with M. tuberculosis suppressed apoptosis of alveolar epithelial cells induced by the kinase inhibitor, staurosporine. Because our findings suggest that M. tuberculosis can modulate the apoptotic response of macrophages and epithelial cells, we carried out an apoptosis pathway-specific cDNA microarray analysis of human macrophages and alveolar epithelial cells. Whereas the inhibitors of apoptosis, bcl-2 and Rb, were upregulated over 2.5-fold in infected (48 h) alveolar epithelial cells, the proapoptotic genes, bad and bax, were downregulated. The opposite was observed when U937 macrophages were infected with M. tuberculosis. Upon infection of alveolar epithelial cells with M. tuberculosis, the generation of apoptosis, as determined by the expression of caspase-1, caspase-3 and caspase-10, was inhibited. Inhibition of replication of intracellular bacteria resulted in an increase in apoptosis in both cell types. Our results showed that the differential induction of apoptosis between macrophages and alveolar epithelial cells represents specific strategies of M. tuberculosis for survival in the host.

Lycium barbarum polysaccharide protects against LPS-induced ARDS by inhibiting apoptosis, oxidative stress, and inflammation in pulmonary endothelial cells.

PubMed

Chen, Lan; Li, Wen; Qi, Di; Wang, Daoxin

2018-04-01

Acute respiratory distress syndrome (ARDS) is a heterogenous syndrome characterised by diffuse alveolar damage, with an increase in lung endothelial and epithelial permeability. Lycium barbarum polysaccharide (LBP), the most biologically active fraction of wolfberry, possesses antiapoptotic and antioxidative effects in distinct situations. In the present study, the protective effects and potential molecular mechanisms of LBP against lipopolysaccharide (LPS)-induced ARDS were investigated in the mice and in the human pulmonary microvascular endothelial cells (HPMECs). The data indicated that pretreatment with LBP significantly attenuated LPS-induced lung inflammation and pulmonary oedema in vivo. LBP significantly reversed LPS-induced decrease in cell viability, increase in apoptosis and oxidative stress via inhibiting caspase-3 activation and intracellular reactive oxygen species (ROS) production in vitro. Moreover, the scratch assay verified that LBP restored the dysfunction of endothelial cells (ECs) migration induced by LPS stimulation. Furthermore, LBP also significantly suppressed LPS-induced NF-κB activation, and subsequently reversed the release of cytochrome c. These results showed the antiapoptosis and antioxidant LBP could partially protect against LPS-induced ARDS through promoting the ECs survival and scavenging ROS via inhibition of NF-κB signalling pathway. Thus, LBP could be potentially used for ARDS against pulmonary inflammation and pulmonary oedema.

[Cleft lip, alveolar and palate sequelae. Proposal of new alveolar score by the Alveolar Cleft Score (ACS) classification].

PubMed

Molé, C; Simon, E

2015-06-01

The management of cleft lip, alveolar and palate sequelae remains problematic today. To optimize it, we tried to establish a new clinical index for diagnostic and prognostic purposes. Seven tissue indicators, that we consider to be important in the management of alveolar sequelae, are listed by assigning them individual scores. The final score, obtained by adding together the individual scores, can take a low, high or maximum value. We propose a new classification (ACS: Alveolar Cleft Score) that guides the therapeutic team to a prognosis approach, in terms of the recommended surgical and prosthetic reconstruction, the type of medical care required, and the preventive and supportive therapy to establish. Current studies are often only based on a standard radiological evaluation of the alveolar bone height at the cleft site. However, the gingival, the osseous and the cellular areas bordering the alveolar cleft sequelae induce many clinical parameters, which should be reflected in the morphological diagnosis, to better direct the surgical indications and the future prosthetic requirements, and to best maintain successful long term aesthetic and functional results. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

An uptake of cationized ferritin by alveolar type I cells in airway-instilled goat lung: distribution of anionic sites on the epithelial surface.

PubMed

Atwal, O S; Viel, L; Minhas, K J

1990-07-01

The present study has investigated ultrastructural localization of anionic sites on the luminal surface of the alveolar epithelium of goat lung by direct airway instillation of cationized ferritin (CF) in the cranial lobe of the right lung through a bronchoscope. The cationic probe decorated preferentially the luminal plasmalemmal vesicles and plasmalemma proper of alveolar type I cell. This indicated the presence of highly charged anionic microdomains at these binding sites. The ligand was internalized in the free plasmalemmal vesicles of alveolar type I cell within 2 min. Heavy decoration of vesicles at 5 min of perfusion indicated that the amount of CF internalization increased with its concentration in the alveoli. It is suggested that exposure of alveolar surface to several gases of ruminal-origin induces changes in the surface charge of luminal plasmalemma of alveolar type I cells. The significance of these anionic plasmalemmal sites is discussed in relation to the adjustment of osmotic pressure gradient across the alveolar-capillary membrane of the ruminant lung.

Remodeling of alveolar bone crest after molar intrusion with skeletal anchorage system in dogs.

PubMed

Kanzaki, Reiko; Daimaruya, Takayoshi; Takahashi, Ichiro; Mitani, Hideo; Sugawara, Junji

2007-03-01

The aim of this study was to clarify the influence of supra-alveolar fibers on alveolar bone crest remodeling when several teeth are intruded simultaneously. The skeletal anchorage system was used to bilaterally intrude the second and third premolars of 10 beagles; supracrestal fiberotomies were performed on 1 side only. The amount of intrusion was greater and the amount of alveolar bone resorption was smaller in the fiberotomy group compared with the nonfiberotomy group. The health status (pocket depth <3 mm) of the dentogingival unit was maintained in the nonfiberotomy group during the experimental period. In the fiberotomy group, the number of osteoclasts on the marginal alveolar crest was less than in the nonfiberotomy group. The dense fiber bundles connecting the second and third premolars and the gingival attachments were maintained in the nonfiberotomy group. Pressure from the supra-alveolar fibers generated by segmental molar intrusion with the skeletal anchorage system induced alveolar bone crest resorption and remodeling, and, as a result, it prevented deepening of the gingival pocket. Periodontal status was good during tooth intrusion.

Probing sub-alveolar length scales with hyperpolarized-gas diffusion NMR

NASA Astrophysics Data System (ADS)

Miller, Wilson; Carl, Michael; Mooney, Karen; Mugler, John; Cates, Gordon

2009-05-01

Diffusion MRI of the lung is a promising technique for detecting alterations of normal lung microstructure in diseases such as emphysema. The length scale being probed using this technique is related to the time scale over which the helium-3 or xenon-129 diffusion is observed. We have developed new MR pulse sequence methods for making diffusivity measurements at sub-millisecond diffusion times, allowing one to probe smaller length scales than previously possible in-vivo, and opening the possibility of making quantitative measurements of the ratio of surface area to volume (S/V) in the lung airspaces. The quantitative accuracy of simulated and experimental measurements in microstructure phantoms will be discussed, and preliminary in-vivo results will be presented.

Fine ambient particles induce oxidative stress and metal binding genes in human alveolar machrophages

EPA Science Inventory

Exposure to ambient pollutant particles (APP) increased respiratory morbidity and mortality. The alveolar macrophages (AMs) are one cell type in the lung directly exposed to APP. Upon contact with APP, AMs are activated and produce reactive oxygen species, but the scope ofthis ox...

Pulmonary effects of synthetic marijuana: chest radiography and CT findings.

PubMed

Berkowitz, Eugene A; Henry, Travis S; Veeraraghavan, Srihari; Staton, Gerald W; Gal, Anthony A

2015-04-01

The purpose of this article is to present the first chest radiographic and CT descriptions of organizing pneumonia in response to smoking synthetic marijuana. Chest radiographs showed a diffuse miliary-micronodular pattern. Chest CT images showed diffuse centrilobular nodules and tree-in-bud pattern and a histopathologic pattern of organizing pneumonia with or without patchy acute alveolar damage. This distinct imaging pattern should alert radiologists to include synthetic marijuana abuse in the differential diagnosis.

The Ets transcription factor Elf5 specifies mammary alveolar cell fate

PubMed Central

Oakes, Samantha R.; Naylor, Matthew J.; Asselin-Labat, Marie-Liesse; Blazek, Katrina D.; Gardiner-Garden, Margaret; Hilton, Heidi N.; Kazlauskas, Michael; Pritchard, Melanie A.; Chodosh, Lewis A.; Pfeffer, Peter L.; Lindeman, Geoffrey J.; Visvader, Jane E.; Ormandy, Christopher J.

2008-01-01

Hormonal cues regulate mammary development, but the consequent transcriptional changes and cell fate decisions are largely undefined. We show that knockout of the prolactin-regulated Ets transcription factor Elf5 prevented formation of the secretory epithelium during pregnancy. Conversely, overexpression of Elf5 in an inducible transgenic model caused alveolar differentiation and milk secretion in virgin mice, disrupting ductal morphogenesis. CD61+ luminal progenitor cells accumulated in Elf5-deficient mammary glands and were diminished in glands with Elf5 overexpression. Thus Elf5 specifies the differentiation of CD61+ progenitors to establish the secretory alveolar lineage during pregnancy, providing a link between prolactin, transcriptional events, and alveolar development. PMID:18316476

Surgical lung biopsy to diagnose Behcet's vasculitis with adult respiratory distress syndrome.

PubMed

Vydyula, Ravikanth; Allred, Charles; Huartado, Mariana; Mina, Bushra

2014-10-01

A 34-year-old female presented with fever and abdominal pain. Past medical history includes Crohn's and Behcet's disease. Examination revealed multiple skin ulcerations, oral aphthae, and bilateral coarse rales. She developed respiratory distress with diffuse bilateral alveolar infiltrates on chest radiograph requiring intubation. PaO2/FiO2 ratio was 132. The chest computed tomography revealed extensive nodular and patchy ground-glass opacities. Bronchoalveolar lavage demonstrated a predominance of neutrophils. Methylprednisolone 60 mg every 6 h and broad-spectrum antimicrobials were initiated. No infectious etiologies were identified. Surgical lung biopsy demonstrated diffuse alveolar damage (DAD) mixed with lymphocytic and necrotizing vasculitis with multiple small infarcts and thrombi consistent with Behcet's vasculitis. As she improved, steroids were tapered and discharged home on oral cyclophosphamide. Pulmonary involvement in Behcet's is unusual and commonly manifests as pulmonary artery aneurysms, thrombosis, infarction, and hemorrhage. Lung biopsy findings demonstrating DAD are consistent with the clinical diagnosis of adult respiratory distress syndrome. The additional findings of necrotizing vasculitis and infarcts may have led to DAD.

Dynamics of Gas Exchange through the Fractal Architecture of the Human Lung, Modeled as an Exactly Solvable Hierarchical Tree

NASA Astrophysics Data System (ADS)

Mayo, Michael; Pfeifer, Peter; Gheorghiu, Stefan

2008-03-01

The acinar airways lie at the periphery of the human lung and are responsible for the transfer of oxygen from air to the blood during respiration. This transfer occurs by the diffusion-reaction of oxygen over the irregular surface of the alveolar membranes lining the acinar airways. We present an exactly solvable diffusion-reaction model on a hierarchically branched tree, allowing a quantitative prediction of the oxygen current over the entire system of acinar airways responsible for the gas exchange. We discuss the effect of diffusional screening, which is strongly coupled to oxygen transport in the human lung. We show that the oxygen current is insensitive to a loss of permeability of the alveolar membranes over a wide range of permeabilities, similar to a ``constant-current source'' in an electric network. Such fault tolerance has been observed in other treatments of the gas exchange in the lung and is obtained here as a fully analytical result.

Acute interstitial pneumonia (AIP): relationship to Hamman-Rich syndrome, diffuse alveolar damage (DAD), and acute respiratory distress syndrome (ARDS).

PubMed

Mukhopadhyay, Sanjay; Parambil, Joseph G

2012-10-01

Acute interstitial pneumonia (AIP) is a term used for an idiopathic form of acute lung injury characterized clinically by acute respiratory failure with bilateral lung infiltrates and histologically by diffuse alveolar damage (DAD), a combination of findings previously known as the Hamman-Rich syndrome. This review aims to clarify the diagnostic criteria of AIP, its relationship with DAD and acute respiratory distress syndrome (ARDS), key etiologies that need to be excluded before making the diagnosis, and the salient clinical features. Cases that meet clinical and pathologic criteria for AIP overlap substantially with those that fulfill clinical criteria for ARDS. The main differences between AIP and ARDS are that AIP requires a histologic diagnosis of DAD and exclusion of known etiologies. AIP should also be distinguished from "acute exacerbation of IPF," a condition in which acute lung injury (usually DAD) supervenes on underlying usual interstitial pneumonia (UIP)/idiopathic pulmonary fibrosis (IPF). Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Exercise-induced bronchoconstriction alters airway nitric oxide exchange in a pattern distinct from spirometry.

PubMed

Shin, Hye-Won; Schwindt, Christina D; Aledia, Anna S; Rose-Gottron, Christine M; Larson, Jennifer K; Newcomb, Robert L; Cooper, Dan M; George, Steven C

2006-12-01

Exhaled nitric oxide (NO) is altered in asthmatic subjects with exercise-induced bronchoconstriction (EIB). However, the physiological interpretation of exhaled NO is limited because of its dependence on exhalation flow and the inability to distinguish completely proximal (large airway) from peripheral (small airway and alveolar) contributions. We estimated flow-independent NO exchange parameters that partition exhaled NO into proximal and peripheral contributions at baseline, postexercise challenge, and postbronchodilator administration in steroid-naive mild-intermittent asthmatic subjects with EIB (24-43 yr old, n = 9) and healthy controls (20-31 yr old, n = 9). The mean +/- SD maximum airway wall flux and airway diffusing capacity were elevated and forced expiratory flow, midexpiratory phase (FEF(25-75)), forced expiratory volume in 1 s (FEV(1)), and FEV(1)/forced vital capacity (FVC) were reduced at baseline in subjects with EIB compared with healthy controls, whereas the steady-state alveolar concentration of NO and FVC were not different. Compared with the response of healthy controls, exercise challenge significantly reduced FEV(1) (-23 +/- 15%), FEF(25-75) (-37 +/- 18%), FVC (-12 +/- 12%), FEV(1)/FVC (-13 +/- 8%), and maximum airway wall flux (-35 +/- 11%) relative to baseline in subjects with EIB, whereas bronchodilator administration only increased FEV(1) (+20 +/- 21%), FEF(25-75) (+56 +/- 41%), and FEV(1)/FVC (+13 +/- 9%). We conclude that mild-intermittent steroid-naive asthmatic subjects with EIB have altered airway NO exchange dynamics at baseline and after exercise challenge but that these changes occur by distinct mechanisms and are not correlated with alterations in spirometry.

Microlithiasis of Seminal Vesicles and Severe Oligoasthenospermia in Pulmonary Alveolar Microlithiasis (PAM): Report of An Unusual Sporadic Case.

PubMed

Castellana, Giuseppe; Carone, Domenico; Castellana, Marco

2015-01-01

Pulmonary alveolar microlithiasis (PAM) is classified as an elective dysmetabolic thesaurotic pneumoalveolitis and characterized by the presence within the alveoli of the lungs of myriad of tiny calculi. The classic presentation of the chest radiography is unmistakable with multiple small "sand-like" opacities diffusely involving both lung fields. We present a case of male infertility for hypoposia and severe oligoasthenospermia in a young patient with recurrent haematuria and small calcifications in the seminal vesicles similar to pulmonary microliths. PAM was diagnosed on routine chest radiography, com- puter tomography (CT), transbronchial biopsy and bronchoalveolar lavage (BAL).

Nitric oxide donor restores lung growth factor and receptor expression in hyperoxia-exposed rat pups.

PubMed

Lopez, Emmanuel; Boucherat, Olivier; Franco-Montoya, Marie-Laure; Bourbon, Jacques R; Delacourt, Christophe; Jarreau, Pierre-Henri

2006-06-01

Exposure of newborn rats to hyperoxia impairs alveolarization. Nitric oxide (NO) may prevent this evolution. Angiogenesis and factors involved in this process, but also other growth factors (GFs) involved in alveolar development, are likely potential therapeutic targets for NO. We studied the effects of the NO donor, [Z]-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)aminio]diazen-1-ium-1, 2-diolate, also termed DETANONOate (D-NO), on hyperoxia-induced changes in key regulatory factors of alveolar development in neonatal rats, and its possible preventive effect on the physiologic consequences of hyperoxia. Newborn rat pups were randomized at birth to hyperoxia (> 95% O2) or room air exposure for 6 or 10 d, while receiving D-NO or its diluent. On Day 6, several GFs and their receptors were studied at pre- and/or post-translational levels. Elastin transcript determination on Day 6, and elastin deposition in tissue and morphometric analysis of the lungs on Day 10, were also performed. Hyperoxia decreased the expression of vascular endothelial growth factor (VEGF) receptor (VEGFR) 2, fibroblast growth factor (FGF)-18, and FGF receptors (FGFRs) FGFR3 and FGFR4, increased mortality, and impaired alveolarization and capillary growth. D-NO treatment of hyperoxia-exposed pups restored the expression level of FGF18 and FGFR4, induced an increase of both VEGF mRNA and protein, enhanced elastin expression, and partially restored elastin deposition in alveolar walls. Although, under the present conditions, D-NO failed to prevent the physiologic consequences of hyperoxia in terms of survival and lung alveolarization, our findings demonstrate molecular effects of NO on GFs involved in alveolar development that may have contributed to the protective effects previously reported for NO.

Protectin DX increases alveolar fluid clearance in rats with lipopolysaccharide-induced acute lung injury.

PubMed

Zhuo, Xiao-Jun; Hao, Yu; Cao, Fei; Yan, Song-Fan; Li, Hui; Wang, Qian; Cheng, Bi-Huan; Ying, Bin-Yu; Smith, Fang Gao; Jin, Sheng-Wei

2018-04-27

Acute respiratory distress syndrome is a life-threatening critical syndrome resulting largely from the accumulation of and the inability to clear pulmonary edema. Protectin DX, an endogenously produced lipid mediator, is believed to exert anti-inflammatory and pro-resolution effects. Protectin DX (5 µg/kg) was injected i.v. 8 h after LPS (14 mg/kg) administration, and alveolar fluid clearance was measured in live rats (n = 8). In primary rat ATII epithelial cells, protectin DX (3.605 × 10 -3  mg/l) was added to the culture medium with LPS for 6 h. Protectin DX improved alveolar fluid clearance (9.65 ± 1.60 vs. 15.85 ± 1.49, p < 0.0001) and decreased pulmonary edema and lung injury in LPS-induced lung injury in rats. Protectin DX markedly regulated alveolar fluid clearance by upregulating sodium channel and Na, K-ATPase protein expression levels in vivo and in vitro. Protectin DX also increased the activity of Na, K-ATPase and upregulated P-Akt via inhibiting Nedd4-2 in vivo. In addition, protectin DX enhanced the subcellular distribution of sodium channels and Na, K-ATPase, which were specifically localized to the apical and basal membranes of primary rat ATII cells. Furthermore, BOC-2, Rp-cAMP, and LY294002 blocked the increased alveolar fluid clearance in response to protectin DX. Protectin DX stimulates alveolar fluid clearance through a mechanism partly dependent on alveolar epithelial sodium channel and Na, K-ATPase activation via the ALX/PI3K/Nedd4-2 signaling pathway.

A co-culture system with an organotypic lung slice and an immortal alveolar macrophage cell line to quantify silica-induced inflammation.

PubMed

Hofmann, Falk; Bläsche, Robert; Kasper, Michael; Barth, Kathrin

2015-01-01

There is growing evidence that amorphous silica nanoparticles cause toxic effects on lung cells in vivo as well as in vitro and induce inflammatory processes. The phagocytosis of silica by alveolar macrophages potentiates these effects. To understand the underlying molecular mechanisms of silica toxicity, we applied a co-culture system including the immortal alveolar epithelial mouse cell line E10 and the macrophage cell line AMJ2-C11. In parallel we exposed precision-cut lung slices (lacking any blood cells as well as residual alveolar macrophages) of wild type and P2rx7-/- mice with or without AMJ2-C11 cells to silica nanoparticles. Exposure of E10 cells as well as slices of wild type mice resulted in an increase of typical alveolar epithelial type 1 cell proteins like T1α, caveolin-1 and -2 and PKC-β1, whereas the co-culture with AMJ2-C11 showed mostly a slightly lesser increase of these proteins. In P2rx7-/- mice most of these proteins were slightly decreased. ELISA analysis of the supernatant of wild type and P2rx7-/- mice precision-cut lung slices showed decreased amounts of IL-6 and TNF-α when incubated with nano-silica. Our findings indicate that alveolar macrophages influence the early inflammation of the lung and also that cell damaging reagents e.g. silica have a smaller impact on P2rx7-/- mice than on wild type mice. The co-culture system with an organotypic lung slice is a useful tool to study the role of alveolar macrophages during lung injury at the organoid level.

Real-time imaging of inflation-induced ATP release in the ex vivo rat lung.

PubMed

Furuya, Kishio; Tan, Ju Jing; Boudreault, Francis; Sokabe, Masahiro; Berthiaume, Yves; Grygorczyk, Ryszard

2016-11-01

Extracellular ATP and other nucleotides are important autocrine/paracrine mediators that regulate diverse processes critical for lung function, including mucociliary clearance, surfactant secretion, and local blood flow. Cellular ATP release is mechanosensitive; however, the impact of physical stimuli on ATP release during breathing has never been tested in intact lungs in real time and remains elusive. In this pilot study, we investigated inflation-induced ATP release in rat lungs ex vivo by real-time luciferin-luciferase (LL) bioluminescence imaging coupled with simultaneous infrared tissue imaging to identify ATP-releasing sites. With LL solution introduced into air spaces, brief inflation of such edematous lung (1 s, ∼20 cmH 2 O) induced transient (<30 s) ATP release in a limited number of air-inflated alveolar sacs during their recruitment/opening. Released ATP reached concentrations of ∼10 -6 M, relevant for autocrine/paracrine signaling, but it remained spatially restricted to single alveolar sacs or their clusters. ATP release was stimulus dependent: prolonged (100 s) inflation evoked long-lasting ATP release that terminated upon alveoli deflation/derecruitment while cyclic inflation/suction produced cyclic ATP release. With LL introduced into blood vessels, inflation induced transient ATP release in many small patchlike areas the size of alveolar sacs. Findings suggest that inflation induces ATP release in both alveoli and the surrounding blood capillary network; the functional units of ATP release presumably consist of alveolar sacs or their clusters. Our study demonstrates the feasibility of real-time ATP release imaging in ex vivo lungs and provides the first direct evidence of inflation-induced ATP release in lung air spaces and in pulmonary blood capillaries, highlighting the importance of purinergic signaling in lung function. Copyright © 2016 the American Physiological Society.

Identification of periplakin as a major regulator of lung injury and repair in mice

PubMed Central

Besnard, Valérie; Dagher, Rania; Madjer, Tania; Joannes, Audrey; Jaillet, Madeleine; Kolb, Martin; Bonniaud, Philippe; Murray, Lynne A.; Sleeman, Matthew A.

2018-01-01

Periplakin is a component of the desmosomes that acts as a cytolinker between intermediate filament scaffolding and the desmosomal plaque. Periplakin is strongly expressed by epithelial cells in the lung and is a target antigen for autoimmunity in idiopathic pulmonary fibrosis. The aim of this study was to determine the role of periplakin during lung injury and remodeling in a mouse model of lung fibrosis induced by bleomycin. We found that periplakin expression was downregulated in the whole lung and in alveolar epithelial cells following bleomycin-induced injury. Deletion of the Ppl gene in mice improved survival and reduced lung fibrosis development after bleomycin-induced injury. Notably, Ppl deletion promoted an antiinflammatory alveolar environment linked to profound changes in type 2 alveolar epithelial cells, including overexpression of antiinflammatory cytokines, decreased expression of profibrotic mediators, and altered cell signaling with a reduced response to TGF-β1. These results identify periplakin as a previously unidentified regulator of the response to injury in the lung. PMID:29515024

ISOZYMES OF ACID PHOSPHATASE IN NORMAL AND CALMETTE-GUÉRIN BACILLUS-INDUCED RABBIT ALVEOLAR MACROPHAGES

PubMed Central

Axline, S. G.

1968-01-01

The acid phosphatase activity of normal alveolar and BCG-induced alveolar macrophages has been examined. Five electrophoretically distinct forms of acid phosphatase have been identified in both normal and BCG-induced macrophages. The acid phosphatases can be divided into two major categories. One category, containing four distinct forms, is readily solubilized after repeated freezing and thawing or mechanical disruption The second category, containing one form, is firmly bound to the lysosomal membrane and can be solubilized by treatment of the lysosomal fraction with Triton X-100. The Triton-extractable acid phosphatase and the predominant aqueous soluble acid phosphatase have been shown to differ in the degree of membrane binding, in solubility, in net charge, and in molecular weight. The two pre-dominant phosphatases possess identical pH optimum and do not differ in response to enzyme inhibitors. BCG stimulation has been shown to result in a nearly twofold increase in acid phosphatase activity. A nearly proportionate increase in the major acid phosphatase forms has been observed. PMID:4878908

Existence, functional impairment, and lung repair potential of endothelial colony-forming cells in oxygen-induced arrested alveolar growth.

PubMed

Alphonse, Rajesh S; Vadivel, Arul; Fung, Moses; Shelley, William Chris; Critser, Paul John; Ionescu, Lavinia; O'Reilly, Megan; Ohls, Robin K; McConaghy, Suzanne; Eaton, Farah; Zhong, Shumei; Yoder, Merv; Thébaud, Bernard

2014-05-27

Bronchopulmonary dysplasia and emphysema are life-threatening diseases resulting from impaired alveolar development or alveolar destruction. Both conditions lack effective therapies. Angiogenic growth factors promote alveolar growth and contribute to alveolar maintenance. Endothelial colony-forming cells (ECFCs) represent a subset of circulating and resident endothelial cells capable of self-renewal and de novo vessel formation. We hypothesized that resident ECFCs exist in the developing lung, that they are impaired during arrested alveolar growth in experimental bronchopulmonary dysplasia, and that exogenous ECFCs restore disrupted alveolar growth. Human fetal and neonatal rat lungs contain ECFCs with robust proliferative potential, secondary colony formation on replating, and de novo blood vessel formation in vivo when transplanted into immunodeficient mice. In contrast, human fetal lung ECFCs exposed to hyperoxia in vitro and neonatal rat ECFCs isolated from hyperoxic alveolar growth-arrested rat lungs mimicking bronchopulmonary dysplasia proliferated less, showed decreased clonogenic capacity, and formed fewer capillary-like networks. Intrajugular administration of human cord blood-derived ECFCs after established arrested alveolar growth restored lung function, alveolar and lung vascular growth, and attenuated pulmonary hypertension. Lung ECFC colony- and capillary-like network-forming capabilities were also restored. Low ECFC engraftment and the protective effect of cell-free ECFC-derived conditioned media suggest a paracrine effect. Long-term (10 months) assessment of ECFC therapy showed no adverse effects with persistent improvement in lung structure, exercise capacity, and pulmonary hypertension. Impaired ECFC function may contribute to arrested alveolar growth. Cord blood-derived ECFC therapy may offer new therapeutic options for lung diseases characterized by alveolar damage. © 2014 American Heart Association, Inc.

The axonal guidance cue semaphorin 3C contributes to alveolar growth and repair.

PubMed

Vadivel, Arul; Alphonse, Rajesh S; Collins, Jennifer J P; van Haaften, Tim; O'Reilly, Megan; Eaton, Farah; Thébaud, Bernard

2013-01-01

Lung diseases characterized by alveolar damage such as bronchopulmonary dysplasia (BPD) in premature infants and emphysema lack efficient treatments. Understanding the mechanisms contributing to normal and impaired alveolar growth and repair may identify new therapeutic targets for these lung diseases. Axonal guidance cues are molecules that guide the outgrowth of axons. Amongst these axonal guidance cues, members of the Semaphorin family, in particular Semaphorin 3C (Sema3C), contribute to early lung branching morphogenesis. The role of Sema3C during alveolar growth and repair is unknown. We hypothesized that Sema3C promotes alveolar development and repair. In vivo Sema3C knock down using intranasal siRNA during the postnatal stage of alveolar development in rats caused significant air space enlargement reminiscent of BPD. Sema3C knock down was associated with increased TLR3 expression and lung inflammatory cells influx. In a model of O2-induced arrested alveolar growth in newborn rats mimicking BPD, air space enlargement was associated with decreased lung Sema3C mRNA expression. In vitro, Sema3C treatment preserved alveolar epithelial cell viability in hyperoxia and accelerated alveolar epithelial cell wound healing. Sema3C preserved lung microvascular endothelial cell vascular network formation in vitro under hyperoxic conditions. In vivo, Sema3C treatment of hyperoxic rats decreased lung neutrophil influx and preserved alveolar and lung vascular growth. Sema3C also preserved lung plexinA2 and Sema3C expression, alveolar epithelial cell proliferation and decreased lung apoptosis. In conclusion, the axonal guidance cue Sema3C promotes normal alveolar growth and may be worthwhile further investigating as a potential therapeutic target for lung repair.

Zoledronic Acid Induces Site-Specific Structural Changes and Decreases Vascular Area in the Alveolar Bone.

PubMed

Soares, Mariana Quirino Silveira; Van Dessel, Jeroen; Jacobs, Reinhilde; da Silva Santos, Paulo Sérgio; Cestari, Tania Mary; Garlet, Gustavo Pompermaier; Duarte, Marco Antonio Hungaro; Imada, Thaís Sumie Nozu; Lambrichts, Ivo; Rubira-Bullen, Izabel Regina Fischer

2018-03-15

The aim was to assess the effect of a relevant regimen of zoledronic acid (ZA) treatment for the study of bisphosphonate-related osteonecrosis of the jaw on alveolar bone microstructure and vasculature. A sub-objective was to use 3-dimensional imaging to describe site-specific changes induced by ZA in the alveolar bone. Five Wistar rats received ZA (0.6 mg/kg) and five (controls) received saline solution in the same volume. The compounds were administered intraperitoneally in 5 doses every 28 days. The rats were euthanized 150 days after therapy onset. The mandibles were scanned using high-resolution (14-μm) micro-computed tomography (micro-CT), decalcified, cut into slices for histologic analysis (5 μm), and stained with hematoxylin-eosin. Bone quality parameters were calculated using CT-Analyser software (Bruker, Kontich, Belgium) in 2 different volumes of interest (VOIs): the region between the first molar roots (VOI-1) and the periapical region under the first and second molars' apex (VOI-2). Blood vessel density and bone histomorphometric parameters were calculated only for the region between the roots of the first molar using AxioVision Imaging software (version 4.8; Carl Zeiss, Gottingen, Germany). ZA-treated rats showed a significant increase in percentage of bone volume and density (P < .05), with thicker and more connected trabeculae. Furthermore, the ZA group showed a significant decrease in the size of the marrow spaces and nutritive canals and in blood vessel density (P < .05). In the micro-CT evaluation, VOI-2 showed better outcomes in measuring the effect of ZA on alveolar bone. ZA treatment induced bone corticalization and decreased alveolar bone vascularization. VOI-2 should be preferred for micro-CT evaluation of the effect of bisphosphonates on alveolar bone. This analysis allowed the effect of ZA on alveolar bone and its vascularization to be characterized. The results of this analysis may add further knowledge to the understanding of the physiopathology of osteonecrosis of the jaw. Copyright © 2018 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

The development and plasticity of alveolar type 1 cells

PubMed Central

Yang, Jun; Hernandez, Belinda J.; Martinez Alanis, Denise; Narvaez del Pilar, Odemaris; Vila-Ellis, Lisandra; Akiyama, Haruhiko; Evans, Scott E.; Ostrin, Edwin J.; Chen, Jichao

2016-01-01

Alveolar type 1 (AT1) cells cover >95% of the gas exchange surface and are extremely thin to facilitate passive gas diffusion. The development of these highly specialized cells and its coordination with the formation of the honeycomb-like alveolar structure are poorly understood. Using new marker-based stereology and single-cell imaging methods, we show that AT1 cells in the mouse lung form expansive thin cellular extensions via a non-proliferative two-step process while retaining cellular plasticity. In the flattening step, AT1 cells undergo molecular specification and remodel cell junctions while remaining connected to their epithelial neighbors. In the folding step, AT1 cells increase in size by more than 10-fold and undergo cellular morphogenesis that matches capillary and secondary septa formation, resulting in a single AT1 cell spanning multiple alveoli. Furthermore, AT1 cells are an unexpected source of VEGFA and their normal development is required for alveolar angiogenesis. Notably, a majority of AT1 cells proliferate upon ectopic SOX2 expression and undergo stage-dependent cell fate reprogramming. These results provide evidence that AT1 cells have both structural and signaling roles in alveolar maturation and can exit their terminally differentiated non-proliferative state. Our findings suggest that AT1 cells might be a new target in the pathogenesis and treatment of lung diseases associated with premature birth. PMID:26586225

Local anesthetic-induced myotoxicity as a cause of severe trismus after inferior alveolar nerve block.

PubMed

Smolka, Wenko; Knoesel, Thomas; Mueller-Lisse, Ullrich

2018-01-01

A case of a 60-year-old man with severe trismus after inferior alveolar nerve block is presented. MRI scans as well as histologic examination revealed muscle fibrosis and degeneration of the medial part of the left temporal muscle due to myotoxicity of a local anesthetic agent.

Mechanical breath profile of airway pressure release ventilation: the effect on alveolar recruitment and microstrain in acute lung injury.

PubMed

Kollisch-Singule, Michaela; Emr, Bryanna; Smith, Bradford; Roy, Shreyas; Jain, Sumeet; Satalin, Joshua; Snyder, Kathy; Andrews, Penny; Habashi, Nader; Bates, Jason; Marx, William; Nieman, Gary; Gatto, Louis A

2014-11-01

Improper mechanical ventilation settings can exacerbate acute lung injury by causing a secondary ventilator-induced lung injury. It is therefore important to establish the mechanism by which the ventilator induces lung injury to develop protective ventilation strategies. It has been postulated that the mechanism of ventilator-induced lung injury is the result of heterogeneous, elevated strain on the pulmonary parenchyma. Acute lung injury has been associated with increases in whole-lung macrostrain, which is correlated with increased pathology. However, the effect of mechanical ventilation on alveolar microstrain remains unknown. To examine whether the mechanical breath profile of airway pressure release ventilation (APRV), consisting of a prolonged pressure-time profile and brief expiratory release phase, reduces microstrain. In a randomized, nonblinded laboratory animal study, rats were randomized into a controlled mandatory ventilation group (n = 3) and an APRV group (n = 3). Lung injury was induced by polysorbate lavage. A thoracotomy was performed and an in vivo microscope was placed on the lungs to measure alveolar mechanics. In the controlled mandatory ventilation group, multiple levels of positive end-expiratory pressure (PEEP; 5, 10, 16, 20, and 24 cm H2O) were tested. In the APRV group, decreasing durations of expiratory release (time at low pressure [T(low)]) were tested. The T(low) was set to achieve ratios of termination of peak expiratory flow rate (T-PEFR) to peak expiratory flow rate (PEFR) of 10%, 25%, 50%, and 75% (the smaller this ratio is [ie, 10%], the more time the lung is exposed to low pressure during the release phase, which decreases end-expiratory lung volume and potentiates derecruitment). Alveolar perimeters were measured at peak inspiration and end expiration using digital image analysis, and strain was calculated by normalizing the change in alveolar perimeter length to the original length. Macrostrain was measured by volume displacement. Higher PEEP (16-24 cm H2O) and a brief T(low) (APRV T-PEFR to PEFR ratio of 75%) reduced microstrain. Microstrain was minimized with an APRV T-PEFR to PEFR ratio of 75% (mean [SEM], 0.05 [0.03]) and PEEP of 16 cm H2O (mean [SEM], 0.09 [0.08]), but an APRV T-PEFR to PEFR ratio of 75% also promoted alveolar recruitment compared with PEEP of 16 cm H2O (mean [SEM] total inspiratory area, 52.0% [2.9%] vs 29.4% [4.3%], respectively; P < .05). Whole-lung strain was correlated with alveolar microstrain in tested settings (P < .05) except PEEP of 16 cm H2O (P > .05). Increased positive-end expiratory pressure and reduced time at low pressure (decreased T(low)) reduced alveolar microstrain. Reduced microstrain and improved alveolar recruitment using an APRV T-PEFR to PEFR ratio of 75% may be the mechanism of lung protection seen in previous clinical and animal studies.

Gallium uptake in tryptophan-related pulmonary disease

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

Kim, S.M.; Park, C.H.; Intenzo, C.M.

1991-02-01

We describe a patient who developed fever, fatigue, muscle weakness, dyspnea, skin rash, and eosinophilia after taking high doses of tryptophan for insomnia for two years. A gallium-67 scan revealed diffuse increased uptake in the lung and no abnormal uptake in the muscular distribution. Bronchoscopy and biopsy confirmed inflammatory reactions with infiltration by eosinophils, mast cells, and lymphocytes. CT scan showed an interstitial alveolar pattern without fibrosis. EMG demonstrated diffuse myopathy. Muscle biopsy from the right thigh showed an inflammatory myositis with eosinophilic and lymphocytic infiltrations.

Therapeutic effects of systemic vitamin k2 and vitamin d3 on gingival inflammation and alveolar bone in rats with experimentally induced periodontitis.

PubMed

Aral, Kübra; Alkan, Banu Arzu; Saraymen, Recep; Yay, Arzu; Şen, Ahmet; Önder, Gözde Özge

2015-05-01

The synergistic effects of vitamin D3 and vitamin K2 on bone loss prevention have been reported. This study evaluates the effects of vitamin D3 and vitamin K2 supplementation in conjunction with conventional periodontal therapy (scaling and root planing [SRP]) on gingival interleukin (IL)-1β and IL-10, serum bone alkaline phosphatase (B-ALP) and tartrate-resistant acid phosphatase 5b (TRAP-5b), and calcium and alveolar bone levels in rats with experimentally induced periodontitis. Seventy-two rats were divided into the following groups: 1) healthy; 2) periodontitis; 3) SRP; 4) SRP + vitamin D3; 5) SRP + vitamin K2; and 6) SRP + vitamins K2 and D3. Periodontitis was induced by ligature placement for 7 days, and vitamin K2 (30 mg/kg) and/or vitamin D3 (2 μg/kg) were administered for 10 days in the SRP + vitamin D3, SRP + vitamin K2, and SRP + vitamins K2 and D3 groups by oral gavage. On day 18, the animals were sacrificed, serum B-ALP, TRAP-5b, and calcium levels were measured, gingiva specimens were extracted for IL-1β and IL-10 analysis, and distances between the cemento-enamel junction and alveolar bone crest were evaluated. Alveolar bone levels in the periodontitis group were significantly greater than those in the other five groups. No significant differences were found in gingival IL-1β and IL-10, serum B-ALP and TRAP-5b, and calcium and alveolar bone levels between the groups receiving SRP and vitamins and the group receiving SRP alone. Within the limitations of this study, vitamin D3 and K2 alone or in combination did not affect gingival IL-1β and IL-10, serum B-ALP and TRAP-5b levels, or alveolar bone compared with conventional periodontal therapy alone.

Acute Penicillium marneffei infection stimulates host M1/M2a macrophages polarization in BALB/C mice.

PubMed

Dai, Xiaoying; Mao, Congzheng; Lan, Xiuwan; Chen, Huan; Li, Meihua; Bai, Jing; Deng, Jingmin; Liang, Qiuli; Zhang, Jianquan; Zhong, Xiaoning; Liang, Yi; Fan, Jiangtao; Luo, Honglin; He, Zhiyi

2017-08-18

Penicillium marneffei (P. marneffei) is a thermally dimorphic fungus pathogen that causes fatal infection. Alveolar macrophages are innate immune cells that have critical roles in protection against pulmonary fungal pathogens and the macrophage polarization state has the potential to be a deciding factor in disease progression or resolution. The aim of this study was to investigate mouse alveolar macrophage polarization states during P. marneffei infection. We used enzyme-linked immunosorbent (ELISA) assays, quantitative real-time PCR (qRT-PCR), and Griess, arginase activity to evaluate the phenotypic markers of alveolar macrophages from BALB/C mice infected with P. marneffei. We then treated alveolar macrophages from infected mice with P. marneffei cytoplasmic yeast antigen (CYA) and investigated alveolar macrophage phenotypic markers in order to identify macrophage polarization in response to P. marneffei antigens. Our results showed: i) P. marneffei infection significantly enhanced the expression of classically activated macrophage (M1)-phenotypic markers (inducible nitric oxide synthase [iNOS] mRNA, nitric oxide [NO], interleukin-12 [IL-12], tumor necrosis factor-alpha [TNF-α]) and alternatively activated macrophage (M2a)-phenotypic markers (arginase1 [Arg1] mRNA, urea) during the second week post-infection. This significantly decreased during the fourth week post-infection. ii) During P. marneffei infection, CYA stimulation also significantly enhanced the expression of M1 and M2a-phenotypic markers, consistent with the results for P. marneffei infection and CYA stimulation preferentially induced M1 subtype. The data from the current study demonstrated that alveolar macrophage M1/M2a subtypes were present in host defense against acute P. marneffei infection and that CYA could mimic P. marneffei to induce a host immune response with enhanced M1 subtype. This could be useful for investigating the enhancement of host anti-P. marneffei immune responses and to provide novel ideas for prevention of P. marneffei-infection.

3He Lung Morphometry Technique: Accuracy Analysis and Pulse Sequence Optimization

PubMed Central

Sukstanskii, A.L.; Conradi, M.S.; Yablonskiy, D.A.

2010-01-01

The 3He lung morphometry technique (Yablonskiy et al, JAP, 2009), based on MRI measurements of hyperpolarized gas diffusion in lung airspaces, provides unique information on the lung microstructure at the alveolar level. 3D tomographic images of standard morphological parameters (mean airspace chord length, lung parenchyma surface-to-volume ratio, and the number of alveoli per unit lung volume) can be created from a rather short (several seconds) MRI scan. These parameters are most commonly used to characterize lung morphometry but were not previously available from in vivo studies. A background of the 3He lung morphometry technique is based on a previously proposed model of lung acinar airways, treated as cylindrical passages of external radius R covered by alveolar sleeves of depth h, and on a theory of gas diffusion in these airways. The initial works approximated the acinar airways as very long cylinders, all with the same R and h. The present work aims at analyzing effects of realistic acinar airway structures, incorporating airway branching, physiological airway lengths, a physiological ratio of airway ducts and sacs, and distributions of R and h. By means of Monte Carlo computer simulations, we demonstrate that our technique allows rather accurate measurements of geometrical and morphological parameters of acinar airways. In particular, the accuracy of determining one of the most important physiological parameter of acinar airways – surface-to-volume ratio – does not exceed several percent. Second, we analyze the effect of the susceptibility induced inhomogeneous magnetic field on the parameter estimate and demonstrate that this effect is rather negligible at B0 ≤ 3T and becomes substantial only at higher B0 Third, we theoretically derive an optimal choice of MR pulse sequence parameters, which should be used to acquire a series of diffusion attenuated MR signals, allowing a substantial decrease in the acquisition time and improvement in accuracy of the results. It is demonstrated that the optimal choice represents three not equidistant b-values: b1 = 0, b2 ~ 2 s/cm2, b3 ~ 8 s/cm2. PMID:20937564

Lingual-Alveolar Contact Pressure during Speech in Amyotrophic Lateral Sclerosis: Preliminary Findings

ERIC Educational Resources Information Center

Searl, Jeff; Knollhoff, Stephanie; Barohn, Richard J.

2017-01-01

Purpose: This preliminary study on lingual-alveolar contact pressures (LACP) in people with amyotrophic lateral sclerosis (ALS) had several aims: (a) to evaluate whether the protocol induced fatigue, (b) to compare LACP during speech (LACP-Sp) and during maximum isometric pressing (LACP-Max) in people with ALS (PALS) versus healthy controls, (c)…

Multisystem involvement of alveolar echinococcosis in a child.

PubMed

Kantarci, Mecit; Bayraktutan, Ummugulsum; Pirimoglu, Berhan; Ogul, Hayri; Oral, Akgun; Eren, Suat; Gundogdu, Betul

2014-11-13

Alveolar echinococcosis (AE) is a chronic progressive infestation inducing a slowly progressing, life-threatening tumor-like growth in the liver. It may spread to other organs by regional extension or hematogenous or lymphatic metastasis. Herein, we report a fifteen-year-old patient diagnosed with AE of the liver and simultaneous lung and brain metastasis with a literature review.

Sulforaphane induces apoptosis in rhabdomyosarcoma and restores TRAIL-sensitivity in the aggressive alveolar subtype leading to tumor elimination in mice

PubMed Central

Bergantin, Elisa; Quarta, Carmelo; Nanni, Cristina; Fanti, Stefano; Pession, Andrea; Cantelli-Forti, Giorgio; Tonelli, Roberto; Hrelia, Patrizia

2014-01-01

Rhadbomyosarcoma (RMS) is the most common soft-tissue sarcoma in children and is subdivided in the embryonal (ERMS) and alveolar (ARMS) subtypes, the latter being associated with the worst prognosis. We report that sulforaphane (SFN), a broccoli-derived anticancer isothiocyanate, causes dose- and time-dependent growth inhibition and apoptosis in both ERMS and ARMS cells. In ARMS, SFN induced the modulation of expression of crucial genes and proteins: mRNA and protein levels of PAX3-FKHR, MYCN, and MET decreased, while those of p21 and TRAIL-receptor DR5 (but not DR4) increased. Since DR5 expression increased specifically in ARMS, we treated ARMS cells with TRAIL, SFN, or their combination. While ARMS cells (RH30 and RH4) proved to be TRAIL-resistant, SFN restored their sensitivity to TRAIL-induced cell-growth inhibition, leading to a stronger effect in combination with TRAIL. ARMS cells transfected with siDR5 showed that SFN-induced DR5 acts as a key regulator, being directly related to the TRAIL-induced cell-growth inhibition. The in vivo anti-tumor activity of SFN and TRAIL was evaluated in a xenograft murine model of ARMS through microPET. The results showed that the systemic treatment (3 wk) of mice with SFN or TRAIL as single agents only delayed tumor evolution, while the combined treatment of SFN and TRAIL led to tumor elimination. These findings indicate that SFN triggers the apoptotic pathway in both alveolar and embryonal rhabdomyosarcomas and that combined treatment with SFN and TRAIL might be a promising therapy for the aggressive alveolar subtype. PMID:24971463

Brain metastasis of crystal-deficient, CD68-positive alveolar soft part sarcoma: ultrastructural features and differential diagnosis

PubMed Central

Cykowski, Matthew D.; Hicks, John; Sandberg, David I.; Olar, Adriana; Bridge, Julia A.; Greipp, Patricia T.; Navarro, Patricia; Kolodziej, Steven; Bhattacharjee, Meenakshi B.

2014-01-01

We report a case of alveolar soft part sarcoma (ASPS) presenting as an isolated frontal lobe metastasis. The tumor demonstrated little or no immunoreactivity for a broad panel of antibodies yet strong, diffuse immunoreactivity with CD68. On electron microscopy, characteristic rectangular to rhomboid crystalline inclusions were not present. Electron-dense granules resembling peroxisomes were present, sometimes in association with elongated granular structures having a periodic, lattice-like arrangement. Metastatic ASPS was confirmed by demonstration of an ASPSCR1-TFE3 fusion and imaging studies that excluded metastatic Xp11.2 translocation renal cell carcinoma. The primary site was subsequently identified in the lower extremity. PMID:25268941

Loss of Nrf2 promotes alveolar type 2 cell loss in irradiated, fibrotic lung.

PubMed

Traver, Geri; Mont, Stacey; Gius, David; Lawson, William E; Ding, George X; Sekhar, Konjeti R; Freeman, Michael L

2017-11-01

The development of radiation-induced pulmonary fibrosis represents a critical clinical issue limiting delivery of therapeutic doses of radiation to non-small cell lung cancer. Identification of the cell types whose injury initiates a fibrotic response and the underlying biological factors that govern that response are needed for developing strategies that prevent or mitigate fibrosis. C57BL/6 mice (wild type, Nrf2 null, Nrf2 flox/flox , and Nrf2 Δ/Δ ; SPC-Cre) were administered a thoracic dose of 12Gy and allowed to recover for 250 days. Whole slide digital and confocal microscopy imaging of H&E, Masson's trichrome and immunostaining were used to assess tissue remodeling, collagen deposition and cell renewal/mobilization during the regenerative process. Histological assessment of irradiated, fibrotic wild type lung revealed significant loss of alveolar type 2 cells 250 days after irradiation. Type 2 cell loss and the corresponding development of fibrosis were enhanced in the Nrf2 null mouse. Yet, conditional deletion of Nrf2 in alveolar type 2 cells in irradiated lung did not impair type 2 cell survival nor yield an increased fibrotic phenotype. Instead, radiation-induced ΔNp63 stem/progenitor cell mobilization was inhibited in the Nrf2 null mouse while the propensity for radiation-induced myofibroblasts derived from alveolar type 2 cells was magnified. In summary, these results indicate that Nrf2 is an important regulator of irradiated lung's capacity to maintain alveolar type 2 cells, whose injury can initiate a fibrotic phenotype. Loss of Nrf2 inhibits ΔNp63 stem/progenitor mobilization, a key event for reconstitution of injured lung, while promoting a myofibroblast phenotype that is central for fibrosis. Copyright © 2017 Elsevier Inc. All rights reserved.

Intermuscular pterygoid-temporal abscess following inferior alveolar nerve block anesthesia–A computer tomography based navigated surgical intervention: Case report and review

PubMed Central

Wallner, Jürgen; Reinbacher, Knut Ernst; Pau, Mauro; Feichtinger, Matthias

2014-01-01

Inferior alveolar nerve block (IANB) anesthesia is a common local anesthetic procedure. Although IANB anesthesia is known for its safety, complications can still occur. Today immediately or delayed occurring disorders following IANB anesthesia and their treatment are well-recognized. We present a case of a patient who developed a symptomatic abscess in the pterygoid region as a result of several inferior alveolar nerve injections. Clinical symptoms included diffuse pain, reduced mouth opening and jaw's hypomobility and were persistent under a first step conservative treatment. Since image-based navigated interventions have gained in importance and are used for various procedures a navigated surgical intervention was initiated as a second step therapy. Thus precise, atraumatic surgical intervention was performed by an optical tracking system in a difficult anatomical region. A symptomatic abscess was treated by a computed tomography-based navigated surgical intervention at our department. Advantages and disadvantages of this treatment strategy are evaluated. PMID:24987612

Intermuscular pterygoid-temporal abscess following inferior alveolar nerve block anesthesia-A computer tomography based navigated surgical intervention: Case report and review.

PubMed

Wallner, Jürgen; Reinbacher, Knut Ernst; Pau, Mauro; Feichtinger, Matthias

2014-01-01

Inferior alveolar nerve block (IANB) anesthesia is a common local anesthetic procedure. Although IANB anesthesia is known for its safety, complications can still occur. Today immediately or delayed occurring disorders following IANB anesthesia and their treatment are well-recognized. We present a case of a patient who developed a symptomatic abscess in the pterygoid region as a result of several inferior alveolar nerve injections. Clinical symptoms included diffuse pain, reduced mouth opening and jaw's hypomobility and were persistent under a first step conservative treatment. Since image-based navigated interventions have gained in importance and are used for various procedures a navigated surgical intervention was initiated as a second step therapy. Thus precise, atraumatic surgical intervention was performed by an optical tracking system in a difficult anatomical region. A symptomatic abscess was treated by a computed tomography-based navigated surgical intervention at our department. Advantages and disadvantages of this treatment strategy are evaluated.

Evidence for minimal oxygen heterogeneity in the healthy human pulmonary acinus

PubMed Central

Tawhai, Merryn H.

2011-01-01

It has been suggested that the human pulmonary acinus operates at submaximal efficiency at rest due to substantial spatial heterogeneity in the oxygen partial pressure (Po2) in alveolar air within the acinus. Indirect measurements of alveolar air Po2 could theoretically mask significant heterogeneity if intra-acinar perfusion is well matched to Po2. To investigate the extent of intra-acinar heterogeneity, we developed a computational model with anatomically based structure and biophysically based equations for gas exchange. This model yields a quantitative prediction of the intra-acinar O2 distribution that cannot be measured directly. Temporal and spatial variations in Po2 in the intra-acinar air and blood are predicted with the model. The model, representative of a single average acinus, has an asymmetric multibranching respiratory airways geometry coupled to a symmetric branching conducting airways geometry. Advective and diffusive O2 transport through the airways and gas exchange into the capillary blood are incorporated. The gas exchange component of the model includes diffusion across the alveolar air-blood membrane and O2-hemoglobin binding. Contrary to previous modeling studies, simulations show that the acinus functions extremely effectively at rest, with only a small degree of intra-acinar Po2 heterogeneity. All regions of the model acinus, including the peripheral generations, maintain a Po2 >100 mmHg. Heterogeneity increases slightly when the acinus is stressed by exercise. However, even during exercise the acinus retains a reasonably homogeneous gas phase. PMID:21071589

Lung Structure and the Intrinsic Challenges of Gas Exchange

PubMed Central

Hsia, Connie C.W.; Hyde, Dallas M.; Weibel, Ewald R.

2016-01-01

Structural and functional complexities of the mammalian lung evolved to meet a unique set of challenges, namely, the provision of efficient delivery of inspired air to all lung units within a confined thoracic space, to build a large gas exchange surface associated with minimal barrier thickness and a microvascular network to accommodate the entire right ventricular cardiac output while withstanding cyclic mechanical stresses that increase several folds from rest to exercise. Intricate regulatory mechanisms at every level ensure that the dynamic capacities of ventilation, perfusion, diffusion, and chemical binding to hemoglobin are commensurate with usual metabolic demands and periodic extreme needs for activity and survival. This article reviews the structural design of mammalian and human lung, its functional challenges, limitations, and potential for adaptation. We discuss (i) the evolutionary origin of alveolar lungs and its advantages and compromises, (ii) structural determinants of alveolar gas exchange, including architecture of conducting bronchovascular trees that converge in gas exchange units, (iii) the challenges of matching ventilation, perfusion, and diffusion and tissue-erythrocyte and thoracopulmonary interactions. The notion of erythrocytes as an integral component of the gas exchanger is emphasized. We further discuss the signals, sources, and limits of structural plasticity of the lung in alveolar hypoxia and following a loss of lung units, and the promise and caveats of interventions aimed at augmenting endogenous adaptive responses. Our objective is to understand how individual components are matched at multiple levels to optimize organ function in the face of physiological demands or pathological constraints. PMID:27065169

The fate of instilled pulmonary surfactant in normal and quartz-treated rats.

PubMed Central

Lewis, R W; Harwood, J L; Richards, R J

1987-01-01

Naturally prepared radiolabelled pulmonary surfactant can be rapidly cleared from the alveolar surface to the lung tissue after intratracheal instillation into experimental rats. This clearance is both time- and dose-dependent, a large dose (10 mg/animal) becoming associated with lung tissue more rapidly than a smaller more physiological dose (0.75 mg/animal). The data indicate that extracellular dipalmitoyl-phosphatidylcholine, the major component of pulmonary surfactant, is not catabolized at the alveolar surface. Alveolar free cells (mainly macrophages) appear to play a minor role in surfactant clearance. Quartz-induced phospholipidosis does not lead to an alteration in the rate of bulk surfactant clearance from the alveolar surface, although the initial distribution of the removed phospholipid complex may change in relation to the enlarged heterogenous free cell population. PMID:2821988

Carbon monoxide alleviates lipopolysaccharide-induced oxidative stress injury through suppressing the expression of Fis1 in NR8383 cells

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

Shi, Jia; Yu, Jian-bo, E-mail: yujianbo11@126.com; Liu, Wei

Acute respiratory distress syndrome (ARDS) is one of the most devastating complications of sepsis lacking of effective therapy. Mitochondrial dynamics undergoing continuous fusion and fission play a crucial role in mitochondrial structure and function. Fis1, as a small protein located on the outer membrane of mitochondria, has been thought to be an important protein mediated mitochondrial fission. During ARDS, alveolar macrophages suffer from increased oxidative stress and apoptosis, and also accompanied by disrupted mitochondrial dynamics. In addition, as one of the products of heme degradation catalyzed by heme oxygenase, carbon monoxide (CO) possesses powerful protective properties in vivo or inmore » vitro models, such as anti-inflammatory, antioxidant and anti-apoptosis function. However, there is little evidence that CO alleviates oxidative stress damage through altering mitochondrial fission in alveolar macrophages. In the present study, our results showed that CO increased cell vitality, improved mitochondrial SOD activity, reduced reactive oxygen species (ROS) production and inhibited cell apoptosis in NR8383 exposed to LPS. Meanwhile, CO decreased the expression of Fis1, increased mitochondrial membrane potential and sustained elongation of mitochondria in LPS-incubated NR8383. Overall, our study underscored a critical role of CO in suppressing the expression of Fis1 and alleviating LPS- induced oxidative stress damage in alveolar macrophages. - Highlights: • LPS exposure triggered cell injury in NR8383. • CO alleviated LPS-induced oxidative stress damage in alveolar macrophages. • CO inhibited Fis1 levels and improved mitochondrial function in LPS-induced NR8383.« less

Structural Measurements from Images of Noble Gas Diffusion

NASA Astrophysics Data System (ADS)

Cadman, Robert V.; Kadlecek, Stephen J.; Emami, Kiarash; MacDuffie Woodburn, John; Vahdat, Vahid; Ishii, Masaru; Rizi, Rahim R.

2009-03-01

Magnetic resonance imaging of externally polarized noble gases such as ^3He has been used for pulmonary imaging for more than a decade. Because gas diffusion is impeded by the alveoli, the diffusion coefficient of gas in the lung, measured on a time scale of milliseconds, is reduced compared to that of the same gas mixture in the absence of restrictions. When the alveolar walls decay, as in emphysema, diffusivity in the lung increases. In this paper, the relationship between diffusion measurements and the size of the restricting structures will be discussed. The simple case of diffusion in an impermeable cylinder, a structure similar to the upper respiratory airways in mammals, has been studied. A procedure will be presented by which airways of order 2 mm in diameter may be accurately measured; demonstration experiments with plastic tubes will also be presented. The additional developments needed before this technique becomes practical will be briefly discussed.

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

Fabbri, L.M.; Danieli, D.; Crescioli, S.

We report the case of a 43-yr-old car painter who died within 1 h of exposure to a polyurethane paint in the workplace. A diagnosis of asthma induced by toluene diisocyanate (TDI) had been established 6 yr before, when he underwent inhalation challenges with carbachol and with TDI. The subject had airway hyperresponsiveness to carbachol (PD20FEV1 carbachol = 0.32 mg; normal value greater than 1.0 mg) and developed an early and long-lasting asthmatic reaction after exposure to TDI in the laboratory. Although it was recommended that he change his job or stop using paints containing isocyanates, he continued to workmore » as a car painter, taking antiasthmatic drugs both at work and at home to control asthma symptoms. On Monday, October 6, 1986, at 11:30 A. M., he developed a severe attack of asthma while he was mixing the 2 components of a polyurethane paint. Taken to hospital, he was dead on arrival. Autopsy showed no evidence of cardiac or brain disease; lungs were overinflated, the cut surface showed grey glistening mucous plugs in in the airways. Histologic examination showed denudation of airway epithelium and thickening of the basement membrane with infiltration of the lamina propria by polymorphonuclear leukocytes, mainly eosinophils, and diffuse mucous plugging of bronchioles. Bronchial smooth muscle appeared hyperplastic and disarrayed, and lung parenchyma showed focal areas of alveolar destruction adjacent to areas of perfectly intact alveolar walls.« less

FGFR4 signaling couples to Bim and not Bmf to discriminate subsets of alveolar rhabdomyosarcoma cells.

PubMed

Wachtel, Marco; Rakic, Jelena; Okoniewski, Michal; Bode, Peter; Niggli, Felix; Schäfer, Beat W

2014-10-01

Biological heterogeneity represents a major obstacle for cancer treatment. Therefore, characterization of treatment-relevant tumor heterogeneity is necessary to develop more effective therapies in the future. Here, we uncovered population heterogeneity among PAX/FOXO1-positive alveolar rhabdomyosarcoma by characterizing prosurvival networks initiated by FGFR4 signaling. We found that FGFR4 signaling rescues only subgroups of alveolar rhabdomyosarcoma cells from apoptosis induced by compounds targeting the IGF1R-PI3K-mTOR pathway. Differences in both proapoptotic machinery and FGFR4-activated signaling are involved in the different behavior of the phenotypes. Proapoptotic stress induced by the kinase inhibitors is sensed by Bim/Bad in rescue cells and by Bmf in nonrescue cells. Anti-apoptotic ERK1/2 signaling downstream of FGFR4 is long-lasting in rescue and short-termed in most non-rescue cells. Gene expression analysis detected signatures specific for these two groups also in biopsy samples. The different cell phenotypes are present in different ratios in alveolar rhabdomyosarcoma tumors and can be identified by AP2β expression levels. Hence, inhibiting FGFR signaling might represent an important strategy to enhance efficacy of current RMS treatments. © 2014 UICC.

Reactive Oxygen Species/Hypoxia-Inducible Factor-1α/Platelet-Derived Growth Factor-BB Autocrine Loop Contributes to Cocaine-Mediated Alveolar Epithelial Barrier Damage

PubMed Central

Yang, Lu; Chen, Xufeng; Simet, Samantha M.; Hu, Guoku; Cai, Yu; Niu, Fang; Kook, Yeonhee

2016-01-01

Abuse of psychostimulants, such as cocaine, has been shown to be closely associated with complications of the lung, such as pulmonary hypertension, edema, increased inflammation, and infection. However, the mechanism by which cocaine mediates impairment of alveolar epithelial barrier integrity that underlies various pulmonary complications has not been well determined. Herein, we investigate the role of cocaine in disrupting the alveolar epithelial barrier function and the associated signaling cascade. Using the combinatorial electric cell–substrate impedance sensing and FITC-dextran permeability assays, we demonstrated cocaine-mediated disruption of the alveolar epithelial barrier, as evidenced by increased epithelial monolayer permeability with a concomitant loss of the tight junction protein zonula occludens-1 (Zo-1) in both mouse primary alveolar epithelial cells and the alveolar epithelial cell line, L2 cells. To dissect the signaling pathways involved in this process, we demonstrated that cocaine-mediated induction of permeability factors, platelet-derived growth factor (PDGF-BB) and vascular endothelial growth factor, involved reactive oxygen species (ROS)-dependent induction of hypoxia-inducible factor (HIF)-1α. Interestingly, we demonstrated that ROS-dependent induction of another transcription factor, nuclear factor erythroid-2–related factor-2, that did not play a role in cocaine-mediated barrier dysfunction. Importantly, this study identifies, for the first time, that ROS/HIF-1α/PDGF-BB autocrine loop contributes to cocaine-mediated barrier disruption via amplification of oxidative stress and downstream signaling. Corroboration of these cell culture findings in vivo demonstrated increased permeability of the alveolar epithelial barrier, loss of expression of Zo-1, and a concomitantly increased expression of both HIF-1α and PDGF-BB. Pharmacological blocking of HIF-1α significantly abrogated cocaine-mediated loss of Zo-1. Understanding the mechanism(s) by which cocaine mediates barrier dysfunction could provide insights into the development of potential therapeutic targets for cocaine-mediated pulmonary hypertension. PMID:27391108

Regulation of ENaC and CFTR expression with K+ channel modulators and effect on fluid absorption across alveolar epithelial cells.

PubMed

Leroy, Claudie; Privé, Anik; Bourret, Jean-Charles; Berthiaume, Yves; Ferraro, Pasquale; Brochiero, Emmanuelle

2006-12-01

In a recent study (Leroy C, Dagenais A, Berthiaume Y, and Brochiero E. Am J Physiol Lung Cell Mol Physiol 286: L1027-L1037, 2004), we identified an ATP-sensitive K(+) (K(ATP)) channel in alveolar epithelial cells, formed by inwardly rectifying K(+) channel Kir6.1/sulfonylurea receptor (SUR)2B subunits. We found that short applications of K(ATP), voltage-dependent K(+) channel KvLQT1, and calcium-activated K(+) (K(Ca)) channel modulators modified Na(+) and Cl(-) currents in alveolar monolayers. In addition, it was shown previously that a K(ATP) opener increased alveolar liquid clearance in human lungs by a mechanism possibly related to epithelial sodium channels (ENaC). We therefore hypothesized that prolonged treatment with K(+) channel modulators could induce a sustained regulation of ENaC activity and/or expression. Alveolar monolayers were treated for 24 h with inhibitors of K(ATP), KvLQT1, and K(Ca) channels identified by PCR. Glibenclamide and clofilium (K(ATP) and KvLQT1 inhibitors) strongly reduced basal transepithelial current, amiloride-sensitive Na(+) current, and forskolin-activated Cl(-) currents, whereas pinacidil, a K(ATP) activator, increased them. Interestingly, K(+) inhibitors or membrane depolarization (induced by valinomycin in high-K(+) medium) decreased alpha-, beta-, and gamma-ENaC and CFTR mRNA. alpha-ENaC and CFTR proteins also declined after glibenclamide or clofilium treatment. Conversely, pinacidil augmented ENaC and CFTR mRNAs and proteins. Since alveolar fluid transport was found to be driven, at least in part, by Na(+) transport through ENaC, we tested the impact of K(+) channel modulators on fluid absorption across alveolar monolayers. We found that glibenclamide and clofilium reduced fluid absorption to a level similar to that seen in the presence of amiloride, whereas pinacidil slightly enhanced it. Long-term regulation of ENaC and CFTR expression by K(+) channel activity could benefit patients with pulmonary diseases affecting ion transport and fluid clearance.

Rhizoma Dioscoreae Extract Protects against Alveolar Bone Loss in Ovariectomized Rats via microRNAs Regulation

PubMed Central

Zhang, Zhiguo; Song, Changheng; Zhang, Fangzhen; Xiang, Lihua; Chen, Yanjing; Li, Yan; Pan, Jinghua; Liu, Hong; Xiao, Gary Guishan; Ju, Dahong

2015-01-01

The aim of this study was to evaluate the osteoprotective effect of aqueous Rhizoma Dioscoreae extract (RDE) on the alveolar bone of rats with ovariectomy-induced bone loss. Female Wistar rats underwent either ovariectomy or sham operation (SHAM). The ovariectomized (OVX) rats were treated with vehicle (OVX), estradiol valerate (EV), or RDE. After treatments, the bone mineral density (BMD) and the three-dimensional microarchitecture of the alveolar bone were analyzed to assess bone mass. Microarrays were used to evaluate microRNA expression profiles in alveolar bone from RDE-treated and OVX rats. The differential expression of microRNAs was validated using real-time quantitative RT-PCR (qRT-PCR), and the target genes of validated microRNAs were predicted and further analyzed using Ingenuity Pathway Analysis (IPA). The key findings were verified using qRT-PCR. Our results show that RDE inhibits alveolar bone loss in OVX rats. Compared to the OVX rats, the RDE-treated rats showed upregulated expression levels of 8 microRNAs and downregulated expression levels of 8 microRNAs in the alveolar bone in the microarray analysis. qRT-PCR helped validate 13 of 16 differentially expressed microRNAs, and 114 putative target genes of the validated microRNAs were retrieved. The IPA showed that these putative target genes had the potential to code for proteins that were involved in the transforming growth factor (TGF)-β/bone morphogenetic proteins (BMPs)/Smad signaling pathway (Tgfbr2/Bmpr2, Smad3/4/5, and Bcl-2) and interleukin (IL)-6/oncostatin M (OSM)/Jak1/STAT3 signaling pathway (Jak1, STAT3, and Il6r). These experiments revealed that RDE could inhibit ovariectomy-induced alveolar bone loss in rats. The mechanism of this anti-osteopenic effect in alveolar bone may involve the simultaneous inhibition of bone formation and bone resorption, which is associated with modulation of the TGF-β/BMPs/Smad and the IL-6/OSM/Jak1/STAT3 signaling pathways via microRNA regulation. PMID:25690421

Rhizoma Dioscoreae extract protects against alveolar bone loss in ovariectomized rats via microRNAs regulation.

PubMed

Zhang, Zhiguo; Song, Changheng; Zhang, Fangzhen; Xiang, Lihua; Chen, Yanjing; Li, Yan; Pan, Jinghua; Liu, Hong; Xiao, Gary Guishan; Ju, Dahong

2015-02-16

The aim of this study was to evaluate the osteoprotective effect of aqueous Rhizoma Dioscoreae extract (RDE) on the alveolar bone of rats with ovariectomy-induced bone loss. Female Wistar rats underwent either ovariectomy or sham operation (SHAM). The ovariectomized (OVX) rats were treated with vehicle (OVX), estradiol valerate (EV), or RDE. After treatments, the bone mineral density (BMD) and the three-dimensional microarchitecture of the alveolar bone were analyzed to assess bone mass. Microarrays were used to evaluate microRNA expression profiles in alveolar bone from RDE-treated and OVX rats. The differential expression of microRNAs was validated using real-time quantitative RT-PCR (qRT-PCR), and the target genes of validated microRNAs were predicted and further analyzed using Ingenuity Pathway Analysis (IPA). The key findings were verified using qRT-PCR. Our results show that RDE inhibits alveolar bone loss in OVX rats. Compared to the OVX rats, the RDE-treated rats showed upregulated expression levels of 8 microRNAs and downregulated expression levels of 8 microRNAs in the alveolar bone in the microarray analysis. qRT-PCR helped validate 13 of 16 differentially expressed microRNAs, and 114 putative target genes of the validated microRNAs were retrieved. The IPA showed that these putative target genes had the potential to code for proteins that were involved in the transforming growth factor (TGF)-β/bone morphogenetic proteins (BMPs)/Smad signaling pathway (Tgfbr2/Bmpr2, Smad3/4/5, and Bcl-2) and interleukin (IL)-6/oncostatin M (OSM)/Jak1/STAT3 signaling pathway (Jak1, STAT3, and Il6r). These experiments revealed that RDE could inhibit ovariectomy-induced alveolar bone loss in rats. The mechanism of this anti-osteopenic effect in alveolar bone may involve the simultaneous inhibition of bone formation and bone resorption, which is associated with modulation of the TGF-β/BMPs/Smad and the IL-6/OSM/Jak1/STAT3 signaling pathways via microRNA regulation.

Morphometric and histopathological evaluation of the effect of grape seed proanthocyanidin on alveolar bone loss in experimental diabetes and periodontitis.

PubMed

Toker, H; Balci Yuce, H; Lektemur Alpan, A; Gevrek, F; Elmastas, M

2018-06-01

Grape seed proanthocyanidine extract (GSPE) is a strong antioxidant derived from the grape seeds (Vitis vinifera, Terral J.F.) and has a polyphenolic structure with a wide range of biological activity. The aim of the present study was to evaluate the effects of GSPE on alveolar bone loss and histopathological changes in rats with diabetes mellitus and ligature-induced periodontitis. Forty rats were divided into 6 study groups. Control (C, 6 rats) group, periodontitis (P, 6 rats) group, diabetes (D, 6 rats) group, diabetes and periodontitis (D+P, 6 rats) group, diabetes, periodontitis and 100 mg/kg/day GSPE (GSPE-100, 8 rats), and diabetes, periodontitis and 200 mg/kg/day GSPE (GSPE-200, 8 rats) group. Diabetes mellitus was induced by intraperitoneal injection of a single dose of streptozotocin (60 mg/kg). Periodontitis was induced via ligation method. Silk ligatures were placed at the mandibular right first molars. GSPE was administered by oral gavage. After 30 days, all rats were killed. Alveolar bone loss was measured morphometrically via a stereomicroscope. For histopathological analyses, Alizarin red staining, and matrix metalloproteinase (MMP)-8, vascular endothelial growth factor and hypoxia inducible factor (HIF)-1α immunohistochemistry were performed. Tartrate-resistant acid phosphatase-positive osteoclast cells and relative total inflammatory cells were also determined. The highest alveolar bone loss was observed in the D+P group (P < .05). GSP-200 group decreased alveolar bone loss (P < .05). The D+P group had the highest osteoclast counts, but the difference was not significant compared to the P, GSPE-100 and GSPE-200 groups (P > .05). The inflammation in the D+P group was also higher than the other groups (P < .05). The osteoblast numbers increased in the GSPE-100 and GSPE-200 groups compared to the P and D+P groups (P < .05). MMP-8 and HIF-1α levels were highest in the D+P group and GSPE significantly decreased these levels (P < .05). Within the limits of this animal study, it can be suggested that GSPE administration may decrease periodontal inflammation and alveolar bone loss via decreasing MMP-8 and HIF-1α levels and increase osteoblastic activity in diabetic rats with experimental periodontitis. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

A novel swine model of ricin-induced acute respiratory distress syndrome

PubMed Central

Katalan, Shahaf; Falach, Reut; Rosner, Amir; Goldvaser, Michael; Brosh-Nissimov, Tal; Dvir, Ayana; Mizrachi, Avi; Goren, Orr; Cohen, Barak; Gal, Yoav; Sapoznikov, Anita; Ehrlich, Sharon; Kronman, Chanoch

2017-01-01

ABSTRACT Pulmonary exposure to the plant toxin ricin leads to respiratory insufficiency and death. To date, in-depth study of acute respiratory distress syndrome (ARDS) following pulmonary exposure to toxins is hampered by the lack of an appropriate animal model. To this end, we established the pig as a large animal model for the comprehensive study of the multifarious clinical manifestations of pulmonary ricinosis. Here, we report for the first time, the monitoring of barometric whole body plethysmography for pulmonary function tests in non-anesthetized ricin-treated pigs. Up to 30 h post-exposure, as a result of progressing hypoxemia and to prevent carbon dioxide retention, animals exhibited a compensatory response of elevation in minute volume, attributed mainly to a large elevation in respiratory rate with minimal response in tidal volume. This response was followed by decompensation, manifested by a decrease in minute volume and severe hypoxemia, refractory to oxygen treatment. Radiological evaluation revealed evidence of early diffuse bilateral pulmonary infiltrates while hemodynamic parameters remained unchanged, excluding cardiac failure as an explanation for respiratory insufficiency. Ricin-intoxicated pigs suffered from increased lung permeability accompanied by cytokine storming. Histological studies revealed lung tissue insults that accumulated over time and led to diffuse alveolar damage. Charting the decline in PaO2/FiO2 ratio in a mechanically ventilated pig confirmed that ricin-induced respiratory damage complies with the accepted diagnostic criteria for ARDS. The establishment of this animal model of pulmonary ricinosis should help in the pursuit of efficient medical countermeasures specifically tailored to deal with the respiratory deficiencies stemming from ricin-induced ARDS. PMID:28067630

Airway delivery of mesenchymal stem cells prevents arrested alveolar growth in neonatal lung injury in rats.

PubMed

van Haaften, Timothy; Byrne, Roisin; Bonnet, Sebastien; Rochefort, Gael Y; Akabutu, John; Bouchentouf, Manaf; Rey-Parra, Gloria J; Galipeau, Jacques; Haromy, Alois; Eaton, Farah; Chen, Ming; Hashimoto, Kyoko; Abley, Doris; Korbutt, Greg; Archer, Stephen L; Thébaud, Bernard

2009-12-01

Bronchopulmonary dysplasia (BPD) and emphysema are characterized by arrested alveolar development or loss of alveoli; both are significant global health problems and currently lack effective therapy. Bone marrow-derived mesenchymal stem cells (BMSCs) prevent adult lung injury, but their therapeutic potential in neonatal lung disease is unknown. We hypothesized that intratracheal delivery of BMSCs would prevent alveolar destruction in experimental BPD. In vitro, BMSC differentiation and migration were assessed using co-culture assays and a modified Boyden chamber. In vivo, the therapeutic potential of BMSCs was assessed in a chronic hyperoxia-induced model of BPD in newborn rats. In vitro, BMSCs developed immunophenotypic and ultrastructural characteristics of type II alveolar epithelial cells (AEC2) (surfactant protein C expression and lamellar bodies) when co-cultured with lung tissue, but not with culture medium alone or liver. Migration assays revealed preferential attraction of BMSCs toward oxygen-damaged lung versus normal lung. In vivo, chronic hyperoxia in newborn rats led to air space enlargement and loss of lung capillaries, and this was associated with a decrease in circulating and resident lung BMSCs. Intratracheal delivery of BMSCs on Postnatal Day 4 improved survival and exercise tolerance while attenuating alveolar and lung vascular injury and pulmonary hypertension. Engrafted BMSCs coexpressed the AEC2-specific marker surfactant protein C. However, engraftment was disproportionately low for cell replacement to account for the therapeutic benefit, suggesting a paracrine-mediated mechanism. In vitro, BMSC-derived conditioned medium prevented O(2)-induced AEC2 apoptosis, accelerated AEC2 wound healing, and enhanced endothelial cord formation. BMSCs prevent arrested alveolar and vascular growth in part through paracrine activity. Stem cell-based therapies may offer new therapeutic avenues for lung diseases that currently lack efficient treatments.

[Pulmonary cystic disease may be a rare complication to recurrent respiratory human papilloma virus infection].

PubMed

Laurberg, Peter Thaysen; Weinreich, Ulla M Øller

2014-12-08

A 19-year-old woman with a history of juvenile laryngeal papillomatosis (JLP), treated since childhood with multiple resections, was admitted with symptoms of pneumonia. A chest X-ray and CAT-scan revealed multiple lung cysts and a bronchoalveolar lavage detected human papilloma virus 11. The patient responded well to antibiotics. A body plethysmography showed small lung volumes and low diffusion capacity for carbon monoxide, but normal volume diffusion capacity divided by alveolar volume. Pulmonary cystic disease should be considered when patients with JLP have symptoms of pneumonia.

Simulation of lung alveolar epithelial wound healing in vitro.

PubMed

Kim, Sean H J; Matthay, Michael A; Mostov, Keith; Hunt, C Anthony

2010-08-06

The mechanisms that enable and regulate alveolar type II (AT II) epithelial cell wound healing in vitro and in vivo remain largely unknown and need further elucidation. We used an in silico AT II cell-mimetic analogue to explore and better understand plausible wound healing mechanisms for two conditions: cyst repair in three-dimensional cultures and monolayer wound healing. Starting with the analogue that validated for key features of AT II cystogenesis in vitro, we devised an additional cell rearrangement action enabling cyst repair. Monolayer repair was enabled by providing 'cells' a control mechanism to switch automatically to a repair mode in the presence of a distress signal. In cyst wound simulations, the revised analogue closed wounds by adhering to essentially the same axioms available for alveolar-like cystogenesis. In silico cell proliferation was not needed. The analogue recovered within a few simulation cycles but required a longer recovery time for larger or multiple wounds. In simulated monolayer wound repair, diffusive factor-mediated 'cell' migration led to repair patterns comparable to those of in vitro cultures exposed to different growth factors. Simulations predicted directional cell locomotion to be critical for successful in vitro wound repair. We anticipate that with further use and refinement, the methods used will develop as a rigorous, extensible means of unravelling mechanisms of lung alveolar repair and regeneration.

Effect of azithromycin on the LPS-induced production and secretion of phospholipase A2 in lung cells.

PubMed

Kitsiouli, Eirini; Antoniou, Georgia; Gotzou, Helen; Karagiannopoulos, Michalis; Basagiannis, Dimitris; Christoforidis, Savvas; Nakos, George; Lekka, Marilena E

2015-07-01

Azithromycin is a member of macrolides, utilized in the treatment of infections. Independently, these antibiotics also possess anti-inflammatory and immunomodulatory properties. Phospholipase A2 isotypes, which are implicated in the pathophysiology of inflammatory lung disorders, are produced by alveolar macrophages and other lung cells during inflammatory response and can promote lung injury by destructing lung surfactant. The aim of the study was to investigate whether in lung cells azithromycin can inhibit secretory and cytosolic phospholipases A2, (sPLA2) and (cPLA2), respectively, which are induced by an inflammatory trigger. In this respect, we studied the lipopolysaccharide (LPS)-mediated production or secretion of sPLA2 and cPLA2 from A549 cells, a cancer bronchial epithelial cell line, and alveolar macrophages, isolated from bronchoalveolar lavage fluid of ARDS and control patients without cardiopulmonary disease or sepsis. Pre-treatment of cells with azithromycin caused a dose-dependent decrease in the LPS-induced sPLA2-IIA levels in A549 cells. This inhibition was rather due to reduced PLA2G2A mRNA expression and secretion of sPLA2-IIA protein levels, as observed by western blotting and indirect immunofluorescence by confocal microscopy, respectively, than to the inhibition of the enzymic activity per se. On the contrary, azithromycin had no effect on the LPS-induced production or secretion of sPLA2-IIA from alveolar macrophages. The levels of LPS-induced c-PLA2 were not significantly affected by azithromycin in either cell type. We conclude that azithromycin exerts anti-inflammatory properties on lung epithelial cells through the inhibition of both the expression and secretion of LPS-induced sPLA2-IIA, while it does not affect alveolar macrophages. Copyright © 2015 Elsevier B.V. All rights reserved.

Endogenous acetylcholine increases alveolar epithelial fluid transport via activation of alveolar epithelial Na,K-ATPase in mice.

PubMed

Li, Xia; Yan, Xi Xin; Li, Hong Lin; Li, Rong Qin

2015-10-01

The contribution of endogenous acetylcholine to alveolar fluid clearance (AFC) and related molecular mechanisms were explored. AFC was measured in Balb/c mice after vagotomy and vagus nerve stimulation. Effects of acetylcholine chloride on AFC in Kunming mice and Na,K-ATPase function in A549 alveolar epithelial cells also were determined. AFC significantly decreased in mice with left cervical vagus nerve transection compared with controls (48.69 ± 2.57 vs. 66.88 ± 2.64, P ≤ 0.01), which was reversed by stimulation of the peripheral (60.81 ± 1.96, P ≤ 0.01). Compared with control, acetylcholine chloride dose-dependently increased AFC and elevated Na,K-ATPase activity, and these increases were blocked or reversed by atropine. These effects were accompanied by recruitment of Na,K-ATPase α1 to the cell membrane. Thus, vagus nerves participate in alveolar epithelial fluid transport by releasing endogenous acetylcholine in the infusion-induced pulmonary edema mouse model. Effects of endogenous acetylcholine on AFC are likely mediated by Na,K-ATPase function through activation of muscarinic acetylcholine receptors on alveolar epithelia. Copyright © 2015 Elsevier B.V. All rights reserved.

Purinergic signalling links mechanical breath profile and alveolar mechanics with the pro-inflammatory innate immune response causing ventilation-induced lung injury.

PubMed

Hasan, Djo; Blankman, Paul; Nieman, Gary F

2017-09-01

Severe pulmonary infection or vigorous cyclic deformation of the alveolar epithelial type I (AT I) cells by mechanical ventilation leads to massive extracellular ATP release. High levels of extracellular ATP saturate the ATP hydrolysis enzymes CD39 and CD73 resulting in persistent high ATP levels despite the conversion to adenosine. Above a certain level, extracellular ATP molecules act as danger-associated molecular patterns (DAMPs) and activate the pro-inflammatory response of the innate immunity through purinergic receptors on the surface of the immune cells. This results in lung tissue inflammation, capillary leakage, interstitial and alveolar oedema and lung injury reducing the production of surfactant by the damaged AT II cells and deactivating the surfactant function by the concomitant extravasated serum proteins through capillary leakage followed by a substantial increase in alveolar surface tension and alveolar collapse. The resulting inhomogeneous ventilation of the lungs is an important mechanism in the development of ventilation-induced lung injury. The high levels of extracellular ATP and the upregulation of ecto-enzymes and soluble enzymes that hydrolyse ATP to adenosine (CD39 and CD73) increase the extracellular adenosine levels that inhibit the innate and adaptive immune responses rendering the host susceptible to infection by invading microorganisms. Moreover, high levels of extracellular adenosine increase the expression, the production and the activation of pro-fibrotic proteins (such as TGF-β, α-SMA, etc.) followed by the establishment of lung fibrosis.

Interstitial lung disease induced by alectinib (CH5424802/RO5424802).

PubMed

Ikeda, Satoshi; Yoshioka, Hiroshige; Arita, Machiko; Sakai, Takahiro; Sone, Naoyuki; Nishiyama, Akihiro; Niwa, Takashi; Hotta, Machiko; Tanaka, Tomohiro; Ishida, Tadashi

2015-02-01

A 75-year-old woman with anaplastic lymphoma kinase (ALK)-rearranged Stage IV lung adenocarcinoma was administered the selective anaplastic lymphoma kinase inhibitor, alectinib, as a third-line treatment in a Phase 1-2 study. On the 102nd day, chest computed tomography showed diffuse ground glass opacities. Laboratory data revealed high serum levels of KL-6, SP-D and lactate dehydrogenase without any clinical symptoms. There was no evidence of infection. Marked lymphocytosis was seen in bronchoalveolar lavage fluid analysis, and transbronchial lung biopsy showed mild thickening of alveolar septa and lymphocyte infiltration. Interstitial lung disease was judged to be related to alectinib based on improvements in imaging findings and serum biomarkers after discontinuation of alectinib. To our knowledge, this is the first reported case of alectinib-induced interstitial lung disease. Alectinib is a promising drug for ALK-rearranged non-small cell lung cancer. Clinical trials of this selective anaplastic lymphoma kinase inhibitor will facilitate the meticulous elucidation of its long-term safety profile. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Therapeutic potential of mesenchymal stem cell transplantation in a nitrofen-induced congenital diaphragmatic hernia rat model.

PubMed

Yuniartha, Ratih; Alatas, Fatima Safira; Nagata, Kouji; Kuda, Masaaki; Yanagi, Yusuke; Esumi, Genshiro; Yamaza, Takayoshi; Kinoshita, Yoshiaki; Taguchi, Tomoaki

2014-09-01

The aim of this study was to evaluate the efficacy of mesenchymal stem cells (MSCs) in a nitrofen-induced congenital diaphragmatic hernia (CDH) rat model. Pregnant rats were exposed to nitrofen on embryonic day 9.5 (E9.5). MSCs were isolated from the enhanced green fluorescent protein (eGFP) transgenic rat lungs. The MSCs were transplanted into the nitrofen-induced E12.5 rats via the uterine vein, and the E21 lung explants were harvested. The study animals were divided into three: the control group, the nitrofen-induced left CDH (CDH group), and the MSC-treated nitrofen-induced left CDH (MSC-treated CDH group). The specimens were morphologically analyzed using HE and immunohistochemical staining with proliferating cell nuclear antigen (PCNA), surfactant protein-C (SP-C), and α-smooth muscle actin. The alveolar and medial walls of the pulmonary arteries were significantly thinner in the MSC-treated CDH group than in the CDH group. The alveolar air space areas were larger, while PCNA and the SP-C positive cells were significantly higher in the MSC-treated CDH group, than in the CDH group. MSC engraftment was identified on immunohistochemical staining of the GFP in the MSC-treated CDH group. MSC transplantation potentially promotes alveolar and pulmonary artery development, thereby reducing the severity of pulmonary hypoplasia.

Protective effects of the angiotensin type 1 receptor antagonist losartan in infection-induced and arthritis-associated alveolar bone loss.

PubMed

Queiroz-Junior, C M; Silveira, K D; de Oliveira, C R; Moura, A P; Madeira, M F M; Soriani, F M; Ferreira, A J; Fukada, S Y; Teixeira, M M; Souza, D G; da Silva, T A

2015-12-01

The angiotensin type 1 (AT1) receptor has been implicated in the pathogenesis of inflammatory bone disorders. This study aimed to investigate the effect of an AT1 receptor antagonist in infection-induced and arthritis-associated alveolar bone loss in mice. Mice were subjected to Aggregatibacter actinomycetemcomitans oral infection or antigen-induced arthritis and treated daily with 10 mg/kg of the prototype AT1 antagonist, losartan. Treatment was conducted for 30 d in the infectious condition and for 17 d and 11 d in the preventive or therapeutic regimens in the arthritic model, respectively. The mice were then killed, and the maxillae, serum and knee joints were collected for histomorphometric and immunoenzymatic assays. In vitro osteoclast assays were performed using RAW 264.7 cells stimulated with A. actinomycetemcomitans lipopolysacharide (LPS). Arthritis and A. actinomycetemcomitans infection triggered significant alveolar bone loss in mice and increased the levels of myeloperoxidase and of TRAP(+) osteoclasts in periodontal tissues. Losartan abolished such a phenotype, as well as the arthritis joint inflammation. Both arthritis and A. actinomycetemcomitans conditions were associated with the release of tumor necrosis factor alpha (TNF-α), interferon-gamma, interleukin-17 and chemokine (C-X-C motif) ligand 1 and an increased RANKL/osteoprotegerin ratio in periodontal tissues, but such expression decreased after losartan treatment, except for TNF-α. The therapeutic approach was as beneficial as the preventive one. In vitro, losartan prevented LPS-induced osteoclast differentiation and activity. The blockade of AT1 receptor exerts anti-inflammatory and anti-osteoclastic effects, thus protecting periodontal tissues in distinct pathophysiological conditions of alveolar bone loss. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Effects of O-methylated (-)-epigallocatechin gallate (EGCG) on LPS-induced osteoclastogenesis, bone resorption, and alveolar bone loss in mice.

PubMed

Tominari, Tsukasa; Ichimaru, Ryota; Yoshinouchi, Shosei; Matsumoto, Chiho; Watanabe, Kenta; Hirata, Michiko; Grundler, Florian M W; Inada, Masaki; Miyaura, Chisato

2017-12-01

(-)-Epigallocatechin-3- O -gallate (EGCG), present in green tea, exhibits antioxidant and antiallergy effects. EGCG3″Me, a 3- O -methylated derivative of EGCG, has been reported to show similar biological functions; the inhibitory activity of EGCG3″Me in a mouse allergy model was more potent than that of EGCG, probably due to the efficiency of absorption from the intestine. However, the functional potency of these EGCGs is controversial in each disease model. We previously observed that EGCG suppressed inflammatory bone resorption and prevented alveolar bone loss in a mouse model of periodontosis. In this study, we examined the role of EGCG3″Me in bone resorption using a mouse model of periodontitis. Lipopolysaccharide (LPS)-induced osteoclast formation was suppressed by adding EGCG3″Me to cocultures of osteoblasts and bone marrow cells, and LPS-induced bone resorption was also inhibited by EGCG3″Me in calvarial organ cultures. EGCG3″Me acted on osteoblasts and suppressed prostaglandin E (PGE) production, which is critical for inflammatory bone resorption, by inhibiting the expression of COX-2 and mPGES-1, key enzymes for PGE synthesis. In osteoclast precursor macrophages, EGCG3″Me suppressed RANKL-dependent differentiation into mature osteoclasts. In a mouse model of periodontitis, LPS-induced bone resorption was suppressed by EGCG3″Me in organ culture of mouse alveolar bone, and the alveolar bone loss was further attenuated by the treatment of EGCG3″Me in the lower gingiva in vivo . EGCG3″Me may be a potential natural compound for the protection of inflammatory bone loss in periodontitis.

[The effect of osteogenic inducer on healing of tooth extraction sockets].

PubMed

Chen, Junliang; Shan, Chuncheng; He, Yun; Xia, Delin

2012-06-01

To study the effect of osteogenic inducer (dexamethasone, beta-sodium glycerophosphate and Vitamin C) carried by gelatin sponge on healing and remodeling of tooth extraction sockets. Fifty rabbits were selected. After extracting the first premolars of bilateral maxillary, the right side tooth extraction sockets were filled with gelatin sponge containing osteogenic inducer as experimental side, tooth extraction sockets on left side were filled with gelatin sponge as control. Every ten rabbits were executed at the end of 1, 2, 4, 8, 12 weeks after tooth extraction. Bone density was measured through digital X-ray images. The specimens were examined by histology. The absorption height of alveolar bone at 12 weeks was measured. X-ray measurement showed that the bone density of experimental side was higher than that of control side at 2, 4, 8, 12 weeks, the difference had statistical significance (P<0.01). The histology examination showed that new bone formation in tooth extraction sockets of experimental side was earlier than that in control side. The absorptional height of alveolar bone had significant difference between experimental side and control side (P<0.01), of which experimental side was less. Filling the osteogenic inducer in tooth extraction sockets can promote the healing and new bone formation and prevent from alveolar bone absorption.

Coal Mine Dust Desquamative Chronic Interstitial Pneumonia: A Precursor of Dust-Related Diffuse Fibrosis and of Emphysema.

PubMed

Jelic, Tomislav M; Estalilla, Oscar C; Sawyer-Kaplan, Phyllis R; Plata, Milton J; Powers, Jeremy T; Emmett, Mary; Kuenstner, John T

2017-07-01

Diseases associated with coal mine dust continue to affect coal miners. Elucidation of initial pathological changes as a precursor of coal dust-related diffuse fibrosis and emphysema, may have a role in treatment and prevention. To identify the precursor of dust-related diffuse fibrosis and emphysema. Birefringent silica/silicate particles were counted by standard microscope under polarized light in the alveolar macrophages and fibrous tissue in 25 consecutive autopsy cases of complicated coal worker's pneumoconiosis and in 21 patients with tobacco-related respiratory bronchiolitis. Coal miners had 331 birefringent particles/high power field while smokers had 4 (p<0.001). Every coal miner had intra-alveolar macrophages with silica/silicate particles and interstitial fibrosis ranging from minimal to extreme. All coal miners, including those who never smoked, had emphysema. Fibrotic septa of centrilobular emphysema contained numerous silica/silicate particles while only a few were present in adjacent normal lung tissue. In coal miners who smoked, tobacco-associated interstitial fibrosis was replaced by fibrosis caused by silica/silicate particles. The presence of silica/silicate particles and anthracotic pigment-laden macrophages inside the alveoli with various degrees of interstitial fibrosis indicated a new disease: coal mine dust desquamative chronic interstitial pneumonia, a precursor of both dust-related diffuse fibrosis and emphysema. In studied coal miners, fibrosis caused by smoking is insignificant in comparison with fibrosis caused by silica/silicate particles. Counting birefringent particles in the macrophages from bronchioalveolar lavage may help detect coal mine dust desquamative chronic interstitial pneumonia, and may initiate early therapy and preventive measures.

Integrated Stress Response Mediates Epithelial Injury in Mechanical Ventilation.

PubMed

Dolinay, Tamas; Himes, Blanca E; Shumyatcher, Maya; Lawrence, Gladys Gray; Margulies, Susan S

2017-08-01

Ventilator-induced lung injury (VILI) is a severe complication of mechanical ventilation that can lead to acute respiratory distress syndrome. VILI is characterized by damage to the epithelial barrier with subsequent pulmonary edema and profound hypoxia. Available lung-protective ventilator strategies offer only a modest benefit in preventing VILI because they cannot impede alveolar overdistension and concomitant epithelial barrier dysfunction in the inflamed lung regions. There are currently no effective biochemical therapies to mitigate injury to the alveolar epithelium. We hypothesize that alveolar stretch activates the integrated stress response (ISR) pathway and that the chemical inhibition of this pathway mitigates alveolar barrier disruption during stretch and mechanical ventilation. Using our established rat primary type I-like alveolar epithelial cell monolayer stretch model and in vivo rat mechanical ventilation that mimics the alveolar overdistension seen in acute respiratory distress syndrome, we studied epithelial responses to mechanical stress. Our studies revealed that the ISR signaling pathway is a key modulator of epithelial permeability. We show that prolonged epithelial stretch and injurious mechanical ventilation activate the ISR, leading to increased alveolar permeability, cell death, and proinflammatory signaling. Chemical inhibition of protein kinase RNA-like endoplasmic reticulum kinase, an upstream regulator of the pathway, resulted in decreased injury signaling and improved barrier function after prolonged cyclic stretch and injurious mechanical ventilation. Our results provide new evidence that therapeutic targeting of the ISR can mitigate VILI.

Histopathological evaluation of the diversity of cells susceptible to H5N1 virulent avian influenza virus.

PubMed

Ogiwara, Haru; Yasui, Fumihiko; Munekata, Keisuke; Takagi-Kamiya, Asako; Munakata, Tsubasa; Nomura, Namiko; Shibasaki, Futoshi; Kuwahara, Kazuhiko; Sakaguchi, Nobuo; Sakoda, Yoshihiro; Kida, Hiroshi; Kohara, Michinori

2014-01-01

Patients infected with highly pathogenic avian influenza A H5N1 viruses (H5N1 HPAIV) show diffuse alveolar damage. However, the temporal progression of tissue damage and repair after viral infection remains poorly defined. Therefore, we assessed the sequential histopathological characteristics of mouse lung after intranasal infection with H5N1 HPAIV or H1N1 2009 pandemic influenza virus (H1N1 pdm). We determined the amount and localization of virus in the lung through IHC staining and in situ hybridization. IHC used antibodies raised against the virus protein and antibodies specific for macrophages, type II pneumocytes, or proliferating cell nuclear antigen. In situ hybridization used RNA probes against both viral RNA and mRNA encoding the nucleoprotein and the hemagglutinin protein. H5N1 HPAIV infection and replication were observed in multiple lung cell types and might result in rapid progression of lung injury. Both type II pneumocytes and macrophages proliferated after H5N1 HPAIV infection. However, the abundant macrophages failed to block the viral attack, and proliferation of type II pneumocytes failed to restore the damaged alveoli. In contrast, mice infected with H1N1 pdm exhibited modest proliferation of type II pneumocytes and macrophages and slight alveolar damage. These results suggest that the virulence of H5N1 HPAIV results from the wide range of cell tropism of the virus, excessive virus replication, and rapid development of diffuse alveolar damage. Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Histopathological Evaluation of the Diversity of Cells Susceptible to H5N1 Virulent Avian Influenza Virus

PubMed Central

Ogiwara, Haru; Yasui, Fumihiko; Munekata, Keisuke; Takagi-Kamiya, Asako; Munakata, Tsubasa; Nomura, Namiko; Shibasaki, Futoshi; Kuwahara, Kazuhiko; Sakaguchi, Nobuo; Sakoda, Yoshihiro; Kida, Hiroshi; Kohara, Michinori

2015-01-01

Patients infected with highly pathogenic avian influenza A H5N1 viruses (H5N1 HPAIV) show diffuse alveolar damage. However, the temporal progression of tissue damage and repair after viral infection remains poorly defined. Therefore, we assessed the sequential histopathological characteristics of mouse lung after intranasal infection with H5N1 HPAIV or H1N1 2009 pandemic influenza virus (H1N1 pdm). We determined the amount and localization of virus in the lung through IHC staining and in situ hybridization. IHC used antibodies raised against the virus protein and antibodies specific for macrophages, type II pneumocytes, or proliferating cell nuclear antigen. In situ hybridization used RNA probes against both viral RNA and mRNA encoding the nucleoprotein and the hemagglutinin protein. H5N1 HPAIV infection and replication were observed in multiple lung cell types and might result in rapid progression of lung injury. Both type II pneumocytes and macrophages proliferated after H5N1 HPAIV infection. However, the abundant macrophages failed to block the viral attack, and proliferation of type II pneumocytes failed to restore the damaged alveoli. In contrast, mice infected with H1N1 pdm exhibited modest proliferation of type II pneumocytes and macrophages and slight alveolar damage. These results suggest that the virulence of H5N1 HPAIV results from the wide range of cell tropism of the virus, excessive virus replication, and rapid development of diffuse alveolar damage. PMID:24200852

Lung Structure and the Intrinsic Challenges of Gas Exchange.

PubMed

Hsia, Connie C W; Hyde, Dallas M; Weibel, Ewald R

2016-03-15

Structural and functional complexities of the mammalian lung evolved to meet a unique set of challenges, namely, the provision of efficient delivery of inspired air to all lung units within a confined thoracic space, to build a large gas exchange surface associated with minimal barrier thickness and a microvascular network to accommodate the entire right ventricular cardiac output while withstanding cyclic mechanical stresses that increase several folds from rest to exercise. Intricate regulatory mechanisms at every level ensure that the dynamic capacities of ventilation, perfusion, diffusion, and chemical binding to hemoglobin are commensurate with usual metabolic demands and periodic extreme needs for activity and survival. This article reviews the structural design of mammalian and human lung, its functional challenges, limitations, and potential for adaptation. We discuss (i) the evolutionary origin of alveolar lungs and its advantages and compromises, (ii) structural determinants of alveolar gas exchange, including architecture of conducting bronchovascular trees that converge in gas exchange units, (iii) the challenges of matching ventilation, perfusion, and diffusion and tissue-erythrocyte and thoracopulmonary interactions. The notion of erythrocytes as an integral component of the gas exchanger is emphasized. We further discuss the signals, sources, and limits of structural plasticity of the lung in alveolar hypoxia and following a loss of lung units, and the promise and caveats of interventions aimed at augmenting endogenous adaptive responses. Our objective is to understand how individual components are matched at multiple levels to optimize organ function in the face of physiological demands or pathological constraints. Copyright © 2016 John Wiley & Sons, Inc.

A computer model for the simulation of nanoparticle deposition in the alveolar structures of the human lungs.

PubMed

Sturm, Robert

2015-11-01

According to epidemiological and experimental studies, inhalation of nanoparticles is commonly believed as a main trigger for several pulmonary dysfunctions and lung diseases. Concerning the transport and deposition of such nano-scale particles in the different structures of the human lungs, some essential questions are still in need of a clarification. Therefore, main objective of the study was the simulation of nanoparticle deposition in the alveolar region of the human respiratory tract (HRT). Respective factors describing the aerodynamic behavior of spherical and non-spherical particles in the inhaled air stream (i.e., Cunningham slip correction factors, dynamic shape factors, equivalent-volume diameters, aerodynamic diameters) were computed. Alveolar deposition of diverse nanomaterials according to several known mechanisms, among which Brownian diffusion and sedimentation play a superior role, was approximated by the use of empirical and analytical formulae. Deposition calculations were conducted with a currently developed program, termed NANODEP, which allows the variation of numerous input parameters with regard to particle geometry, lung morphometry, and aerosol inhalation. Generally, alveolar deposition of nanoparticles concerned for this study varies between 0.1% and 12.4% during sitting breathing and between 2.0% and 20.1% during heavy-exercise breathing. Prolate particles (e.g., nanotubes) exhibit a significant increase in deposition, when their aspect ratio is enhanced. In contrast, deposition of oblate particles (e.g., nanoplatelets) is remarkably declined with any reduction of the aspect ratio. The study clearly demonstrates that alveolar deposition of nanoparticles represents a topic certainly being of superior interest for physicists and respiratory physicians in future.

The histopathological and morphometric investigation of the effects of systemically administered boric acid on alveolar bone loss in ligature-induced periodontitis in diabetic rats.

PubMed

Balci Yuce, Hatice; Toker, Hulya; Goze, Fahrettin

2014-11-01

The purpose of this study was to evaluate the effects of systemically administered boric acid on alveolar bone loss, histopathological changes and oxidant/antioxidant status in ligature-induced periodontitis in diabetic rats. Forty-four Wistar rats were divided into six experimental groups: (1) non-ligated (NL, n = 6) group, (2) ligature only (LO, n = 6) group, (3) Streptozotocin only (STZ, n = 8) group, (4) STZ and ligature (STZ+LO, n = 8) group, (5) STZ, ligature and systemic administration of 15 mg/kg/day boric acid for 15 days (BA15, n = 8) group and (6) STZ, ligature and systemic administration of 30 mg/kg/day boric acid for 15 days (BA30, n = 8) group. Diabetes mellitus was induced by 60 mg/kg streptozotocin. Silk ligatures were placed at the gingival margin of lower first molars of the mandibular quadrant. The study duration was 15 days after diabetes induction and the animals were sacrificed at the end of this period. Changes in alveolar bone levels were clinically measured and tissues were histopathologically examined. Serum total antioxidant status (TAS), total oxidant status (TOS), calcium (Ca) and magnesium (Mg) levels and oxidative stress index (OSI) were evaluated. Primary outcome was alveolar bone loss. Seconder outcome (osteoblast number) was also measured. At the end of 15 days, the alveolar bone loss was significantly higher in the STZ+LO group compared to the other groups (p < 0.05). There was no significant difference in alveolar bone loss between the STZ+LO 15 mg/kg boric acid and STZ+LO 30 mg/kg boric acid groups (p > 0.05). Systemically administered boric acid significantly decreased alveolar bone loss compared to the STZ+LO group (p < 0.05). The osteoblast number in the BA30 group was significantly higher than those of the NL, STZ and STZ+LO groups (p < 0.05). Inflammatory cell infiltration was significantly higher in the STZ+LO group the other groups (p < 0.05). Serum TAS levels were significantly higher in the NL and LO groups than the other groups (p < 0.05). The differences in TOS levels were not found to be significant among all the groups (p > 0.05). The OSI values of the BA30 group were significantly lower than the STZ+LO group (p < 0.05). Also, the differences in serum calcium and magnesium levels were insignificant among the all groups (p > 0.05). Within the limits of this study, it can be suggested that BA, when administered systemically, may reduce alveolar bone loss in the diabetic rat model.

Macrophage functions measured by magnetic microparticles in vivo and in vitro

NASA Astrophysics Data System (ADS)

Möller, Winfried; Kreyling, Wolfgang G.; Kohlhäufl, Martin; Häussinger, Karl; Heyder, Joachim

2001-01-01

Monodisperse ferrimagnetic iron-oxide particles of 1.4 μm geometric diameter were used to study alveolar macrophage functions (phagocytosis, phagosome transport) and cytoskeletal integrity in healthy subjects and in patients with idiopathic pulmonary fibrosis as well as in cultured macrophages. Dysfunctions in phagocytosis, in phagosome transport and cytoskeletal integrity correlated with an impaired alveolar clearance and could be induced in vitro by cytoskeletal drugs.

Ceramides: a potential therapeutic target in pulmonary emphysema.

PubMed

Tibboel, Jeroen; Reiss, Irwin; de Jongste, Johan C; Post, Martin

2013-10-01

The aim of this manuscript was to characterize airway ceramide profiles in a rodent model of elastase-induced emphysema and to examine the effect of pharmacological intervention directed towards ceramide metabolism. Adult mice were anesthetized and treated with an intratracheal instillation of elastase. Lung function was measured, broncho-alveolar lavage fluid collected and histological and morphometrical analysis of lung tissue performed within 3 weeks after elastase injection, with and without sphingomyelinase inhibitors or serine palmitoyltransferase inhibitor. Ceramides in broncho-alveolar lavage (BAL) fluid were quantified by tandem mass spectrometry. BAL fluid showed a transient increase in total protein and IgM, and activated macrophages and neutrophils. Ceramides were transiently upregulated at day 2 after elastase treatment. Histology showed persistent patchy alveolar destruction at day 2 after elastase installation. Acid and neutral sphingomyelinase inhibitors had no effect on BAL ceramide levels, lung function or histology. Addition of a serine palmitoyltransferase inhibitor ameliorated lung function changes and reduced ceramides in BAL. Ceramides were increased during the acute inflammatory phase of elastase-induced lung injury. Since addition of a serine palmitoyltransferase inhibitor diminished the rise in ceramides and ameliorated lung function, ceramides likely contributed to the early phase of alveolar destruction and are a potential therapeutic target in the elastase model of lung emphysema.

Pirfenidone inhibits p38-mediated generation of procoagulant microparticles by human alveolar epithelial cells.

PubMed

Neri, Tommaso; Lombardi, Stefania; Faìta, Francesca; Petrini, Silvia; Balìa, Cristina; Scalise, Valentina; Pedrinelli, Roberto; Paggiaro, Pierluigi; Celi, Alessandro

2016-08-01

Pirfenidone is a drug recently approved for idiopathic pulmonary fibrosis but its mechanisms of action are partially unknown. We have previously demonstrated that the airways of patients with idiopathic pulmonary fibrosis contain procoagulant microparticles that activate coagulation factor X to its active form, Xa, a proteinase that signals fibroblast growth and differentiation, thus potentially contributing to the pathogenesis of the disease. We also reported that in vitro exposure of human alveolar cells to H2O2 causes microparticle generation. Since p38 activation is involved in microparticle generation in some cell models and p38 inhibition is one of the mechanisms of action of pirfenidone, we investigated the hypothesis that H2O2-induced generation of microparticles by alveolar cells is dependent on p38 phosphorylation and is inhibited by pirfenidone. H2O2 stimulation of alveolar cells caused p38 phosphorylation that was inhibited by pirfenidone. The drug also inhibited H2O2 induced microparticle generation as assessed by two independent methods (solid phase thrombin generation and flow cytometry). The shedding of microparticle-bound tissue factor activity was also inhibited by pirfenidone. Inhibition of p38-mediated generation of procoagulant microparticle is a previously unrecognized mechanism of action of the antifibrotic drug, pirfenidone. Copyright © 2016 Elsevier Ltd. All rights reserved.

Morphometric Characterization of Rat and Human Alveolar Macrophage Cell Models and their Response to Amiodarone using High Content Image Analysis.

PubMed

Hoffman, Ewelina; Patel, Aateka; Ball, Doug; Klapwijk, Jan; Millar, Val; Kumar, Abhinav; Martin, Abigail; Mahendran, Rhamiya; Dailey, Lea Ann; Forbes, Ben; Hutter, Victoria

2017-12-01

Progress to the clinic may be delayed or prevented when vacuolated or "foamy" alveolar macrophages are observed during non-clinical inhalation toxicology assessment. The first step in developing methods to study this response in vitro is to characterize macrophage cell lines and their response to drug exposures. Human (U937) and rat (NR8383) cell lines and primary rat alveolar macrophages obtained by bronchoalveolar lavage were characterized using high content fluorescence imaging analysis quantification of cell viability, morphometry, and phospholipid and neutral lipid accumulation. Cell health, morphology and lipid content were comparable (p < 0.05) for both cell lines and the primary macrophages in terms of vacuole number, size and lipid content. Responses to amiodarone, a known inducer of phospholipidosis, required analysis of shifts in cell population profiles (the proportion of cells with elevated vacuolation or lipid content) rather than average population data which was insensitive to the changes observed. A high content image analysis assay was developed and used to provide detailed morphological characterization of rat and human alveolar-like macrophages and their response to a phospholipidosis-inducing agent. This provides a basis for development of assays to predict or understand macrophage vacuolation following inhaled drug exposure.

Acute Lung Injury Edema Fluid Decreases Net Fluid Transport across Human Alveolar Epithelial Type II Cells*

PubMed Central

Lee, Jae W.; Fang, Xiaohui; Dolganov, Gregory; Fremont, Richard D.; Bastarache, Julie A.; Ware, Lorraine B.; Matthay, Michael A.

2009-01-01

Most patients with acute lung injury (ALI) have reduced alveolar fluid clearance that has been associated with higher mortality. Several mechanisms may contribute to the decrease in alveolar fluid clearance. In this study, we tested the hypothesis that pulmonary edema fluid from patients with ALI might reduce the expression of ion transport genes responsible for vectorial fluid transport in primary cultures of human alveolar epithelial type II cells. Following exposure to ALI pulmonary edema fluid, the gene copy number for the major sodium and chloride transport genes decreased. By Western blot analyses, protein levels of αENaC, α1Na,K-ATPase, and cystic fibrosis transmembrane conductance regulator decreased as well. In contrast, the gene copy number for several inflammatory cytokines increased markedly. Functional studies demonstrated that net vectorial fluid transport was reduced for human alveolar type II cells exposed to ALI pulmonary edema fluid compared with plasma (0.02±0.05 versus 1.31±0.56 μl/cm2/h, p<0.02). An inhibitor of p38 MAPK phosphorylation (SB202190) partially reversed the effects of the edema fluid on net fluid transport as well as gene and protein expression of the main ion transporters. In summary, alveolar edema fluid from patients with ALI induced a significant reduction in sodium and chloride transport genes and proteins in human alveolar epithelial type II cells, effects that were associated with a decrease in net vectorial fluid transport across human alveolar type II cell monolayers. PMID:17580309

Adrenal medullary hyperplasia. Hyperplasia-pheochromocytoma sequence.

PubMed

Kurihara, K; Mizuseki, K; Kondo, T; Ohoka, H; Mannami, M; Kawai, K

1990-09-01

We present a case of unilateral adrenal medullary hyperplasia in a 63-year-old woman with clinical signs and symptoms of pheochromocytoma unassociated with multiple endocrine neoplasia. The surgically removed adrenal gland revealed diffuse medullary hyperplasia with multiple micronodules measuring up to 2 mm. The micronodules were composed of enlarged chromaffin cells with atypia, histologically similar to those of pheochromocytoma, forming small solid alveolar patterns separated by a fibrovascular stroma. Removal of the hyperplastic adrenal gland resulted in disappearance of paroxysmal nocturnal hypertension and palpitation. These results suggest that diffuse and nodular medullary hyperplasia is the precursor of pheochromocytoma.

NOD2 enhances the innate response of alveolar macrophages to Mycobacterium tuberculosis in humans.

PubMed

Juárez, Esmeralda; Carranza, Claudia; Hernández-Sánchez, Fernando; León-Contreras, Juan C; Hernández-Pando, Rogelio; Escobedo, Dante; Torres, Martha; Sada, Eduardo

2012-04-01

A role for the nucleotide-binding oligomerization domain 2 (NOD2) receptor in pulmonary innate immune responses has recently been explored. In the present study, we investigated the role that NOD2 plays in human alveolar macrophage innate responses and determined its involvement in the response to infection with virulent Mycobacterium tuberculosis. Our results showed that NOD2 was expressed in human alveolar macrophages, and significant amounts of IL-1β, IL-6, and TNF-α were produced upon ligand recognition with muramyldipeptide (MDP). NOD2 ligation induced the transcription and protein expression of the antimicrobial peptide LL37 and the autophagy enzyme IRGM in alveolar macrophages, demonstrating a novel function for this receptor in these cells. MDP treatment of alveolar macrophages improved the intracellular growth control of virulent M. tuberculosis; this was associated with a significant release of TNF-α and IL-6 and overexpression of bactericidal LL37. In addition, the autophagy proteins IRGM, LC3 and ATG16L1 were recruited to the bacteria-containing autophagosome after treatment with MDP. In conclusion, our results suggest that NOD2 can modulate the innate immune response of alveolar macrophages and play a role in the initial control of respiratory M. tuberculosis infections. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Multi-walled carbon nanotube length as a critical determinant of bioreactivity with primary human pulmonary alveolar cells

PubMed Central

Sweeney, Sinbad; Berhanu, Deborah; Misra, Superb K.; Thorley, Andrew J.; Valsami-Jones, Eugenia; Tetley, Teresa D.

2015-01-01

Multiwalled carbon nanotube (MWCNT) length is suggested to critically determine their pulmonary toxicity. This stems from in vitro and in vivo rodent studies and in vitro human studies using cell lines (typically cancerous). There is little data using primary human lung cells. We addressed this knowledge gap, using highly relevant, primary human alveolar cell models exposed to precisely synthesized and thoroughly characterized MWCNTs. In this work, transformed human alveolar type-I-like epithelial cells (TT1), primary human alveolar type-II epithelial cells (ATII) and alveolar macrophages (AM) were treated with increasing concentrations of MWCNTs before measuring cytotoxicity, inflammatory mediator release and MAP kinase signalling. Strikingly, we observed that short MWCNTs (~0.6 µm in length) induced significantly greater responses from the epithelial cells, whilst AM were particularly susceptible to long MWCNTs (~20 µm). These differences in the pattern of mediator release were associated with alternative profiles of JNK, p38 and ERK1/2 MAP kinase signal transduction within each cell type. This study, using highly relevant target human alveolar cells and well defined and characterized MWCNTs, shows marked cellular responses to the MWCNTs that vary according to the target cell type, as well as the aspect ratio of the MWCNT. PMID:25780270

Platelet-Rich Fibrin Promotes Periodontal Regeneration and Enhances Alveolar Bone Augmentation

PubMed Central

Li, Qi; Pan, Shuang; Dangaria, Smit J.; Gopinathan, Gokul; Kolokythas, Antonia; Chu, Shunli; Geng, Yajun; Zhou, Yanmin; Luan, Xianghong

2013-01-01

In the present study we have determined the suitability of platelet-rich fibrin (PRF) as a complex scaffold for periodontal tissue regeneration. Replacing PRF with its major component fibrin increased mineralization in alveolar bone progenitors when compared to periodontal progenitors, suggesting that fibrin played a substantial role in PRF-induced osteogenic lineage differentiation. Moreover, there was a 3.6-fold increase in the early osteoblast transcription factor RUNX2 and a 3.1-fold reduction of the mineralization inhibitor MGP as a result of PRF application in alveolar bone progenitors, a trend not observed in periodontal progenitors. Subcutaneous implantation studies revealed that PRF readily integrated with surrounding tissues and was partially replaced with collagen fibers 2 weeks after implantation. Finally, clinical pilot studies in human patients documented an approximately 5 mm elevation of alveolar bone height in tandem with oral mucosal wound healing. Together, these studies suggest that PRF enhances osteogenic lineage differentiation of alveolar bone progenitors more than of periodontal progenitors by augmenting osteoblast differentiation, RUNX2 expression, and mineralized nodule formation via its principal component fibrin. They also document that PRF functions as a complex regenerative scaffold promoting both tissue-specific alveolar bone augmentation and surrounding periodontal soft tissue regeneration via progenitor-specific mechanisms. PMID:23586051

Platelet-rich fibrin promotes periodontal regeneration and enhances alveolar bone augmentation.

PubMed

Li, Qi; Pan, Shuang; Dangaria, Smit J; Gopinathan, Gokul; Kolokythas, Antonia; Chu, Shunli; Geng, Yajun; Zhou, Yanmin; Luan, Xianghong

2013-01-01

In the present study we have determined the suitability of platelet-rich fibrin (PRF) as a complex scaffold for periodontal tissue regeneration. Replacing PRF with its major component fibrin increased mineralization in alveolar bone progenitors when compared to periodontal progenitors, suggesting that fibrin played a substantial role in PRF-induced osteogenic lineage differentiation. Moreover, there was a 3.6-fold increase in the early osteoblast transcription factor RUNX2 and a 3.1-fold reduction of the mineralization inhibitor MGP as a result of PRF application in alveolar bone progenitors, a trend not observed in periodontal progenitors. Subcutaneous implantation studies revealed that PRF readily integrated with surrounding tissues and was partially replaced with collagen fibers 2 weeks after implantation. Finally, clinical pilot studies in human patients documented an approximately 5 mm elevation of alveolar bone height in tandem with oral mucosal wound healing. Together, these studies suggest that PRF enhances osteogenic lineage differentiation of alveolar bone progenitors more than of periodontal progenitors by augmenting osteoblast differentiation, RUNX2 expression, and mineralized nodule formation via its principal component fibrin. They also document that PRF functions as a complex regenerative scaffold promoting both tissue-specific alveolar bone augmentation and surrounding periodontal soft tissue regeneration via progenitor-specific mechanisms.

Simulation of lung alveolar epithelial wound healing in vitro

PubMed Central

Kim, Sean H. J.; Matthay, Michael A.; Mostov, Keith; Hunt, C. Anthony

2010-01-01

The mechanisms that enable and regulate alveolar type II (AT II) epithelial cell wound healing in vitro and in vivo remain largely unknown and need further elucidation. We used an in silico AT II cell-mimetic analogue to explore and better understand plausible wound healing mechanisms for two conditions: cyst repair in three-dimensional cultures and monolayer wound healing. Starting with the analogue that validated for key features of AT II cystogenesis in vitro, we devised an additional cell rearrangement action enabling cyst repair. Monolayer repair was enabled by providing ‘cells’ a control mechanism to switch automatically to a repair mode in the presence of a distress signal. In cyst wound simulations, the revised analogue closed wounds by adhering to essentially the same axioms available for alveolar-like cystogenesis. In silico cell proliferation was not needed. The analogue recovered within a few simulation cycles but required a longer recovery time for larger or multiple wounds. In simulated monolayer wound repair, diffusive factor-mediated ‘cell’ migration led to repair patterns comparable to those of in vitro cultures exposed to different growth factors. Simulations predicted directional cell locomotion to be critical for successful in vitro wound repair. We anticipate that with further use and refinement, the methods used will develop as a rigorous, extensible means of unravelling mechanisms of lung alveolar repair and regeneration. PMID:20236957

Traffic-related air pollution and alveolar nitric oxide in southern California children.

PubMed

Eckel, Sandrah P; Zhang, Zilu; Habre, Rima; Rappaport, Edward B; Linn, William S; Berhane, Kiros; Zhang, Yue; Bastain, Theresa M; Gilliland, Frank D

2016-05-01

Mechanisms for the adverse respiratory effects of traffic-related air pollution (TRAP) have yet to be established. We evaluated the acute effects of TRAP exposure on proximal and distal airway inflammation by relating indoor nitric oxide (NO), a marker of TRAP exposure in the indoor microenvironment, to airway and alveolar sources of exhaled nitric oxide (FeNO).FeNO was collected online at four flow rates in 1635 schoolchildren (aged 12-15 years) in southern California (USA) breathing NO-free air. Indoor NO was sampled hourly and linearly interpolated to the time of the FeNO test. Estimated parameters quantifying airway wall diffusivity (DawNO) and flux (J'awNO) and alveolar concentration (CANO) sources of FeNO were related to exposure using linear regression to adjust for potential confounders.We found that TRAP exposure indoors was associated with elevated alveolar NO. A 10 ppb higher indoor NO concentration at the time of the FeNO test was associated with 0.10 ppb higher average CANO (95% CI 0.04-0.16) (equivalent to a 7.1% increase from the mean), 4.0% higher J'awNO (95% CI -2.8-11.3) and 0.2% lower DawNO (95% CI -4.8-4.6).These findings are consistent with an airway response to TRAP exposure that was most marked in the distal airways. Copyright ©ERS 2016.

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

Sunil, Vasanthi R., E-mail: sunilvr@eohsi.rutgers.edu; Patel, Kinal J., E-mail: kinalv5@gmail.com; Shen, Jianliang, E-mail: jianliangs@gmail.com

Nitrogen mustard is a vesicant that causes damage to the respiratory tract. In these studies, we characterized the acute effects of nitrogen mustard on lung structure, inflammatory mediator expression, and pulmonary function, with the goal of identifying mediators potentially involved in toxicity. Treatment of rats (male Wistar, 200-225 g) with nitrogen mustard (mechlorethamine hydrochloride, i.t., 0.25 mg/kg) resulted in marked histological changes in the respiratory tract, including necrotizing bronchiolitis, thickening of alveolar septa, and inflammation which was evident within 24 h. This was associated with increases in bronchoalveolar lavage protein and cells, confirming injury to alveolar epithelial regions of themore » lung. Nitrogen mustard administration also resulted in increased expression of inducible nitric oxide synthase and cyclooxygenase-2, pro-inflammatory proteins implicated in lung injury, in alveolar macrophages and alveolar and bronchial epithelial cells. Expression of connective tissue growth factor and matrix metalloproteinase-9, mediators regulating extracellular matrix turnover was also increased, suggesting that pathways leading to chronic lung disease are initiated early in the pathogenic process. Following nitrogen mustard exposure, alterations in lung mechanics and function were also observed. These included decreases in baseline static compliance, end-tidal volume and airway resistance, and a pronounced loss of methacholine responsiveness in resistance, tissue damping and elastance. Taken together, these data demonstrate that nitrogen mustard induces rapid structural and inflammatory changes in the lung which are associated with altered lung functioning. Understanding the nature of the injury induced by nitrogen mustard and related analogs may aid in the development of efficacious therapies for treatment of pulmonary injury resulting from exposure to vesicants.« less

Injurious mechanical ventilation in the normal lung causes a progressive pathologic change in dynamic alveolar mechanics.

PubMed

Pavone, Lucio A; Albert, Scott; Carney, David; Gatto, Louis A; Halter, Jeffrey M; Nieman, Gary F

2007-01-01

Acute respiratory distress syndrome causes a heterogeneous lung injury, and without protective mechanical ventilation a secondary ventilator-induced lung injury can occur. To ventilate noncompliant lung regions, high inflation pressures are required to 'pop open' the injured alveoli. The temporal impact, however, of these elevated pressures on normal alveolar mechanics (that is, the dynamic change in alveolar size and shape during ventilation) is unknown. In the present study we found that ventilating the normal lung with high peak pressure (45 cmH(2)0) and low positive end-expiratory pressure (PEEP of 3 cmH(2)O) did not initially result in altered alveolar mechanics, but alveolar instability developed over time. Anesthetized rats underwent tracheostomy, were placed on pressure control ventilation, and underwent sternotomy. Rats were then assigned to one of three ventilation strategies: control group (n = 3, P control = 14 cmH(2)O, PEEP = 3 cmH(2)O), high pressure/low PEEP group (n = 6, P control = 45 cmH(2)O, PEEP = 3 cmH(2)O), and high pressure/high PEEP group (n = 5, P control = 45 cmH(2)O, PEEP = 10 cmH(2)O). In vivo microscopic footage of subpleural alveolar stability (that is, recruitment/derecruitment) was taken at baseline and than every 15 minutes for 90 minutes following ventilator adjustments. Alveolar recruitment/derecruitment was determined by measuring the area of individual alveoli at peak inspiration (I) and end expiration (E) by computer image analysis. Alveolar recruitment/derecruitment was quantified by the percentage change in alveolar area during tidal ventilation (%I - E Delta). Alveoli were stable in the control group for the entire experiment (low %I - E Delta). Alveoli in the high pressure/low PEEP group were initially stable (low %I - E Delta), but with time alveolar recruitment/derecruitment developed. The development of alveolar instability in the high pressure/low PEEP group was associated with histologic lung injury. A large change in lung volume with each breath will, in time, lead to unstable alveoli and pulmonary damage. Reducing the change in lung volume by increasing the PEEP, even with high inflation pressure, prevents alveolar instability and reduces injury. We speculate that ventilation with large changes in lung volume over time results in surfactant deactivation, which leads to alveolar instability.

Thirteen Week Oral Toxicity Study of WR242511 in Rats. Volume 1

DTIC Science & Technology

1994-01-14

hypercholesterolemia and hypertriglyceridemia seen in high dose females, as previously discussed. Heptatobiliary changes were suggested by significant elevations in...lung (alveolar histiocytosis) lesions. Severe thymic lymphocyte depletion was also observed in these animals where the thymus could be identified...this animal, but it was attributed to the severe and diffuse chronic-active inflammation. As indicated above, treatment-related histopathologic

Acute diffuse alveolar haemorrhage accompanied by gastrointestinal bleeding in a patient with serious systemic lupus erythematosus: A case report.

PubMed

Du, Jing; Wang, Ying; Li, Yan-Chun; Wang, Tong-Tong; Zhou, Yong-Lie; Ying, Zhen-Hua

2018-05-01

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects many organs, but multisystem dysfunction is rare. Here, we report a case of a 29-year-old woman who was initially diagnosed with SLE complications including lupus nephritis, lupus encephalopathy, renal hypertension, thrombocytopenia, anaemia and hyperkalaemia. She recovered following treatment with high dose methylprednisolone, intravenous immunoglobulin (IVIG) and continuous renal replacement therapy (CRRT). However, a few days after hospital discharge, she developed gastrointestinal bleeding. Although intensive treatment was administered, the patient deteriorated rapidly and had a progressive decline in oxygen saturation followed by diffuse alveolar haemorrhage and acute left heart failure. Inotropic therapy, mechanical ventilation, blood transfusion, CRRT, antibiotics, intravenous glucocorticoids and other support therapies were initiated and gradually the patient's vital signs stabilized and haemoptysis subsided. This case report emphasises that complications of SLE can occur at any stage of the disease, especially in patients with active SLE. Therefore, it is important for clinicians to be aware of the rare presentations of SLE and its complex management. For multisystem dysfunction, early intensive treatment with high dose corticosteroids and cyclophosphamide is advocated.

A novel swine model of ricin-induced acute respiratory distress syndrome.

PubMed

Katalan, Shahaf; Falach, Reut; Rosner, Amir; Goldvaser, Michael; Brosh-Nissimov, Tal; Dvir, Ayana; Mizrachi, Avi; Goren, Orr; Cohen, Barak; Gal, Yoav; Sapoznikov, Anita; Ehrlich, Sharon; Sabo, Tamar; Kronman, Chanoch

2017-02-01

Pulmonary exposure to the plant toxin ricin leads to respiratory insufficiency and death. To date, in-depth study of acute respiratory distress syndrome (ARDS) following pulmonary exposure to toxins is hampered by the lack of an appropriate animal model. To this end, we established the pig as a large animal model for the comprehensive study of the multifarious clinical manifestations of pulmonary ricinosis. Here, we report for the first time, the monitoring of barometric whole body plethysmography for pulmonary function tests in non-anesthetized ricin-treated pigs. Up to 30 h post-exposure, as a result of progressing hypoxemia and to prevent carbon dioxide retention, animals exhibited a compensatory response of elevation in minute volume, attributed mainly to a large elevation in respiratory rate with minimal response in tidal volume. This response was followed by decompensation, manifested by a decrease in minute volume and severe hypoxemia, refractory to oxygen treatment. Radiological evaluation revealed evidence of early diffuse bilateral pulmonary infiltrates while hemodynamic parameters remained unchanged, excluding cardiac failure as an explanation for respiratory insufficiency. Ricin-intoxicated pigs suffered from increased lung permeability accompanied by cytokine storming. Histological studies revealed lung tissue insults that accumulated over time and led to diffuse alveolar damage. Charting the decline in PaO2/FiO2 ratio in a mechanically ventilated pig confirmed that ricin-induced respiratory damage complies with the accepted diagnostic criteria for ARDS. The establishment of this animal model of pulmonary ricinosis should help in the pursuit of efficient medical countermeasures specifically tailored to deal with the respiratory deficiencies stemming from ricin-induced ARDS. © 2017. Published by The Company of Biologists Ltd.

Reasons for mini-implants failure: choosing installation site should be valued!

PubMed Central

Consolaro, Alberto; Romano, Fábio Lourenço

2014-01-01

Mini-implant loss is often associated with physical and mechanical aspects that result from choosing an inappropriate placement site. It is worth highlighting that: a) Interdental alveolar bone crests are flexible and deformable. For this reason, they may not offer the ideal absolute anchorage. The more cervical the structures, the more delicate they are, thus offering less physical support for mini-implant placement; b) Alveolar bone crests of triangular shape are more deformable, whereas those of rectangular shape are more flexible; c) The bases of the alveolar processes of the maxilla and the mandible are not flexible, for this reason, they are more likely to receive mini-implants; d) The more cervical a mini-implant is placed, the higher the risk of loss; the more apical a mini-implant is placed, the better its prognosis will be; e) 3D evaluations play a major role in planning the use of mini-implants. Based on the aforementioned considerations, the hypotheses about mini-implant loss are as follows: 1) Deflection of maxillary and mandibular alveolar processes when mini-implants are more cervically placed; 2) Mini-implants placed too near the periodontal ligament, with normal intra-alveolar tooth movement; 3) Low bone density, low thickness and low alveolar bone volume; 4) Low alveolar cortical bone thickness; 5) Excessive pressure inducing trabecular bone microfracture; 6) Sites of higher anatomical weakness in the mandible and the maxilla; 7) Thicker gingival tissue not considered when choosing the mini-implant. PMID:24945511

Blockage of glycolysis by targeting PFKFB3 alleviates sepsis-related acute lung injury via suppressing inflammation and apoptosis of alveolar epithelial cells.

PubMed

Gong, Yuanqi; Lan, Haibing; Yu, Zhihong; Wang, Meng; Wang, Shu; Chen, Yu; Rao, Haiwei; Li, Jingying; Sheng, Zhiyong; Shao, Jianghua

2017-09-16

Sepsis-related acute lung injury (ALI) is characterized by excessive lung inflammation and apoptosis of alveolar epithelial cells resulting in acute hypoxemic respiratory failure. Recent studies indicated that anaerobic glycolysis play an important role in sepsis. However, whether inhibition of aerobic glycolysis exhibits beneficial effect on sepsis-induced ALI is not known. In vivo, a cecal ligation and puncture (CLP)-induced ALI mouse model was set up and mice treated with glycolytic inhibitor 3PO after CLP. The mice treated with the 3PO ameliorated the survival rate, histopathological changes, lung inflammation, lactate increased and lung apoptosis of mice with CLP-induced sepsis. In vitro, the exposure of human alveolar epithelial A549 cells to lipopolysaccharide (LPS) resulted in cell apoptosis, inflammatory cytokine production, enhanced glycolytic flux and reactive oxygen species (ROS) increased. While these changes were attenuated by 3PO treatment. Sequentially, treatment of A549 cells with lactate caused cell apoptosis and enhancement of ROS. Pretreatment with N-acetylcysteine (NAC) significantly lowered LPS and lactate-induced the generation of ROS and cell apoptosis in A549 cells. Therefore, these results indicate that anaerobic glycolysis may be an important contributor in cell apoptosis of sepsis-related ALI. Moreover, LPS specifically induces apoptotic insults to A549 cell through lactate-mediated enhancement of ROS. Copyright © 2017 Elsevier Inc. All rights reserved.

Deficient retinoid-driven angiogenesis may contribute to failure of adult human lung regeneration in emphysema.

PubMed

Ng-Blichfeldt, John-Poul; Alçada, Joana; Montero, M Angeles; Dean, Charlotte H; Griesenbach, Uta; Griffiths, Mark J; Hind, Matthew

2017-06-01

Molecular pathways that regulate alveolar development and adult repair represent potential therapeutic targets for emphysema. Signalling via retinoic acid (RA), derived from vitamin A, is required for mammalian alveologenesis, and exogenous RA can induce alveolar regeneration in rodents. Little is known about RA signalling in the human lung and its potential role in lung disease. To examine regulation of human alveolar epithelial and endothelial repair by RA, and characterise RA signalling in human emphysema. The role of RA signalling in alveolar epithelial repair was investigated with a scratch assay using an alveolar cell line (A549) and primary human alveolar type 2 (AT2) cells from resected lung, and the role in angiogenesis using a tube formation assay with human lung microvascular endothelial cells (HLMVEC). Localisation of RA synthetic (RALDH-1) and degrading (cytochrome P450 subfamily 26 A1 (CYP26A1)) enzymes in human lung was determined by immunofluorescence. Regulation of RA pathway components was investigated in emphysematous and control human lung tissue by quantitative real-time PCR and Western analysis. RA stimulated HLMVEC angiogenesis in vitro; this was partially reproduced with a RAR-α agonist. RA induced mRNA expression of vascular endothelial growth factor A (VEGFA) and VEGFR2. RA did not modulate AT2 repair. CYP26A1 protein was identified in human lung microvasculature, whereas RALDH-1 partially co-localised with vimentin-positive fibroblasts. CYP26A1 mRNA and protein were increased in emphysema. RA regulates lung microvascular angiogenesis; the endothelium produces CYP26A1 which is increased in emphysema, possibly leading to reduced RA availability. These data highlight a role for RA in maintenance of the human pulmonary microvascular endothelium. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Airway diffusing capacity of nitric oxide and steroid therapy in asthma.

PubMed

Shin, Hye-Won; Rose-Gottron, Christine M; Cooper, Dan M; Newcomb, Robert L; George, Steven C

2004-01-01

Exhaled nitric oxide (NO) concentration is a noninvasive index for monitoring lung inflammation in diseases such as asthma. The plateau concentration at constant flow is highly dependent on the exhalation flow rate and the use of corticosteroids and cannot distinguish airway and alveolar sources. In subjects with steroid-naive asthma (n = 8) or steroid-treated asthma (n = 12) and in healthy controls (n = 24), we measured flow-independent NO exchange parameters that partition exhaled NO into airway and alveolar regions and correlated these with symptoms and lung function. The mean (+/-SD) maximum airway flux (pl/s) and airway tissue concentration [parts/billion (ppb)] of NO were lower in steroid-treated asthmatic subjects compared with steroid-naive asthmatic subjects (1,195 +/- 836 pl/s and 143 +/- 66 ppb compared with 2,693 +/- 1,687 pl/s and 438 +/- 312 ppb, respectively). In contrast, the airway diffusing capacity for NO (pl.s-1.ppb-1) was elevated in both asthmatic groups compared with healthy controls, independent of steroid therapy (11.8 +/- 11.7, 8.71 +/- 5.74, and 3.13 +/- 1.57 pl.s-1.ppb-1 for steroid treated, steroid naive, and healthy controls, respectively). In addition, the airway diffusing capacity was inversely correlated with both forced expired volume in 1 s and forced vital capacity (%predicted), whereas the airway tissue concentration was positively correlated with forced vital capacity. Consistent with previously reported results from Silkoff et al. (Silkoff PE, Sylvester JT, Zamel N, and Permutt S, Am J Respir Crit Med 161: 1218-1228, 2000) that used an alternate technique, we conclude that the airway diffusing capacity for NO is elevated in asthma independent of steroid therapy and may reflect clinically relevant changes in airways.

Alveolar-Membrane Diffusing Capacity Limits Performance in Boston Marathon Qualifiers

PubMed Central

Lavin, Kaleen M.; Straub, Allison M.; Uhranowsky, Kathleen A.; Smoliga, James M.; Zavorsky, Gerald S.

2012-01-01

Purpose (1) to examine the relation between pulmonary diffusing capacity and marathon finishing time, and (2), to evaluate the accuracy of pulmonary diffusing capacity for nitric oxide (DLNO) in predicting marathon finishing time relative to that of pulmonary diffusing capacity for carbon monoxide (DLCO). Methods 28 runners [18 males, age = 37 (SD 9) years, body mass = 70 (13) kg, height = 173 (9) cm, percent body fat = 17 (7) %] completed a test battery consisting of measurement of DLNO and DLCO at rest, and a graded exercise test to determine running economy and aerobic capacity prior to the 2011 Steamtown Marathon (Scranton, PA). One to three weeks later, all runners completed the marathon (range: 2∶22:38 to 4∶48:55). Linear regressions determined the relation between finishing time and a variety of anthropometric characteristics, resting lung function variables, and exercise parameters. Results In runners meeting Boston Marathon qualification standards, 74% of the variance in marathon finishing time was accounted for by differences in DLNO relative to body surface area (BSA) (SEE = 11.8 min, p<0.01); however, the relation between DLNO or DLCO to finishing time was non-significant in the non-qualifiers (p = 0.14 to 0.46). Whereas both DLCO and DLNO were predictive of finishing time for all finishers, DLNO showed a stronger relation (r2 = 0.30, SEE = 33.4 min, p<0.01) compared to DLCO when considering BSA. Conclusion DLNO is a performance-limiting factor in only Boston qualifiers. This suggests that alveolar-capillary membrane conductance is a limitation to performance in faster marathoners. Additionally, DLNO/BSA predicts marathon finishing time and aerobic capacity more accurately than DLCO. PMID:22984520

Lung response to ultrafine Kevlar aramid synthetic fibrils following 2-year inhalation exposure in rats.

PubMed

Lee, K P; Kelly, D P; O'Neal, F O; Stadler, J C; Kennedy, G L

1988-07-01

Four groups of 100 male and 100 female rats were exposed to ultrafine Kevlar fibrils at concentrations of 0, 2.5, 25, and 100 fibrils/cc for 6 hr/day, 5 days/week for 2 years. One group was exposed to 400 fibrils/cc for 1 year and allowed to recover for 1 year. At 2.5 fibrils/cc, the lungs had normal alveolar architecture with a few dust-laden macrophages (dust cell response) in the alveolar airspaces. At 25 fibrils/cc, the lungs showed a dust cell response, slight Type II pneumocyte hyperplasia, alveolar bronchiolarization, and a negligible amount of collagenized fibrosis in the alveolar duct region. At 100 fibrils/cc, the same pulmonary responses were seen as at 25 fibrils/cc. In addition, cystic keratinizing squamous cell carcinoma (CKSCC) was found in 4 female rats, but not in male rats. Female rats had more prominent foamy alveolar macrophages, cholesterol granulomas, and alveolar bronchiolarization. These pulmonary lesions were related to the development of CKSCC. The lung tumors were derived from metaplastic squamous cells in areas of alveolar bronchiolarization. At 400 fibrils/cc following 1 year of recovery, the lung dust content, average fiber length, and the pulmonary lesions were markedly reduced, but slight centriacinar emphysema and minimal collagenized fibrosis were found in the alveolar duct region. One male and 6 female rats developed CKSCC. The lung tumors were a unique type of experimentally induced tumors in the rats and have not been seen as spontaneous tumors in man or animals. Therefore, the relevance of this type of lung tumor to the human situation is minimal.

β-Liddle mutation of the epithelial sodium channel increases alveolar fluid clearance and reduces the severity of hydrostatic pulmonary oedema in mice

PubMed Central

Randrianarison, Nadia; Escoubet, Brigitte; Ferreira, Chrystophe; Fontayne, Alexandre; Fowler-Jaeger, Nicole; Clerici, Christine; Hummler, Edith; Rossier, Bernard C; Planès, Carole

2007-01-01

Transepithelial sodium transport via alveolar epithelial Na+ channels and Na+,K+-ATPase constitutes the driving force for removal of alveolar oedema fluid. Decreased activity of the amiloride-sensitive epithelial Na+ channel (ENaC) in the apical membrane of alveolar epithelial cells impairs sodium-driven alveolar fluid clearance (AFC) and predisposes to pulmonary oedema. We hypothesized that hyperactivity of ENaC in the distal lung could improve AFC and facilitate the resolution of pulmonary oedema. AFC and lung fluid balance were studied at baseline and under conditions of hydrostatic pulmonary oedema in the β-Liddle (L) mouse strain harbouring a gain-of-function mutation (R566stop) within the Scnn1b gene. As compared with wild-type (+/+), baseline AFC was increased by 2- and 3-fold in heterozygous (+/L) and homozygous mutated (L/L) mice, respectively, mainly due to increased amiloride-sensitive AFC. The β2-agonist terbutaline stimulated AFC in +/+ and +/L mice, but not in L/L mice. Acute volume overload induced by saline infusion (40% of body weight over 2 h) significantly increased extravascular (i.e. interstitial and alveolar) lung water as assessed by the bloodless wet-to-dry lung weight ratio in +/+ and L/L mice, as compared with baseline. However, the increase was significantly larger in +/+ than in L/L groups (P= 0.01). Volume overload also increased the volume of the alveolar epithelial lining fluid in +/+ mice, indicating the presence of alveolar oedema, but not in L/L mice. Cardiac function as evaluated by echocardiography was comparable in both groups. These data show that constitutive ENaC activation improved sodium-driven AFC in the mouse lung, and attenuated the severity of hydrostatic pulmonary oedema. PMID:17430990

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

Zhang, Wei

Background: Silicosis is a systemic disease caused by inhaling silicon dioxide (SiO{sub 2}); early stages are characterized by alveolar inflammation, and later stages are characterized by progressive lung fibrosis. Mounting evidence indicates that high-mobility group box 1 (HMGB1) is involved in pulmonary fibrosis. Whether neogambogic acid (NGA) inhibits macrophage and fibroblast activation induced by SiO{sub 2} by targeting HMGB1 remains unclear. Methods and results: Experiments using cultured mouse macrophages (RAW264.7 cells) demonstrated that SiO{sub 2} treatment induces the expression of HMGB1 in a time- and dose-dependent manner via mitogen-activated protein kinases (MAPKs) and the phosphatidylinositol 3-kinase (PI3K)/Akt pathway; in turn,more » this expression causes macrophage apoptosis and fibroblast activation. Pretreating macrophages with NGA inhibited the HMGB1 expression induced by SiO{sub 2} and attenuated both macrophage apoptosis and fibroblast activation. Moreover, NGA directly inhibited MCP-1-induced protein 1 (MCPIP1) expression, as well as markers of fibroblast activation and migration induced by SiO{sub 2}. Furthermore, the effects of NGA on macrophages and fibroblasts were confirmed in vivo by exposing mice to SiO{sub 2}. Conclusion: NGA can prevent SiO{sub 2}-induced macrophage activation and apoptosis via HMGB1 inhibition and SiO{sub 2}-induced fibrosis via the MCPIP1 pathway. Targeting HMGB1 and MCPIP1 with NGA could provide insights into the potential development of a therapeutic approach for alleviating the inflammation and fibrosis induced by SiO{sub 2}. - Highlights: • The SiO{sub 2} induced HMGB1 in alveolar macrophage and MCPIP1 in fibroblast. • NGA rescued the SiO{sub 2}-induced apoptosis of alveolar macrophages via HMGB1 signaling. • NGA inhibited the fibroblast activation induced by SiO{sub 2} via MCPIP1 signaling. • NGA might represent a potential therapeutic approach for silicosis.« less

Alveolar Macrophages Prevent Lethal Influenza Pneumonia By Inhibiting Infection Of Type-1 Alveolar Epithelial Cells

PubMed Central

Cardani, Amber; Boulton, Adam; Kim, Taeg S.; Braciale, Thomas J.

2017-01-01

The Influenza A virus (IAV) is a major human pathogen that produces significant morbidity and mortality. To explore the contribution of alveolar macrophages (AlvMΦs) in regulating the severity of IAV infection we employed a murine model in which the Core Binding Factor Beta gene is conditionally disrupted in myeloid cells. These mice exhibit a selective deficiency in AlvMΦs. Following IAV infection these AlvMΦ deficient mice developed severe diffuse alveolar damage, lethal respiratory compromise, and consequent lethality. Lethal injury in these mice resulted from increased infection of their Type-1 Alveolar Epithelial Cells (T1AECs) and the subsequent elimination of the infected T1AECs by the adaptive immune T cell response. Further analysis indicated AlvMΦ-mediated suppression of the cysteinyl leukotriene (cysLT) pathway genes in T1AECs in vivo and in vitro. Inhibition of the cysLT pathway enzymes in a T1AECs cell line reduced the susceptibility of T1AECs to IAV infection, suggesting that AlvMΦ-mediated suppression of this pathway contributes to the resistance of T1AECs to IAV infection. Furthermore, inhibition of the cysLT pathway enzymes, as well as blockade of the cysteinyl leukotriene receptors in the AlvMΦ deficient mice reduced the susceptibility of their T1AECs to IAV infection and protected these mice from lethal infection. These results suggest that AlvMΦs may utilize a previously unappreciated mechanism to protect T1AECs against IAV infection, and thereby reduce the severity of infection. The findings further suggest that the cysLT pathway and the receptors for cysLT metabolites represent potential therapeutic targets in severe IAV infection. PMID:28085958

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.

Uremia Induces Dental Pulp Ossification but Reciprocally Inhibits Adjacent Alveolar Bone Osteogenesis.

PubMed

Yang, Chih-Yu; Chang, Zee-Fen; Chau, Yat-Pang; Chen, Ann; Lee, Oscar Kuang-Sheng; Yang, An-Hang

2015-11-01

Uremic patients are predisposed to atrophy of the alveolar bone and narrowing of the dental pulp chamber. Such pulp chamber changes have only been diagnosed radiologically; however, this has not been supported by any pathological evidence. We used a uremic rat model with secondary hyperparathyroidism induced by 5/6 nephrectomy surgery and high-phosphate diet to examine the dental pulp and adjacent alveolar bone pathology. In addition, we collected pulp tissues for real-time PCR. We found an opposite histopathological presentation of the ossified dental pulp and the osteomalacic adjacent alveolar bone. Furthermore, pulp cells with positive staining for Thy-1, a surrogate stem cell marker, were significantly reduced in the pulp of uremic rats compared to the controls, indicating a paucity of stem cells. This was further evidenced by the reduced pulp expression of dickkopf-1 (Dkk-1), a Wnt/β-catenin signaling inhibitor produced by mesenchymal stem cells. In contrast, expressions of receptor activator of nuclear factor κB ligand (RANKL) and RANK in uremic pulp were up-regulated, probably to counteract the ossifying process of uremic pulp. In conclusion, uremic pulp ossifications were associated with a paucity of stem cells and dysregulated Dkk-1 and RANKL signaling systems, further shifting the imbalance toward osteogenesis. Strategies to counteract such an imbalance may offer a potential therapeutic target to improve dental health in uremic patients, which warrants further interventional studies.

Decreased levels of irisin, a skeletal muscle cell-derived myokine, are related to emphysema associated with chronic obstructive pulmonary disease.

PubMed

Sugiyama, Yukari; Asai, Kazuhisa; Yamada, Kazuhiro; Kureya, Yuko; Ijiri, Naoki; Watanabe, Tetsuya; Kanazawa, Hiroshi; Hirata, Kazuto

2017-01-01

Cigarette smoking-induced oxidant-antioxidant imbalance is a factor that contributes to the pathogenesis of COPD through epithelial cell apoptosis. Irisin is a skeletal muscle cell-derived myokine associated with physical activity. Irisin is also known to decrease oxidant-induced apoptosis in patients with diabetes mellitus. However, the correlation between irisin and emphysema in COPD and its role in epithelial cell apoptosis remains unknown. Forty patients with COPD were enrolled in this study. Pulmonary function tests and measurements of the percentage of low-attenuation area on high-resolution computed tomography images were performed, and the results were evaluated for correlation with serum irisin levels. The effect of irisin on cigarette-smoke extract-induced A549 cell apoptosis and the expression of Nrf2, a transcription factor for antioxidants, was also examined in vitro. Serum irisin levels were significantly correlated with lung diffusing capacity for carbon monoxide divided by alveolar volume ( r =0.56, P <0.01) and percentage of low-attenuation area ( r =-0.79, P <0.01). Moreover, irisin significantly enhanced Nrf2 expression ( P <0.05) and reduced cigarette-smoke extract-induced A549 cell apoptosis ( P <0.05). Decreased serum irisin levels are related to emphysema in patients with COPD and involved in epithelial apoptosis, resulting in emphysema. Irisin could be a novel treatment for emphysema in patients with COPD.

Grainyhead-like 2 (GRHL2) distribution reveals novel pathophysiological differences between human idiopathic pulmonary fibrosis and mouse models of pulmonary fibrosis

PubMed Central

Mahavadi, Poornima; Sasikumar, Satish; Cushing, Leah; Hyland, Tessa; Rosser, Ann E.; Riccardi, Daniela; Lu, Jining; Kalin, Tanya V.; Kalinichenko, Vladimir V.; Guenther, Andreas; Ramirez, Maria I.; Pardo, Annie; Selman, Moisés; Warburton, David

2013-01-01

Chronic injury of alveolar lung epithelium leads to epithelial disintegrity in idiopathic pulmonary fibrosis (IPF). We had reported earlier that Grhl2, a transcriptional factor, maintains alveolar epithelial cell integrity by directly regulating components of adherens and tight junctions and thus hypothesized an important role of GRHL2 in pathogenesis of IPF. Comparison of GRHL2 distribution at different stages of human lung development showed its abundance in developing lung epithelium and in adult lung epithelium. However, GRHL2 is detected in normal human lung mesenchyme only at early fetal stage (week 9). Similar mesenchymal reexpression of GRHL2 was also observed in IPF. Immunofluorescence analysis in serial sections from three IPF patients revealed at least two subsets of alveolar epithelial cells (AEC), based on differential GRHL2 expression and the converse fluorescence intensities for epithelial vs. mesenchymal markers. Grhl2 was not detected in mesenchyme in intraperitoneal bleomycin-induced injury as well as in spontaneously occurring fibrosis in double-mutant HPS1 and HPS2 mice, whereas in contrast in a radiation-induced fibrosis model, with forced Forkhead box M1 (Foxm1) expression, an overlap of Grhl2 with a mesenchymal marker was observed in fibrotic regions. Grhl2's role in alveolar epithelial cell plasticity was confirmed by altered Grhl2 gene expression analysis in IPF and further validated by in vitro manipulation of its expression in alveolar epithelial cell lines. Our findings reveal important pathophysiological differences between human IPF and specific mouse models of fibrosis and support a crucial role of GRHL2 in epithelial activation in lung fibrosis and perhaps also in epithelial plasticity. PMID:24375798

Prenatal retinoic acid increases lipofibroblast expression in hypoplastic rat lungs with experimental congenital diaphragmatic hernia.

PubMed

Friedmacher, Florian; Fujiwara, Naho; Hofmann, Alejandro D; Takahashi, Hiromizu; Alvarez, Luis A J; Gosemann, Jan-Hendrik; Puri, Prem

2014-06-01

Prenatal administration of all-trans retinoic acid (ATRA) has been shown to stimulate alveolarization in nitrofen-induced pulmonary hypoplasia (PH) associated with congenital diaphragmatic hernia (CDH). Lipid-containing interstitial lipofibroblasts (LIFs), characterized by adipocyte differentiation-related protein (ADRP), play a critical role in alveolar development by coordinating lipid homeostasis. Previous studies have demonstrated that ATRA positively affects LIF expression in developing lungs. We hypothesized that pulmonary LIF expression is increased after prenatal ATRA treatment in the nitrofen model of CDH-associated PH. Timed-pregnant rats were treated with nitrofen or vehicle on E9.5, followed by injection of ATRA or placebo on E18.5, E19.5, and E20.5. Fetal lungs were dissected on E21.5 and divided into Control+Placebo, Control+ATRA, Nitrofen+Placebo, and Nitrofen+ATRA. Pulmonary gene expression levels of ADRP were analyzed by quantitative real-time polymerase chain reaction, and LIF expression was investigated by ADRP immunohistochemistry, oil-red-O-, and immunofluorescence-double-staining. Relative mRNA expression of pulmonary ADRP was significantly increased in Nitrofen+ATRA compared to Nitrofen+Placebo (0.31±0.02 vs. 0.08±0.01; P<0.0001). ADRP immunoreactivity and oil-red-O-staining were markedly increased in alveolar interstitium of Nitrofen+ATRA compared to Nitrofen+Placebo. Immunofluorescence-double-staining confirmed markedly increased LIF expression in alveolar walls of Nitrofen+ATRA compared to Nitrofen+Placebo. Increased LIF expression after prenatal treatment with ATRA in nitrofen-induced PH suggests that ATRA may have a therapeutic potential in attenuating CDH-associated PH by stimulating alveolar development. Copyright © 2014 Elsevier Inc. All rights reserved.

Arctigenin Induces an Activation Response in Porcine Alveolar Macrophage Through TLR6-NOX2-MAPKs Signaling Pathway.

PubMed

Lu, Zheng; Chang, Lingling; Du, Qian; Huang, Yong; Zhang, Xiujuan; Wu, Xingchen; Zhang, Jie; Li, Ruizhen; Zhang, Zelin; Zhang, Wenlong; Zhao, Xiaomin; Tong, Dewen

2018-01-01

Arctigenin (ARG), one of the most active ingredients abstracted from seeds of Arctium lappa L. , has been proved to exert promising biological activities such as immunomodulatory, anti-viral, and anti-cancer etc. However, the mechanism behind its immunomodulatory function still remains elusive to be further investigated. In this study, we found that ARG had no significant effects on the cell proliferation in both porcine alveolar macrophage cell line (3D4/21) and primary porcine derived alveolar macrophage. It remarkably increased the expression and secretion of the two cytokines including tumor necrosis factor-alpha (TNF-α) and transforming growth factor beta1 (TGF-β1) in a dose-dependent manner with the concomitant enhancement of phagocytosis, which are the indicators of macrophage activation. ARG also elevated the intracellular reactive oxygen species (ROS) production by activating NOX2-based NADPH oxidase. Furthermore, inhibition of ROS generation by diphenyliodonium and apocynin significantly suppressed ARG-induced cytokine secretion and phagocytosis increase, indicating the requirement of ROS for the porcine alveolar macrophage activation. In addition, TLR6-My88 excitation, p38 MAPK and ERK1/2 phosphorylation were all involved in the process. As blocking TLR6 receptor dramatically attenuated the NOX2 oxidase activation, cytokine secretion and phagocytosis increase. Inhibiting ROS generation almost abolished p38 and ERK1/2 phosphorylation, and the cytokine secretion could also be remarkably reduced by p38 and ERK1/2 inhibitors (SB203580 and UO126). Our finding gave a new insight of understanding that ARG could improve the immune-function of porcine alveolar macrophages through TLR6-NOX2 oxidase-MAPKs signaling pathway.

Arctigenin Induces an Activation Response in Porcine Alveolar Macrophage Through TLR6-NOX2-MAPKs Signaling Pathway

PubMed Central

Lu, Zheng; Chang, Lingling; Du, Qian; Huang, Yong; Zhang, Xiujuan; Wu, Xingchen; Zhang, Jie; Li, Ruizhen; Zhang, Zelin; Zhang, Wenlong; Zhao, Xiaomin; Tong, Dewen

2018-01-01

Arctigenin (ARG), one of the most active ingredients abstracted from seeds of Arctium lappa L., has been proved to exert promising biological activities such as immunomodulatory, anti-viral, and anti-cancer etc. However, the mechanism behind its immunomodulatory function still remains elusive to be further investigated. In this study, we found that ARG had no significant effects on the cell proliferation in both porcine alveolar macrophage cell line (3D4/21) and primary porcine derived alveolar macrophage. It remarkably increased the expression and secretion of the two cytokines including tumor necrosis factor-alpha (TNF-α) and transforming growth factor beta1 (TGF-β1) in a dose-dependent manner with the concomitant enhancement of phagocytosis, which are the indicators of macrophage activation. ARG also elevated the intracellular reactive oxygen species (ROS) production by activating NOX2-based NADPH oxidase. Furthermore, inhibition of ROS generation by diphenyliodonium and apocynin significantly suppressed ARG-induced cytokine secretion and phagocytosis increase, indicating the requirement of ROS for the porcine alveolar macrophage activation. In addition, TLR6-My88 excitation, p38 MAPK and ERK1/2 phosphorylation were all involved in the process. As blocking TLR6 receptor dramatically attenuated the NOX2 oxidase activation, cytokine secretion and phagocytosis increase. Inhibiting ROS generation almost abolished p38 and ERK1/2 phosphorylation, and the cytokine secretion could also be remarkably reduced by p38 and ERK1/2 inhibitors (SB203580 and UO126). Our finding gave a new insight of understanding that ARG could improve the immune-function of porcine alveolar macrophages through TLR6-NOX2 oxidase-MAPKs signaling pathway. PMID:29867481

γδ T cells protect against LPS-induced lung injury

PubMed Central

Wehrmann, Fabian; Lavelle, James C.; Collins, Colm B.; Tinega, Alex N.; Thurman, Joshua M.; Burnham, Ellen L.; Simonian, Philip L.

2016-01-01

γδ T lymphocytes are a unique T cell population with important anti-inflammatory capabilities. Their role in acute lung injury, however, is poorly understood but may provide significant insight into lung-protective mechanisms occurring after injury. In a murine model of lung injury, wild-type C57BL/6 and TCRδ−/− mice were exposed to Escherichia coli LPS, followed by analysis of γδ T cell and macrophage subsets. In the absence of γδ T cells, TCRδ−/− mice developed increased inflammation and alveolar-capillary leak compared with wild-type C57BL/6 mice after LPS exposure that correlated with expansion of distinct macrophage populations. Classically activated M1 macrophages were increased in the lung of TCRδ−/− mice at d 1, 4, and 7 after LPS exposure that peaked at d 4 and persisted at d 7 compared with wild-type animals. In response to LPS, Vγ1 and Vγ7 γδ T cells were expanded in the lung and expressed IL-4. Coculture experiments showed decreased expression of TNF-α by resident alveolar macrophages in the presence of γδ T cells that was reversed in the presence of an anti-IL-4-blocking antibody. Treatment of mice with rIL4 resulted in reduced numbers of M1 macrophages, inflammation, and alveolar-capillary leak. Therefore, one mechanism by which Vγ1 and Vγ7 γδ T cells protect against LPS-induced lung injury is through IL-4 expression, which decreases TNF-α production by resident alveolar macrophages, thus reducing accumulation of M1 macrophages, inflammation, and alveolar-capillary leak. PMID:26428678

Adrenomedullin promotes lung angiogenesis, alveolar development, and repair.

PubMed

Vadivel, Arul; Abozaid, Sameh; van Haaften, Tim; Sawicka, Monika; Eaton, Farah; Chen, Ming; Thébaud, Bernard

2010-08-01

Bronchopulmonary dysplasia (BPD) and emphysema are significant global health problems at the extreme stages of life. Both are characterized by alveolar simplification and abnormal distal airspace enlargement due to arrested development or loss of alveoli, respectively. Both lack effective treatments. Mechanisms that inhibit distal lung growth are poorly understood. Adrenomedullin (AM), a recently discovered potent vasodilator, promotes angiogenesis and has protective effects on the cardiovascular and respiratory system. Its role in the developing lung is unknown. We hypothesized that AM promotes lung angiogenesis and alveolar development. Accordingly, we report that lung mRNA expression of AM increases during normal alveolar development. In vivo, intranasal administration of the AM antagonist, AM22-52 decreases lung capillary density (12.4 +/- 1.5 versus 18 +/- 1.5 in control animals; P < 0.05) and impairs alveolar development (mean linear intercept, 52.3 +/- 1.5 versus 43.8 +/- 1.8 [P < 0.05] and septal counts 62.0 +/- 2.7 versus 90.4 +/- 3.5 [P < 0.05]) in neonatal rats, resulting in larger and fewer alveoli, reminiscent of BPD. This was associated with decreased lung endothelial nitric oxide synthase and vascular endothelial growth factor-A mRNA expression. In experimental oxygen-induced BPD, a model of arrested lung vascular and alveolar growth, AM attenuates arrested lung angiogenesis (vessel density, 6.9 +/- 1.1 versus 16.2 +/- 1.3, P < 0.05) and alveolar development (mean linear intercept, 51.9 +/- 3.2 versus 44.4 +/- 0.7, septal counts 47.6 +/- 3.4 versus 67.7 +/- 4.0, P < 0.05), an effect in part mediated by inhibition of apoptosis. AM also prevents pulmonary hypertension in this model, as assessed by decreased right ventricular hypertrophy and pulmonary artery medial wall thickness. Our findings suggest a role for AM during normal alveolar development. AM may have therapeutic potential in diseases associated with alveolar injury.

Alveolar bone dynamics in osteoporotic rats treated with raloxifene or alendronate: confocal microscopy analysis

NASA Astrophysics Data System (ADS)

Ramalho-Ferreira, Gabriel; Faverani, Leonardo Perez; Grossi-Oliveira, Gustavo Augusto; Okamoto, Tetuo; Okamoto, Roberta

2015-03-01

In this study, the characteristics of the alveolar bone of rats with induced osteoporosis were examined. Thirty-two rats were divided into four groups according to the induction of osteoporosis and drugs administered: OG, osteoporotic rats without treatment (negative control); SG, rats which underwent sham surgery ovariectomy (SHAM); alendronate (AG), osteoporotic rats treated with alendronate; and RG, osteoporotic rats treated with raloxifene (RG). On the 8th day after ovariectomy and SHAM surgeries, drug therapy was started with AG or RG. On the 52nd day, 20 mg/kg calcein was administered to all of the rats, and on the 80th day, 20 mg/kg alizarin red was administered. Euthanasia was performed on the 98th day. The bone area marked by fluorochromes was calculated and data were subjected to two-way ANOVA test and Tukey's post-hoc test (p<0.05). The comparison of the induced osteoporosis groups showed no statistically significant differences in bone turnover only between RG and SG (p=0.074) and AG and OG (p=0.138). All other comparisons showed significant differences (p<0.001). The largest bone turnover was observed in RG and SG groups. RG was the medication that improved the dynamics of the alveolar bone of rats with induced osteoporosis, resembling that of healthy rats.

Dose- and time-dependent activation of rat alveolar macrophages by glucocorticoids

PubMed Central

BROUG-HOLUB, E; KRAAL, G

1996-01-01

Effects of glucocorticoids on immune functions are generally thought to be suppressive and anti-inflammatory. However, most reports dealing with this issue describe effects of long-term treatment with high doses of glucocorticoids on immune functions. In the present study we have investigated both dose and timing effects of exposure of alveolar macrophages with dexamethasone on lipopolysaccharide (LPS)-induced IL-1β and nitric oxide secretion. For this purpose, alveolar macrophages were preincubated with various doses of dexamethasone during varying intervals, followed by stimulation of the cells with endotoxin, either in the absence or presence of dexamethasone. Subsequently, the effects of this treatment on IL-1β and nitric oxide secretion were measured. It was shown that both short-term incubation of alveolar macrophages with high doses of dexamethasone and long-term incubation with low doses of dexamethasone lead to enhanced nitric oxide and enhanced IL-1β secretion upon subsequent stimulation of the cells with LPS. In contrast, long-term incubation of alveolar macrophages with high-dose dexamethasone leads to decreased IL-1β and nitric oxide secretion upon subsequent stimulation. Thus, it is concluded that the effects of dexamethasone on rat alveolar macrophages are both time- and dose-dependent. It is therefore argued that effects of glucocorticoids on immune functions are not a priori suppressive, but that both dose and timing effects should be taken into account. PMID:8625529

Bilateral pneumothorax, lung cavitations, and pleural empyema in a cocaine addict.

PubMed

Solaini, Leonardo; Solini, Leonardo; Gourgiotis, Stavros; Salemis, Nikolaos S; Koukis, Ioannis

2008-12-01

A case of bilateral pneumothorax, lung cavitations, and pleural empyema in a cocaine user is described. The patient was treated by left tube thoracostomy and right lower lobectomy. The postoperative course was uneventful. Six months later, the patient remains asymptomatic. The pathology examination of the specimen revealed infected bronchiectasis, interstitial desquamative pneumonia, diffuse alveolar damage, subsegmental arterial thrombosis, and consequent areas of pulmonary infarction.

Juglone alleviates pneumolysin-induced human alveolar epithelial cell injury via inhibiting the hemolytic activity of pneumolysin.

PubMed

Song, Meng; Lu, Gejin; Li, Meng; Deng, Xuming; Wang, Jianfeng

2017-08-01

Streptococcus pneumoniae (the pneumococcus) is an opportunistic pathogen responsible for several human diseases, including acute otitis media, pneumonia, sepsis and bacterial meningitis, and possesses numerous virulence factors associated with pneumococcal infection and pathogenesis. With the capacity to form pores in cholesterol-rich membranes, pneumolysin (PLY) is a key virulence factor of S. pneumoniae and causes severe tissue damage during pneumococcal infection. Juglone (JG), a natural 1,4-naphthoquinone widely found in the roots, leaves, woods and fruits of Juglandaceae walnut trees, inhibits PLY-induced hemolysis via inhibition of the oligomerization of PLY and exhibits minimal anti-S. pneumoniae activity. In addition, when human alveolar epithelial (A549) cells were co-cultured with PLY and JG, PLY-mediated cell injury was significantly alleviated. These results indicate that JG directly interacts with PLY to reduce the cytotoxicity of the toxin in human alveolar epithelial cells. Hence, JG is an effective inhibitor of PLY and protects lung cells from PLY-mediated cell injury. This study also provides the basis for the development of anti-virulence drugs for the treatment of S. pneumoniae infections.

Different signal pathways regulate IL-1β-induced mature and primary miRNA-146a expression in human alveolar epithelial cells.

PubMed

Jiang, Xiaoying

2014-09-01

It was known that IL-1β-induced rapid expression of miR-146a, which regulated the secretion of inflammatory chemokines in human A549 alveolar epithelial cells. However, little is known about the level of primary miR-146a and the downstream biogenesis of miR-146a in A549 cells. We examined the levels of primary miR-146a and mature miR-146a in A549 cells following treatment with pharmacological inhibitors of IKK-2 (TPCA-1), MEK-1/2 (PD098059), JNK-1/2 (SP600125), p38 MAPK (SB 203580) and PI-3k (LY294002). Our studies showed that exposure to PD98059, TPCA-1 and LY294002 resulted in a dose-dependent reduction in the expression of mature miR-146a while the primary miR-146a expression was not changed by any inhibitor. Western blot showed that IL-1β induced an increase of TRBP at 30 min, following by an extended expression at 24 h compared to the non-IL-1β controls in A549 cells. In conclusion, our studies indicated that miR-146a expression in alveolar epithelial cells was regulated at the post-transcriptional level via a MEK-1/2 and IKK2 pathway, and also for the first time via PI-3k pathway. The longer expression of TRBP following stimulation with IL-1β suggests that TRBP might play a role in the process of regulating the processing of primary miR-146a to mature miR-146a in human alveolar epithelial cells.

Human mesenchymal stromal cells reduce influenza A H5N1-associated acute lung injury in vitro and in vivo

PubMed Central

Chan, Michael C. W.; Kuok, Denise I. T.; Leung, Connie Y. H.; Hui, Kenrie P. Y.; Valkenburg, Sophie A.; Lau, Eric H. Y.; Nicholls, John M.; Fang, Xiaohui; Guan, Yi; Lee, Jae W.; Chan, Renee W. Y.; Webster, Robert G.; Matthay, Michael A.; Peiris, J. S. Malik

2016-01-01

Influenza can cause acute lung injury. Because immune responses often play a role, antivirals may not ensure a successful outcome. To identify pathogenic mechanisms and potential adjunctive therapeutic options, we compared the extent to which avian influenza A/H5N1 virus and seasonal influenza A/H1N1 virus impair alveolar fluid clearance and protein permeability in an in vitro model of acute lung injury, defined the role of virus-induced soluble mediators in these injury effects, and demonstrated that the effects are prevented or reduced by bone marrow-derived multipotent mesenchymal stromal cells. We verified the in vivo relevance of these findings in mice experimentally infected with influenza A/H5N1. We found that, in vitro, the alveolar epithelium’s protein permeability and fluid clearance were dysregulated by soluble immune mediators released upon infection with avian (A/Hong Kong/483/97, H5N1) but not seasonal (A/Hong Kong/54/98, H1N1) influenza virus. The reduced alveolar fluid transport associated with down-regulation of sodium and chloride transporters was prevented or reduced by coculture with mesenchymal stromal cells. In vivo, treatment of aged H5N1-infected mice with mesenchymal stromal cells increased their likelihood of survival. We conclude that mesenchymal stromal cells significantly reduce the impairment of alveolar fluid clearance induced by A/H5N1 infection in vitro and prevent or reduce A/H5N1-associated acute lung injury in vivo. This potential adjunctive therapy for severe influenza-induced lung disease warrants rapid clinical investigation. PMID:26976597

Human mesenchymal stromal cells reduce influenza A H5N1-associated acute lung injury in vitro and in vivo.

PubMed

Chan, Michael C W; Kuok, Denise I T; Leung, Connie Y H; Hui, Kenrie P Y; Valkenburg, Sophie A; Lau, Eric H Y; Nicholls, John M; Fang, Xiaohui; Guan, Yi; Lee, Jae W; Chan, Renee W Y; Webster, Robert G; Matthay, Michael A; Peiris, J S Malik

2016-03-29

Influenza can cause acute lung injury. Because immune responses often play a role, antivirals may not ensure a successful outcome. To identify pathogenic mechanisms and potential adjunctive therapeutic options, we compared the extent to which avian influenza A/H5N1 virus and seasonal influenza A/H1N1 virus impair alveolar fluid clearance and protein permeability in an in vitro model of acute lung injury, defined the role of virus-induced soluble mediators in these injury effects, and demonstrated that the effects are prevented or reduced by bone marrow-derived multipotent mesenchymal stromal cells. We verified the in vivo relevance of these findings in mice experimentally infected with influenza A/H5N1. We found that, in vitro, the alveolar epithelium's protein permeability and fluid clearance were dysregulated by soluble immune mediators released upon infection with avian (A/Hong Kong/483/97, H5N1) but not seasonal (A/Hong Kong/54/98, H1N1) influenza virus. The reduced alveolar fluid transport associated with down-regulation of sodium and chloride transporters was prevented or reduced by coculture with mesenchymal stromal cells. In vivo, treatment of aged H5N1-infected mice with mesenchymal stromal cells increased their likelihood of survival. We conclude that mesenchymal stromal cells significantly reduce the impairment of alveolar fluid clearance induced by A/H5N1 infection in vitro and prevent or reduce A/H5N1-associated acute lung injury in vivo. This potential adjunctive therapy for severe influenza-induced lung disease warrants rapid clinical investigation.

Omeprazole Attenuates Pulmonary Aryl Hydrocarbon Receptor Activation and Potentiates Hyperoxia-Induced Developmental Lung Injury in Newborn Mice.

PubMed

Shivanna, Binoy; Zhang, Shaojie; Patel, Ananddeep; Jiang, Weiwu; Wang, Lihua; Welty, Stephen E; Moorthy, Bhagavatula

2015-11-01

Hyperoxia contributes to the development of bronchopulmonary dysplasia (BPD) in human preterm infants and a similar lung phenotype characterized by alveolar simplification in newborn mice. Omeprazole (OM) is a proton pump inhibitor that is used to treat humans with gastric acid related disorders. OM-mediated aryl hydrocarbon receptor (AhR) activation attenuates acute hyperoxic lung injury (HLI) in adult mice. Whether OM activates pulmonary AhR and protects C57BL/6J newborn mice against hyperoxia-induced developmental lung (alveolar and pulmonary vascular simplification, inflammation, and oxidative stress) injury (HDLI) is unknown. Therefore, we tested the hypothesis that OM will activate pulmonary AhR and mitigate HDLI in newborn mice. Newborn mice were treated daily with i.p. injections of OM at doses of 10 (OM10) or 25 (OM25) mg/kg while being exposed to air or hyperoxia (FiO2 of 85%) for 14 days, following which their lungs were harvested to determine alveolarization, pulmonary vascularization, inflammation, oxidative stress, vascular injury, and AhR activation. To our surprise, hyperoxia-induced alveolar and pulmonary vascular simplification, inflammation, oxidative stress, and vascular injury were augmented in OM25-treated animals. These findings were associated with attenuated pulmonary vascular endothelial growth factor receptor 2 expression and decreased pulmonary AhR activation in the OM25 group. We conclude that contrary to our hypothesis, OM decreases functional activation of pulmonary AhR and potentiates HDLI in newborn mice. These observations are consistent with our previous findings, which suggest that AhR activation plays a protective role in HDLI in newborn mice. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Alveolar derecruitment and collapse induration as crucial mechanisms in lung injury and fibrosis.

PubMed

Lutz, Dennis; Gazdhar, Amiq; Lopez-Rodriguez, Elena; Ruppert, Clemens; Mahavadi, Poornima; Günther, Andreas; Klepetko, Walter; Bates, Jason H; Smith, Bradford; Geiser, Thomas; Ochs, Matthias; Knudsen, Lars

2015-02-01

Idiopathic pulmonary fibrosis (IPF) and bleomycin-induced pulmonary fibrosis are associated with surfactant system dysfunction, alveolar collapse (derecruitment), and collapse induration (irreversible collapse). These events play undefined roles in the loss of lung function. The purpose of this study was to quantify how surfactant inactivation, alveolar collapse, and collapse induration lead to degradation of lung function. Design-based stereology and invasive pulmonary function tests were performed 1, 3, 7, and 14 days after intratracheal bleomycin-instillation in rats. The number and size of open alveoli was correlated to mechanical properties. Active surfactant subtypes declined by Day 1, associated with a progressive alveolar derecruitment and a decrease in compliance. Alveolar epithelial damage was more pronounced in closed alveoli compared with ventilated alveoli. Collapse induration occurred on Day 7 and Day 14 as indicated by collapsed alveoli overgrown by a hyperplastic alveolar epithelium. This pathophysiology was also observed for the first time in human IPF lung explants. Before the onset of collapse induration, distal airspaces were easily recruited, and lung elastance could be kept low after recruitment by positive end-expiratory pressure (PEEP). At later time points, the recruitable fraction of the lung was reduced by collapse induration, causing elastance to be elevated at high levels of PEEP. Surfactant inactivation leading to alveolar collapse and subsequent collapse induration might be the primary pathway for the loss of alveoli in this animal model. Loss of alveoli is highly correlated with the degradation of lung function. Our ultrastructural observations suggest that collapse induration is important in human IPF.

Radiographic appearance of bronchoalveolar carcinoma in nine cats.

PubMed

Ballegeer, Elizabeth A; Forrest, Lisa J; Stepien, Rebecca L

2002-01-01

Thoracic radiographs of nine cats with confirmed bronchoalveolar carcinoma (BAC) were reviewed retrospectively. Radiographic appearance of BAC was divided into three categories: mixed bronchoalveolar pattern, ill-defined alveolar mass, or mass with cavitation. In addition to these radiographic signs, all nine cats had evidence of some form of bronchial disease. Cavitary lesions were the most common finding (n = 5). In addition, three cats in this category had diffuse bronchointerstitial opacity and one cat had focal peribronchial cuffing. Five cats had either a mixed bronchoalveolar pattern with bronchiectasis (n = 3) or an ill-defined alveolar mass with peribronchial cuffing (n = 2). One cat had both a mixed bronchoalveolar pattern and a cavitary mass. Each of these nine cats had some form of bronchial disease (bronchointerstitial pattern, peribronchial cuffing, or bronchiectasis), which aids in the radiographic diagnosis of bronchoalveolar carcinoma and may represent airway metastasis.

Plant Proteinase Inhibitor BbCI Modulates Lung Inflammatory Responses and Mechanic and Remodeling Alterations Induced by Elastase in Mice.

PubMed

Almeida-Reis, Rafael; Theodoro-Junior, Osmar A; Oliveira, Bruno T M; Oliva, Leandro V; Toledo-Arruda, Alessandra C; Bonturi, Camila R; Brito, Marlon V; Lopes, Fernanda D T Q S; Prado, Carla M; Florencio, Ariana C; Martins, Mílton A; Owen, Caroline A; Leick, Edna A; Oliva, Maria L V; Tibério, Iolanda F L C

2017-01-01

Background. Proteinases play a key role in emphysema. Bauhinia bauhinioides cruzipain inhibitor (BbCI) is a serine-cysteine proteinase inhibitor. We evaluated BbCI treatment in elastase-induced pulmonary alterations. Methods.  C57BL / 6 mice received intratracheal elastase (ELA group) or saline (SAL group). One group of mice was treated with BbCI (days 1, 15, and 21 after elastase instillation, ELABC group). Controls received saline and BbCI (SALBC group). After 28 days, we evaluated respiratory mechanics, exhaled nitric oxide, and bronchoalveolar lavage fluid. In lung tissue we measured airspace enlargement, quantified neutrophils, TNF α -, MMP-9-, MMP-12-, TIMP-1-, iNOS-, and eNOS-positive cells, 8-iso-PGF2 α , collagen, and elastic fibers in alveolar septa and airways. MUC-5-positive cells were quantified only in airways. Results. BbCI reduced elastase-induced changes in pulmonary mechanics, airspace enlargement and elastase-induced increases in total cells, and neutrophils in BALF. BbCI reduced macrophages and neutrophils positive cells in alveolar septa and neutrophils and TNF α -positive cells in airways. BbCI attenuated elastic and collagen fibers, MMP-9- and MMP-12-positive cells, and isoprostane and iNOS-positive cells in alveolar septa and airways. BbCI reduced MUC5ac-positive cells in airways. Conclusions. BbCI improved lung mechanics and reduced lung inflammation and airspace enlargement and increased oxidative stress levels induced by elastase. BbCI may have therapeutic potential in chronic obstructive pulmonary disease.

Plant Proteinase Inhibitor BbCI Modulates Lung Inflammatory Responses and Mechanic and Remodeling Alterations Induced by Elastase in Mice

PubMed Central

Theodoro-Junior, Osmar A.; Oliveira, Bruno T. M.; Oliva, Leandro V.; Toledo-Arruda, Alessandra C.; Bonturi, Camila R.; Brito, Marlon V.; Prado, Carla M.; Florencio, Ariana C.; Martins, Mílton A.; Owen, Caroline A.; Oliva, Maria L. V.

2017-01-01

Background. Proteinases play a key role in emphysema. Bauhinia bauhinioides cruzipain inhibitor (BbCI) is a serine-cysteine proteinase inhibitor. We evaluated BbCI treatment in elastase-induced pulmonary alterations. Methods.  C57BL/6 mice received intratracheal elastase (ELA group) or saline (SAL group). One group of mice was treated with BbCI (days 1, 15, and 21 after elastase instillation, ELABC group). Controls received saline and BbCI (SALBC group). After 28 days, we evaluated respiratory mechanics, exhaled nitric oxide, and bronchoalveolar lavage fluid. In lung tissue we measured airspace enlargement, quantified neutrophils, TNFα-, MMP-9-, MMP-12-, TIMP-1-, iNOS-, and eNOS-positive cells, 8-iso-PGF2α, collagen, and elastic fibers in alveolar septa and airways. MUC-5-positive cells were quantified only in airways. Results. BbCI reduced elastase-induced changes in pulmonary mechanics, airspace enlargement and elastase-induced increases in total cells, and neutrophils in BALF. BbCI reduced macrophages and neutrophils positive cells in alveolar septa and neutrophils and TNFα-positive cells in airways. BbCI attenuated elastic and collagen fibers, MMP-9- and MMP-12-positive cells, and isoprostane and iNOS-positive cells in alveolar septa and airways. BbCI reduced MUC5ac-positive cells in airways. Conclusions. BbCI improved lung mechanics and reduced lung inflammation and airspace enlargement and increased oxidative stress levels induced by elastase. BbCI may have therapeutic potential in chronic obstructive pulmonary disease. PMID:28466019

Cigarette Smoke-Induced Emphysema and Pulmonary Hypertension Can Be Prevented by Phosphodiesterase 4 and 5 Inhibition in Mice

PubMed Central

Pichl, Alexandra; Bednorz, Mariola; Ghofrani, Hossein Ardeschir; Schermuly, Ralph Theo; Seeger, Werner; Grimminger, Friedrich; Weissmann, Norbert

2015-01-01

Rationale Chronic obstructive pulmonary disease (COPD) is a widespread disease, with no curative therapies available. Recent findings suggest a key role of NO and sGC-cGMP signaling for the pathogenesis of the disease. Previous data suggest a downregulation/inactivation of the cGMP producing soluble guanylate cyclase, and sGC stimulation prevented cigarette smoke-induced emphysema and pulmonary hypertension (PH) in mice. We thus aimed to investigate if the inhibition of the cGMP degrading phosphodiesterase (PDE)5 has similar effects. Results were compared to the effects of a PDE 4 inhibitor (cAMP elevating) and a combination of both. Methods C57BL6/J mice were chronically exposed to cigarette smoke and in parallel either treated with Tadalafil (PDE5 inhibitor), Piclamilast (PDE4 inhibitor) or both. Functional measurements (lung compliance, hemodynamics) and structural investigations (alveolar and vascular morphometry) as well as the heart ratio were determined after 6 months of tobacco smoke exposure. In addition, the number of alveolar macrophages in the respective lungs was counted. Results Preventive treatment with Tadalafil, Piclamilast or a combination of both almost completely prevented the development of emphysema, the increase in lung compliance, tidal volume, structural remodeling of the lung vasculature, right ventricular systolic pressure, and right ventricular hypertrophy induced by cigarette smoke exposure. Single, but not combination treatment prevented or reduced smoke-induced increase in alveolar macrophages. Conclusion Cigarette smoke-induced emphysema and PH could be prevented by inhibition of the phosphodiesterases 4 and 5 in mice. PMID:26058042

Investigation of change of tumor optical properties after laser-induced plasmon-resonant photothermal treatment of transplanted tumors in rats

NASA Astrophysics Data System (ADS)

Genin, Vadim D.; Genina, Elina A.; Bucharskaya, Alla B.; Tuchin, Valery V.; Khlebtsov, Nikolay G.; Terentyuk, Georgy S.; Bashkatov, Alexey N.

2018-04-01

The paper presents the investigation of change of tumor optical properties of the rat tumor doped by gold nanoparticles after laser-induced plasmon-resonant photothermal treatment. To obtain the model tumors the rats have been implanted by suspension of alveolar kidney cancer cells. An hour before the experiment the animals have been injected by the suspension of gold nanorods intratumorally. For irradiation a diode laser with wavelength 808 nm has been used. After the irradiation the tumor has been removed and sliced. Spectra of total and collimated transmission and diffuse reflectance of the samples of different layers of the tumors have been measured in the wavelength range 350-2500 nm. Absorption, scattering, reduced scattering coefficients and scattering anisotropy factor of tumor tissues have been calculated with inverse adding-doubling method. The results of the experiment have shown that after doping the tumor tissue by the plasmon resonant nanoparticles and NIR laser irradiating, there is the decreases of absorption as well as scattering properties of the tumor and surrounding tissues. However, despite the sufficiently high temperature on the surface (about 80°C), the changes in the center of the tumor are insignificant.

Trichostatin A inhibits radiation-induced epithelial-to-mesenchymal transition in the alveolar epithelial cells

PubMed Central

Nagarajan, Devipriya; Wang, Lei; Zhao, Weiling; Han, Xiaochen

2017-01-01

Radiation-induced pneumonitis and fibrosis are major complications following thoracic radiotherapy. Epithelial-to-mesenchymal transition (EMT) plays an important role in tissue injury leading to organ fibrosis, including lung. Our previous studies have reported that radiation can induce EMT in the type II alveolar epithelial cells in both in vitro and in vivo. HDAC inhibitors are a new family of anti-cancer agents currently being used in several clinical trials. In addition to their intrinsic anti-tumor properties, HDAC inhibition is also important in other human diseases, including fibrosis and radiation-induced damage. In this study, we evaluated the effect of Trichostatin A (TSA), a HDAC inhibitor, on radiation-induced EMT in type II alveolar epithelial cells (RLE-6TN). Pre-treatment of RLE-6TN cells with TSA inhibited radiation-induced EMT-like morphological alterations including elevated protein level of α-SMA and Snail, reduction of E-cadherin expression, enhanced phosphorylation of GSK3β and ERK1/2, increased generation of ROS. Radiation enhanced the protein level of TGF-β1, which was blocked by N-acetylcysteine, an antioxidant. Treating cells with SB-431542, TGF-β1 type I receptor inhibitor, diminished radiation-induced alterations in the protein levels of p-GSK-3β, Snail-1 and α-SMA, suggesting a regulatory role of TGF-β1 in EMT. Pre-incubation of cells with TSA showed significant decrease in the level of TGF-β1 compared to radiation control. Collectively, these results demonstrate that i] radiation-induced EMT in RLE-6TN cells is mediated by ROS/MEK/ERK and ROS/TGF-β1 signaling pathways and ii] the inhibitory role of TSA in radiation-induced EMT appears to be due, at least in part, to its action of blocking ROS and TGF-β1 signaling. PMID:29254201

Innate Immune Responses to Bacterial Ligands in the Peripheral Human Lung – Role of Alveolar Epithelial TLR Expression and Signalling

PubMed Central

Thorley, Andrew J.; Grandolfo, Davide; Lim, Eric; Goldstraw, Peter; Young, Alan; Tetley, Teresa D.

2011-01-01

It is widely believed that the alveolar epithelium is unresponsive to LPS, in the absence of serum, due to low expression of TLR4 and CD14. Furthermore, the responsiveness of the epithelium to TLR-2 ligands is also poorly understood. We hypothesised that human alveolar type I (ATI) and type II (ATII) epithelial cells were responsive to TLR2 and TLR4 ligands (MALP-2 and LPS respectively), expressed the necessary TLRs and co-receptors (CD14 and MD2) and released distinct profiles of cytokines via differential activation of MAP kinases. Primary ATII cells and alveolar macrophages and an immortalised ATI cell line (TT1) elicited CD14 and MD2-dependent responses to LPS which did not require the addition of exogenous soluble CD14. TT1 and primary ATII cells expressed CD14 whereas A549 cells did not, as confirmed by flow cytometry. Following LPS and MALP-2 exposure, macrophages and ATII cells released significant amounts of TNFα, IL-8 and MCP-1 whereas TT1 cells only released IL-8 and MCP-1. P38, ERK and JNK were involved in MALP-2 and LPS-induced cytokine release from all three cell types. However, ERK and JNK were significantly more important than p38 in cytokine release from macrophages whereas all three were similarly involved in LPS-induced mediator release from TT1 cells. In ATII cells, JNK was significantly more important than p38 and ERK in LPS-induced MCP-1 release. MALP-2 and LPS exposure stimulated TLR4 protein expression in all three cell types; significantly more so in ATII cells than macrophages and TT1 cells. In conclusion, this is the first study describing the expression of CD14 on, and TLR2 and 4 signalling in, primary human ATII cells and ATI cells; suggesting that differential activation of MAP kinases, cytokine secretion and TLR4 expression by the alveolar epithelium and macrophages is important in orchestrating a co-ordinated response to inhaled pathogens. PMID:21789185

APOPTOTIC AND INFLAMMATORY EFFECTS INDUCED BY DIFFERENT PARTICLES IN HUMAN ALVEOLAR MACROPHAGES

EPA Science Inventory

Pollutant particles induce apoptosis and inflammation, but the relationship between these two biological processes is not entirely clear. In this study, we compared the proapoptotic and proinflammatory effects of four particles: residual oil fly ash (ROFA), St. Louis particles SR...

Immunohistochemical detection of ubiquitin-positive intracytoplasmic eosinophilic inclusion bodies in diffuse alveolar damage.

PubMed

Yamada, T; Uehara, K; Kawanishi, R; Mizutani, T; Sunagawa, K; Araya, J; Kawabata, Y

2006-06-01

To clarify the relationship between ubiquitin-positive pneumocytes and intracytoplasmic eosinophilic inclusion bodies (IB) in patients who died of diffuse alveolar damage (DAD). Eighteen patients with DAD were studied, in whom hyaline membranes were present in one or more out of five sections from each lobe of the lungs and 15 patients with no DAD. Light microscopy revealed hyaline membrane in over 25% of lobes from 18 patients with DAD. The cytoplasm of pneumocytes from six of 18 cases of DAD contained IB. Immunohistochemically, all IBs were characteristically positive for both ubiquitin (Ub) and cytokeratin KL-1. Cytoplasmic granules were also Ub+ in four cases of DAD without IB. IB+ or Ub+ pneumocytes were undetectable in non-DAD patients. We evaluated DAD severity based on hyaline membrane formation; the mean score in DAD with IB (3.60; n = 6) was significantly higher than that in Ub- (2.92; n = 8). Ub+ pneumocytes were found with or without IB among those cases with high DAD scores. These findings suggest that disordered proteolysis in the Ub-mediated proteasome system leads to the accumulation of abnormal ubiquitinated protein, which includes cytokeratin, in pneumocytes. This is the first report to suggest that Ub+ pneumocytes are associated with disease severity in patients with DAD.

Low-, medium- and high-dose steroids with or without aminocaproic acid in adult hematopoietic SCT patients with diffuse alveolar hemorrhage.

PubMed

Rathi, N K; Tanner, A R; Dinh, A; Dong, W; Feng, L; Ensor, J; Wallace, S K; Haque, S A; Rondon, G; Price, K J; Popat, U; Nates, J L

2015-03-01

Diffuse alveolar hemorrhage (DAH) is a poorly understood complication of transplantation carrying a high mortality. Patients commonly deteriorate and require intensive care unit (ICU) admission. Treatment with high-dose steroids and aminocaproic acid (ACA) has been suggested. The current study examined 119 critically ill adult hematopoietic transplant patients treated for DAH. Patients were subdivided into low-, medium- and high-dose steroid groups with or without ACA. All groups had similar baseline characteristics and severity of illness scores. Primary objectives were 30, 60, 100 day, ICU and hospital mortality. Overall mortality (n=119) on day 100 was high at 85%. In the steroids and ACA cohort (n=82), there were no significant differences in 30, 60, 100, day, ICU and hospital mortality between the dosing groups. In the steroids only cohort (n=37), the low-dose steroid group had a lower ICU and hospital mortality (P=0.02). Adjunctive treatment with ACA did not produce differences in outcomes. In the multivariate analysis, medium- and high-dose steroids were associated with a higher ICU mortality (P=0.01) as compared with the low-dose group. Our data suggest that treatment strategies may need to be reanalyzed to avoid potentially unnecessary and potentially harmful therapies.

Silencing hyperoxia-induced C/EBPα in neonatal mice improves lung architecture via enhanced proliferation of alveolar epithelial cells

PubMed Central

Yang, Guang; Hinson, Maurice D.; Bordner, Jessica E.; Lin, Qing S.; Fernando, Amal P.; La, Ping; Wright, Clyde J.

2011-01-01

Postnatal lung development requires proliferation and differentiation of specific cell types at precise times to promote proper alveolar formation. Hyperoxic exposure can disrupt alveolarization by inhibiting cell growth; however, it is not fully understood how this is mediated. The transcription factor CCAAT/enhancer binding protein-α (C/EBPα) is highly expressed in the lung and plays a role in cell proliferation and differentiation in many tissues. After 72 h of hyperoxia, C/EBPα expression was significantly enhanced in the lungs of newborn mice. The increased C/EBPα protein was predominantly located in alveolar type II cells. Silencing of C/EBPα with a transpulmonary injection of C/EBPα small interfering RNA (siRNA) prior to hyperoxic exposure reduced expression of markers of type I cell and differentiation typically observed after hyperoxia but did not rescue the altered lung morphology at 72 h. Nevertheless, when C/EBPα hyperoxia-exposed siRNA-injected mice were allowed to recover for 2 wk in room air, lung epithelial cell proliferation was increased and lung morphology was restored compared with hyperoxia-exposed control siRNA-injected mice. These data suggest that C/EBPα is an important regulator of postnatal alveolar epithelial cell proliferation and differentiation during injury and repair. PMID:21571903

Effect of odanacatib on root resorption and alveolar bone metabolism during orthodontic tooth movement.

PubMed

Wei, X X; Chu, J P; Zou, Y Z; Ru, N; Cui, S X; Bai, Y X

2015-12-22

The aim of this study was to investigate the effect of local administration of odanacatib (ODN) on orthodontic root resorption and the status of alveolar bone metabolism in rat molars. All specimens were scanned using microcomputed tomography and then the raw images were reconstructed. The total volume of the root resorption craters of the 60 g-NS (normal saline) group was higher than in the 60 g-ODN group and the control group. In the 60 g-NS group, the bone volume fraction values of alveolar bone were significantly decreased compared with the other 2 groups. There were no significant differences in the bone volume fraction values of the tibiae among the 3 groups. The results of tartrate-resistant acid phosphatase-positive (TRAP+) numbers showed that there was no difference between the 60 g-NS group and the 60 g-ODN group. The expression of cathepsin K was decreased significantly in the 60 g-ODN group. These results indicate that ODN reduces orthodontics-induced external root resorption and increases alveolar bone metabolism. This may be because ODN inhibits the activity of odontoclasts, but maintains the quantity of odontoclasts and enhances bone formation. ODN promotes local alveolar bone metabolism, but does not affect systemic bone metabolism.

Health effects of sulfur-related environmental air pollution. V. Lung structure.

PubMed

Takenaka, S; Godleski, J J; Heini, A; Karg, E; Kreyling, W G; Ritter, B; Schulz, H; Ziesenis, A; Heyder, J

1999-05-01

The lungs of 8 male beagle dogs were examined morphologically and morphometrically after exposure for 13 mo to a respirable sulfur(IV) aerosol at a mass concentration of 1.53 mg m(-3) (16.5 h/day), and to an acidic sulfate aerosol carrying 15.2 micromol m(-3) hydrogen ions into the lungs (6 h/day). An additional eight dogs served as unexposed controls. Standard morphometric analyses of both the surface epithelia of the conducting airways and the alveolar region were performed. These analyses showed no difference between the exposure group and control group. However, there was a tendency to an increase in the volume density of bronchial glands in the exposure group. Five of eight exposed animals showed thickened ridges (knob-like structures) at the entrance to alveoli in the alveolar duct and alveolar sac. Transmission electron microscopy revealed that the thickening was mainly due to type II cell proliferation. As the previous experiment using sulfite aerosol only showed no alterations in the proximal alveolar regions, the changes observed may be considered as effects of acidic sulfate aerosol alone or in combination with sulfite. These findings suggest that sulfur aerosols have the potential to induce epithelial alterations in the proximal alveolar region, which is a primary target for air pollutants.

Standardisation and application of the single-breath determination of nitric oxide uptake in the lung.

PubMed

Zavorsky, Gerald S; Hsia, Connie C W; Hughes, J Michael B; Borland, Colin D R; Guénard, Hervé; van der Lee, Ivo; Steenbruggen, Irene; Naeije, Robert; Cao, Jiguo; Dinh-Xuan, Anh Tuan

2017-02-01

Diffusing capacity of the lung for nitric oxide ( D LNO ), otherwise known as the transfer factor, was first measured in 1983. This document standardises the technique and application of single-breath D LNO This panel agrees that 1) pulmonary function systems should allow for mixing and measurement of both nitric oxide (NO) and carbon monoxide (CO) gases directly from an inspiratory reservoir just before use, with expired concentrations measured from an alveolar "collection" or continuously sampled via rapid gas analysers; 2) breath-hold time should be 10 s with chemiluminescence NO analysers, or 4-6 s to accommodate the smaller detection range of the NO electrochemical cell; 3) inspired NO and oxygen concentrations should be 40-60 ppm and close to 21%, respectively; 4) the alveolar oxygen tension ( P AO 2 ) should be measured by sampling the expired gas; 5) a finite specific conductance in the blood for NO (θNO) should be assumed as 4.5 mL·min -1 ·mmHg -1 ·mL -1 of blood; 6) the equation for 1/θCO should be (0.0062· P AO 2 +1.16)·(ideal haemoglobin/measured haemoglobin) based on breath-holding P AO 2 and adjusted to an average haemoglobin concentration (male 14.6 g·dL -1 , female 13.4 g·dL -1 ); 7) a membrane diffusing capacity ratio ( D MNO / D MCO ) should be 1.97, based on tissue diffusivity. Copyright ©ERS 2017.

Myricetin Prevents Alveolar Bone Loss in an Experimental Ovariectomized Mouse Model of Periodontitis

PubMed Central

Huang, Jialiang; Wu, Chuanlong; Tian, Bo; Zhou, Xiao; Ma, Nian; Qian, Yufen

2016-01-01

Periodontitis is a common chronic inflammatory disease, which leads to alveolar bone resorption. Healthy and functional alveolar bone, which can support the teeth and enable their movement, is very important for orthodontic treatment. Myricetin inhibited osteoclastogenesis by suppressing the expression of some genes, signaling pathways, and cytokines. This study aimed to investigate the effects of myricetin on alveolar bone loss in an ovariectomized (OVX) mouse model of periodontitis as well as in vitro osteoclast formation and bone resorption. Twenty-four healthy eight-week-old C57BL/J6 female mice were assigned randomly to four groups: phosphate-buffered saline (PBS) control (sham) OVX + ligature + PBS (vehicle), and OVX + ligature + low or high (2 or 5 mg∙kg−1∙day−1, respectively) doses of myricetin. Myricetin or PBS was injected intraperitoneally (i.p.) every other day for 30 days. The maxillae were collected and subjected to further examination, including micro-computed tomography (micro-CT), hematoxylin and eosin (H&E) staining, and tartrate-resistant acid phosphatase (TRAP) staining; a resorption pit assay was also performed in vitro to evaluate the effects of myricetin on receptor activator of nuclear factor κ-B ligand (RANKL)-induced osteoclastogenesis. Myricetin, at both high and low doses, prevented alveolar bone resorption and increased alveolar crest height in the mouse model and inhibited osteoclast formation and bone resorption in vitro. However, myricetin was more effective at high dose than at low dose. Our study demonstrated that myricetin had a positive effect on alveolar bone resorption in an OVX mouse model of periodontitis and, therefore, may be a potential agent for the treatment of periodontitis and osteoporosis. PMID:27011174

Increasing the amount of corticotomy does not affect orthodontic tooth movement or root resorption, but accelerates alveolar bone resorption in rats.

PubMed

Kurohama, Takeshi; Hotokezaka, Hitoshi; Hashimoto, Megumi; Tajima, Takako; Arita, Kotaro; Kondo, Takanobu; Ino, Airi; Yoshida, Noriaki

2017-06-01

The purpose of this study was to evaluate the relationships among the volume of bone cut during corticotomy, amount of tooth movement, volume of root resorption, and volume of the resultant alveolar bone resorption after tooth movement. Ten-week-old female Wistar rats were distributed into the corticotomy groups and a control group that underwent sham corticotomy. Two experiments employing two different orthodontic forces (10 or 25g) and experimental periods (14 or 21 days) were performed. The volumes of the bone cut by corticotomy were 0.1, 1.0, and 1.7mm3 in the 25g groups, and 1.0 and 1.7mm3 in the 10g groups. Nickel-titanium closed-coil springs were set on the maxillary left first molars to induce mesial movement. After orthodontic tooth movement, the amount of tooth movement, volume of root resorption, and volume of alveolar bone resorption were measured. Despite differences in the volume of bone cut among the different corticotomy groups, there were not significant differences in the amount of tooth movement and volume of root resorption between the control group and any of the corticotomy groups. However, higher volume of bone cut during corticotomy was significantly related to the decreased alveolar bone volume-in particular, to the reduced height of the alveolar bone crest after tooth movement. The volume of the alveolar bone cut during corticotomy does not affect tooth movement or root resorption in 10-week-old female Wistar rats; however, it may increase alveolar bone loss after tooth movement. © The Author 2016. Published by Oxford University Press on behalf of the European Orthodontic Society. All rights reserved. For permissions, please email: journals.permissions@oup.com

Micro-imaging of the Mouse Lung via MRI

NASA Astrophysics Data System (ADS)

Wang, Wei

Quantitative measurement of lung microstructure is of great significance in assessment of pulmonary disease, particularly in the earliest stages. Conventional stereological assessment of ex-vivo fixed tissue specimens under the microscope has a long and successful tradition and is regarded as a gold standard, but the invasive nature limits its applications and the practicality of use in longitudinal studies. The technique for diffusion MRI-based 3He lung morphometry was previously developed and validated for human lungs, and was recently extended to ex-vivo mouse lungs. The technique yields accurate, quantitative information about the microstructure and geometry of acinar airways. In this dissertation, the 3He lung morphometry technique is for the first time successfully implemented for in-vivo studies of mice. It can generate spatially-resolved maps of parameters that reveal the microstructure of mouse lung. Results in healthy mice indicate excellent agreement between in-vivo morphometry via 3He MRI and microscopic morphometry after sacrifice. The implementation and validation of 3He morphometry in healthy mice open up new avenues for application of the technique as a precise, noninvasive, in-vivo biomarker of changes in lung microstructure, within various mouse models of lung disease. We have applied 3He morphometry to the Sendai mouse model of lung disease. Specifically, the Sendai-virus model of chronic obstructive lung disease has demonstrated an innate immune response in mouse airways that exhibits similarities to the chronic airway inflammation in human COPD and asthma, but the effect on distal lung parenchyma had not been investigated. We imaged the time course and regional distribution of mouse lung microstructural changes in vivo after Sendai virus (SeV) infection with 1H and 3He diffusion MRI. 1H MR images detected the SeV-induced pulmonary inflammation in vivo and 3He lung morphometry showed modest increase in alveolar duct radius distal to airway inflammation, particularly in the lung periphery, indicating airspace enlargement after virus infection. Another important application of the imaging technique is the study of lung regeneration in a pneumonectomy (PNX) model. Partial resection of the lung by unilateral PNX is a robust model of compensatory lung growth. It is typically studied by postmortem morphometry in which longitudinal assessment in the same animal cannot be achieved. Here we successfully assess the microstructural changes and quantify the compensatory lung growth in vivo in the PNX mouse model via 1H and hyperpolarized 3He diffusion MRI. Our results show complete restoration in lung volume and total alveolar number with enlargement of alveolar size, which is consistent with prior histological studies conducted in different animals at various time points. This dissertation demonstrates that 3He lung morphometry has good sensitivity in quantifying small microstructural changes in the mouse lung and can be applied to a variety of mouse pulmonary models. Particularly, it has great potential to become a valuable tool in understanding the time course and the mechanism of lung growth in individual animals and may provide insight into post-natal lung growth and lung regeneration.

Edaravone protects rats and human pulmonary alveolar epithelial cells against hyperoxia injury: heme oxygenase-1 and PI3K/Akt pathway may be involved.

PubMed

Cao, Huifang; Feng, Ying; Ning, Yunye; Zhang, Zinan; Li, Weihao; Li, Qiang

2015-01-01

Hyperoxic acute lung injury (HALI) is a clinical syndrome as a result of prolonged supplement of high concentrations of oxygen. As yet, no specific treatment is available for HALI. The present study aims to investigate the effects of edaravone on hyperoxia-induced oxidative injury and the underlying mechanism. We treated rats and human pulmonary alveolar epithelial cells with hyperoxia and different concentration of edaravone, then examined the effects of edaravone on cell viability, cell injury and two oxidative products. The roles of heme oxygenase-1 (HO-1) and PI3K/Akt pathway were explored using Western blot and corresponding inhibitors. The results showed that edaravone reduced lung biochemical alterations induced by hyperoxia and mortality of rats, dose-dependently alleviated cell mortality, cell injury, and peroxidation of cellular lipid and DNA oxidative damage. It upregulated cellular HO-1 expression and activity, which was reversed by PI3K/Akt pathway inhibition. The administration of zinc protoporphyrin-IX, a HO-1 inhibitor, and LY249002, a PI3K/Akt pathway inhibitor, abolished the protective effects of edaravone in cells. This study indicates that edaravone protects rats and human pulmonary alveolar epithelial cells against hyperoxia-induced injury and the antioxidant effect may be related to upregulation of HO-1, which is regulated by PI3K/Akt pathway.

Tamoxifen induces apoptotic neutrophil efferocytosis in horses.

PubMed

Olave, C; Morales, N; Uberti, B; Henriquez, C; Sarmiento, J; Ortloff, A; Folch, H; Moran, G

2018-03-01

Macrophages and neutrophils are important cellular components in the process of acute inflammation and its subsequent resolution, and evidence increasingly suggests that they play important functions during the resolution of chronic, adaptive inflammatory processes. Exacerbated neutrophil activity can be harmful to surrounding tissues; this is important in a range of diseases, including allergic asthma and chronic obstructive pulmonary disease in humans, and equine asthma (also known as recurrent airway obstruction (RAO). Tamoxifen (TX) is a non-steroidal estrogen receptor modulator with effects on cell growth and survival. Previous studies showed that TX treatment in horses with induced acute pulmonary inflammation promoted early apoptosis of blood and BALF neutrophils, reduction of BALF neutrophils, and improvement in animals' clinical status. The aim of this study was to describe if TX induces in vitro efferocytosis of neutrophils by alveolar macrophages. Efferocytosis assay, myeloperoxidase (MPO) detection and translocation phosphatidylserine (PS) were performed on neutrophils isolated from peripheral blood samples from five healthy horses. In in vitro samples from heathy horses, TX treatment increases the phenomenon of efferocytosis of peripheral neutrophils by alveolar macrophages. Similar increases in supernatant MPO concentration and PS translocation were observed in TX-treated neutrophils, compared to control cells. In conclusion, these results confirm that tamoxifen has a direct effect on equine peripheral blood neutrophils, through stimulation of the engulfment of apoptotic neutrophils by alveolar macrophages.

ACUTE OZONE-INDUCED INFLAMMATORY GENE EXPRESSION IN THE RAT LUNG IS NOT RELATED TO LEVELS OF ANTIOXIDANTS IN THE LAVAGE FLUID

EPA Science Inventory

ABSTRACT BODY: Ozone causes oxidative stress and lung inflammation. We hypothesized that rat strains with or without genetic susceptibility to cardiovascular disease will have different antioxidant levels in alveolar lining, and that ozone induced inflammatory gene expression wil...

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

Reiss, T.F.; Golden, J.

Pneumocystis carinii pneumonia was suggested by a diffuse, bilateral pulmonary uptake of gallium-67 in an asymptomatic, homosexual male with the antibody to the immunodeficiency virus (HIV) who was undergoing staging evaluation for lymphoma clinically localized to a left inguinal lymph node. Chest radiograph and pulmonary function evaluation, including lung volumes, diffusing capacity and arterial blood gases, were within normal limits. Bronchoalveolar lavage revealed Pneumocystis carinii organisms. In this asymptomatic, HIV-positive patient, active alveolar infection, evidenced by abnormal gallium-67 scanning, predated pulmonary physiologic abnormalities. This observation raises questions concerning the natural history of this disease process and the specificity of physiologicmore » tests for excluding disease. It also has implications for the treatment of neoplasia in the HIV-positive patient population.« less

Preventing cleavage of Mer promotes efferocytosis and suppresses acute lung injury in bleomycin treated mice

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

Lee, Ye-Ji; Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul; Lee, Seung-Hae

2012-08-15

Mer receptor tyrosine kinase (Mer) regulates macrophage activation and promotes apoptotic cell clearance. Mer activation is regulated through proteolytic cleavage of the extracellular domain. To determine if membrane-bound Mer is cleaved during bleomycin-induced lung injury, and, if so, how preventing the cleavage of Mer enhances apoptotic cell uptake and down-regulates pulmonary immune responses. During bleomycin-induced acute lung injury in mice, membrane-bound Mer expression decreased, but production of soluble Mer and activity as well as expression of disintegrin and metalloproteinase 17 (ADAM17) were enhanced . Treatment with the ADAM inhibitor TAPI-0 restored Mer expression and diminished soluble Mer production. Furthermore, TAPI-0more » increased Mer activation in alveolar macrophages and lung tissue resulting in enhanced apoptotic cell clearance in vivo and ex vivo by alveolar macrophages. Suppression of bleomycin-induced pro-inflammatory mediators, but enhancement of hepatocyte growth factor induction were seen after TAPI-0 treatment. Additional bleomycin-induced inflammatory responses reduced by TAPI-0 treatment included inflammatory cell recruitment into the lungs, levels of total protein and lactate dehydrogenase activity in bronchoalveolar lavage fluid, as well as caspase-3 and caspase-9 activity and alveolar epithelial cell apoptosis in lung tissue. Importantly, the effects of TAPI-0 on bleomycin-induced inflammation and apoptosis were reversed by coadministration of specific Mer-neutralizing antibodies. These findings suggest that restored membrane-bound Mer expression by TAPI-0 treatment may help resolve lung inflammation and apoptosis after bleomycin treatment. -- Highlights: ►Mer expression is restored by TAPI-0 treatment in bleomycin-stimulated lung. ►Mer signaling is enhanced by TAPI-0 treatment in bleomycin-stimulated lung. ►TAPI-0 enhances efferocytosis and promotes resolution of lung injury.« less

Hydrogen protects against hyperoxia-induced apoptosis in type II alveolar epithelial cells via activation of PI3K/Akt/Foxo3a signaling pathway.

PubMed

Wu, Dan; Liang, Mulin; Dang, Hongxing; Fang, Fang; Xu, Feng; Liu, Chengjun

2018-01-08

Oxidative stress is regarded as a key regulator in the pathogenesis of prolonged hyperoxia-induced lung injury, which causes injury to alveolar epithelial cells and eventually leads to development of bronchopulmonary dysplasia (BPD). Many studies have shown that hydrogen has a protective effect in a variety of cells. However, the mechanisms by which hydrogen rescues cells from damage due to oxidative stress in BPD remains to be fully elucidated. This study sought to evaluate the effects of hydrogen on hyperoxia-induced lung injury and to investigate the underlying mechanism. Primary type II alveolar epithelial cells (AECIIs) were divided into four groups: control (21% oxygen), hyperoxia (95% oxygen), hyperoxia + hydrogen, and hyperoxia + hydrogen + LY294002 (a PI3K/Akt inhibitor). Proliferation and apoptosis of AECIIs were assessed using MTS assay and flow cytometry (FCM), respectively. Gene and protein expression were detected by quantitative polymerase chain reaction (q-PCR) and western blot analysis. Stimulation with hyperoxia decreased the expression of P-Akt, P- FoxO3a, cyclinD1 and Bcl-2. Hyperoxic conditions increased levels of Bim, Bax, and Foxo3a, which induced proliferation restriction and apoptosis of AECIIs. These effects of hyperoxia were reversed with hydrogen pretreatment. Furthermore, the protective effects of hydrogen were abrogated by PI3K/Akt inhibitor LY294002. The results indicate that hydrogen protects AECIIs from hyperoxia-induced apoptosis by inhibiting apoptosis factors and promoting the expression of anti-apoptosis factors. These effects were associated with activation of the PI3K/Akt/FoxO3a pathway. Copyright © 2017 Elsevier Inc. All rights reserved.

Lactation induces increases in the RANK/RANKL/OPG system in maxillary bone.

PubMed

Macari, Soraia; Sharma, Lavanya A; Wyatt, Amanda; da Silva, Janine Maíra; Dias, George J; Silva, Tarcília A; Szawka, Raphael E; Grattan, David R

2018-05-01

The underlying causes of maxillary bone loss during lactation remain poorly understood. We evaluated the impact of lactation on physiological and mechanically-induced alveolar bone remodeling. Nulliparous non-lactating (N-LAC) and 21-day lactating (LAC) mice underwent mechanically-induced bone remodeling by orthodontic tooth movement (OTM). Micro-computed tomography (microCT) was performed in the maxilla, femur and vertebra. Tartrate-resistant-acid phosphatase (TRAP) and Masson's trichrome labelling was performed in the maxillary bone and gene expression was determined in the periodontal ligament. The effect of prolactin on osteoclast (OCL) and osteoblast (OBL) differentiation was also investigated in N-LAC and LAC mice. Lactation increased alveolar bone loss in the maxilla, femur and vertebra, while OTM was enhanced. The number of OCL and OBL was higher in the maxilla of LAC mice. OTM increased OCL in both groups; while OBL was increased only in N-LAC but not in LAC mice, in which cell numbers were already elevated. The alveolar bone loss during lactation was associated with increased expression of receptor activator of nuclear factor-KappaB (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG) in the maxilla. OTM induced the same responses in N-LAC mice, whereas it had no further effect in LAC mice. Lactation enhanced differentiation of OCL and OBL from bone marrow cells, and prolactin recapitulated OCL differentiation in N-LAC mice. Thus, lactation increases physiological maxillary bone remodeling and OTM, and both require activation of RANK/RANKL/OPG system. These findings expand our knowledge of lactation-induced osteopenia and have possible impact on clinical practice regarding orthodontic treatments and dental implants in lactating women. Copyright © 2018 Elsevier Inc. All rights reserved.

β-Glucans (Saccharomyces cereviseae) Reduce Glucose Levels and Attenuate Alveolar Bone Loss in Diabetic Rats with Periodontal Disease

PubMed Central

2015-01-01

The objective of this study was to assess the effects of oral ingestion of β-glucans isolated from Saccharomyces cereviseae on the metabolic profile, expression of gingival inflammatory markers and amount of alveolar bone loss in diabetic rats with periodontal disease. Diabetes mellitus was induced in 48 Wistar rats by intraperitoneal injection of streptozotocin (80 mg/kg). After confirming the diabetes diagnosis, the animals were treated with β-glucans (by gavage) for 28 days. On the 14th day of this period, periodontal disease was induced using a ligature protocol. β-glucans reduced the amount of alveolar bone loss in animals with periodontal disease in both the diabetic and non-diabetic groups (p < 0.05). β-glucans reduced blood glucose, cholesterol and triacylglycerol levels in diabetic animals, both with and without periodontal disease (p < 0.05). Furthermore, treatment with β-glucans reduced the expression of cyclooxygenase-2 and receptor activator of nuclear factor kappa-B ligand and increased osteoprotegerin expression in animals with diabetes and periodontal disease (p < 0.05). It was concluded that treatment with β-glucans has beneficial metabolic and periodontal effects in diabetic rats with periodontal disease. PMID:26291983

Fenspiride and membrane transduction signals in rat alveolar macrophages.

PubMed

Féray, J C; Mohammadi, K; Taouil, K; Brunet, J; Garay, R P; Hannaert, P

1997-07-15

Fenspiride inhibits the calcium signal evoked by the inflammatory peptide formyl-Met-Leu-Phe (fMLP) in peritoneal macrophages, but at concentrations (approximately 1 mM) far above the therapeutic range (approximately 1 microM). Here, in rat alveolar macrophages, high fenspiride concentrations (1 mM) were required to inhibit the calcium signals evoked by the calcium agonist Bay K8644 or by ionomycin. Moreover, fenspiride (1 mM) was a poor inhibitor of the cell membrane depolarization induced by gramicidine D. By contrast, fenspiride blocked Na+-H+ antiport activation by (i) fMLP with an IC50 = 3.1 +/- 1.9 nM and (ii) PMA (phorbol 12-myristate 13-acetate) with an IC50 = 9.2 +/- 3.1 nM. Finally, protein kinase C (PKC) activity of macrophage homogenate was not significantly modified by 10 or 100 microM fenspiride (at 100 microM: 2.57 +/- 1.60 vs. 2.80 +/- 1.71 pmol/10(6) cells/min). In conclusion, fenspiride inhibits fMLP- and PMA-induced pH signals in rat alveolar macrophages, probably by acting distally on the PKC transduction signal. This pH antagonistic action may be relevant for the antiinflammatory mechanism of fenspiride and requires further investigation.

Pre-existing periodontitis exacerbates experimental arthritis in a mouse model.

PubMed

Cantley, Melissa D; Haynes, David R; Marino, Victor; Bartold, P Mark

2011-06-01

Previous studies have shown a higher incidence of alveolar bone loss in patients with rheumatoid arthritis (RA) and that patients with periodontitis are at a greater risk of developing RA. The aim of this study was to develop an animal model to assess the relationship between pre-existing periodontitis and experimental arthritis (EA). Periodontitis was first induced in mice by oral gavage with Porphyromonas gingivalis followed by EA using the collagen antibody-induced arthritis model. These animals were compared with animals with periodontitis alone, EA alone and no disease (controls). Visual changes in paw swelling were assessed to determine clinical development of EA. Alveolar bone and joint changes were assessed using micro-CT, histological analyses and immunohistochemistry. Serum levels of C-reactive protein were used to monitor systemic inflammation. Mice with pre-existing periodontitis developed more severe arthritis, which developed at a faster rate. Mice with periodontitis only also showed evidence of loss of bone within the radiocarpal joint. There was also evidence of alveolar bone loss in mice with EA alone. The results of this study indicate that pre-existing periodontitis exacerbated experimental arthritis in a mouse model. © 2011 John Wiley & Sons A/S.

Loss of hypoxia-inducible factor 2 alpha in the lung alveolar epithelium of mice leads to enhanced eosinophilic inflammation in cobalt-induced lung injury.

PubMed

Proper, Steven P; Saini, Yogesh; Greenwood, Krista K; Bramble, Lori A; Downing, Nathaniel J; Harkema, Jack R; Lapres, John J

2014-02-01

Hard metal lung disease (HMLD) is an occupational lung disease specific to inhalation of cobalt-containing particles whose mechanism is largely unknown. Cobalt is a known hypoxia mimic and stabilizer of the alpha subunits of hypoxia-inducible factors (HIFs). Previous work revealed that though HIF1α contrib utes to cobalt toxicity in vitro, loss of HIF1α in the alveolar epithelial cells does not provide in vivo protection from cobalt-induced lung inflammation. HIF1α and HIF2α show unique tissue expression profiles, and HIF2α is known to be the predominant HIF mRNA isoform in the adult lung. Thus, if HIF2α activation by cobalt contributes to pathophysiology of HMLD, we hypothesized that loss of HIF2α in lung epithelium would provide protection from cobalt-induced inflammation. Mice with HIF2α-deficiency in Club and alveolar type II epithelial cells (ATIIs) (HIF2α(Δ/Δ)) were exposed to cobalt (60 µg/day) or saline using a subacute occupational exposure model. Bronchoalveolar lavage cellularity, cytokines, qRT-PCR, and histopathology were analyzed. Results show that loss of HIF2α leads to enhanced eosinophilic inflammation and increased goblet cell metaplasia. Additionally, control mice demonstrated a mild recovery from cobalt-induced lung injury compared with HIF2α(Δ/Δ) mice, suggesting a role for epithelial HIF2α in repair mechanisms. The expression of important cytokines, such as interleukin (IL)-5 and IL-10, displayed significant differences following cobalt exposure when HIF2α(Δ/Δ) and control mice were compared. In summary, our data suggest that although loss of HIF2α does not afford protection from cobalt-induced lung inflammation, epithelial HIF2α signaling does play an important role in modulating the inflammatory and repair response in the lung.

Citral inhibits lipopolysaccharide-induced acute lung injury by activating PPAR-γ.

PubMed

Shen, Yongbin; Sun, Zhanfeng; Guo, Xiaotong

2015-01-15

Citral, a component of lemongrass oil, has been reported to have many pharmacological activities such as anti-bacterial and anti-inflammatory effects. However, the effects of citral on acute lung injury (ALI) and the molecular mechanisms have not been reported. The aim of this study was to detect the effects of citral on lipopolysaccharide (LPS)-induced acute lung injury and investigate the molecular mechanisms. LPS-induced acute lung injury model was used to detect the anti-inflammatory effect of citral in vivo. The alveolar macrophages were used to investigate the molecular mechanism of citral in vitro. The results showed that pretreatment with citral remarkably attenuated pulmonary edema, histological severities, TNF-α, IL-6 and IL-1β production in LPS-induced ALI in vivo. In vitro, citral inhibited LPS-induced TNF-α, IL-6 and IL-1β production in alveolar macrophages. LPS-induced NF-κB activation was also inhibited by citral. Furthermore, we found that citral activated PPAR-γ and the anti-inflammatory effects of citral can be reversed by PPAR-γ antagonist GW9662. In conclusion, this is the first to demonstrate that citral protects LPS-induced ALI in mice. The anti-inflammatory mechanism of citral is associated with activating PPAR-γ, thereby inhibiting LPS-induced inflammatory response. Copyright © 2014 Elsevier B.V. All rights reserved.

Decreased proteasomal function accelerates cigarette smoke-induced pulmonary emphysema in mice.

PubMed

Yamada, Yosuke; Tomaru, Utano; Ishizu, Akihiro; Ito, Tomoki; Kiuchi, Takayuki; Ono, Ayako; Miyajima, Syota; Nagai, Katsura; Higashi, Tsunehito; Matsuno, Yoshihiro; Dosaka-Akita, Hirotoshi; Nishimura, Masaharu; Miwa, Soichi; Kasahara, Masanori

2015-06-01

Chronic obstructive pulmonary disease (COPD) is a disease common in elderly people, characterized by progressive destruction of lung parenchyma and chronic inflammation of the airways. The pathogenesis of COPD remains unclear, but recent studies suggest that oxidative stress-induced apoptosis in alveolar cells contributes to emphysematous lung destruction. The proteasome is a multicatalytic enzyme complex that plays a critical role in proteostasis by rapidly destroying misfolded and modified proteins generated by oxidative and other stresses. Proteasome activity decreases with aging in many organs including lungs, and an age-related decline in proteasomal function has been implicated in various age-related pathologies. However, the role of the proteasome system in the pathogenesis of COPD has not been investigated. Recently, we have established a transgenic (Tg) mouse model with decreased proteasomal chymotrypsin-like activity, showing age-related phenotypes. Using this model, we demonstrate here that decreased proteasomal function accelerates cigarette smoke (CS)-induced pulmonary emphysema. CS-exposed Tg mice showed remarkable airspace enlargement and increased foci of inflammation compared with wild-type controls. Importantly, apoptotic cells were found in the alveolar walls of the affected lungs. Impaired proteasomal activity also enhanced apoptosis in cigarette smoke extract (CSE)-exposed fibroblastic cells derived from mice and humans in vitro. Notably, aggresome formation and prominent nuclear translocation of apoptosis-inducing factor were observed in CSE-exposed fibroblastic cells isolated from Tg mice. Collective evidence suggests that CS exposure and impaired proteasomal activity coordinately enhance apoptotic cell death in the alveolar walls that may be involved in the development and progression of emphysema in susceptible individuals such as the elderly.

Restricted diffusion in a model acinar labyrinth by NMR: Theoretical and numerical results

NASA Astrophysics Data System (ADS)

Grebenkov, D. S.; Guillot, G.; Sapoval, B.

2007-01-01

A branched geometrical structure of the mammal lungs is known to be crucial for rapid access of oxygen to blood. But an important pulmonary disease like emphysema results in partial destruction of the alveolar tissue and enlargement of the distal airspaces, which may reduce the total oxygen transfer. This effect has been intensively studied during the last decade by MRI of hyperpolarized gases like helium-3. The relation between geometry and signal attenuation remained obscure due to a lack of realistic geometrical model of the acinar morphology. In this paper, we use Monte Carlo simulations of restricted diffusion in a realistic model acinus to compute the signal attenuation in a diffusion-weighted NMR experiment. We demonstrate that this technique should be sensitive to destruction of the branched structure: partial removal of the interalveolar tissue creates loops in the tree-like acinar architecture that enhance diffusive motion and the consequent signal attenuation. The role of the local geometry and related practical applications are discussed.

Evidence for decreased lipofibroblast expression in hypoplastic rat lungs with congenital diaphragmatic hernia.

PubMed

Friedmacher, Florian; Fujiwara, Naho; Hofmann, Alejandro Daniel; Takahashi, Hiromizu; Gosemann, Jan-Hendrik; Puri, Prem

2014-10-01

Pulmonary hypoplasia (PH) is a serious condition in newborns with congenital diaphragmatic hernia (CDH). Lipid-containing interstitial fibroblasts (LIFs) play an essential role in fetal lung maturation by stimulating alveolarization and lipid homeostasis. In rodents, LIFs are first evident during the canalicular phase of lung development with a significant increase over the last 4 days of gestation. Adipocyte differentiation-related protein (ADRP), a functional lipogenic molecular marker characterizing LIFs, is highly expressed in fetal lungs during this critical time period. We hypothesized that LIF expression in hypoplastic rat lungs is decreased in the nitrofen-induced CDH model, which is accompanied by reduced alveolar ADRP expression and lipid content. On embryonic day 9.5 (E9.5), time-mated rats received either nitrofen or vehicle. Fetuses were sacrificed on selected time points E18.5 and E21.5, and dissected lungs were divided into controls and CDH-associated PH. Pulmonary gene expression levels of ADRP were determined by quantitative real-time polymerase chain reaction. ADRP immunohistochemistry and oil red O staining were used to assess pulmonary protein expression and lipid content. Immunofluorescence double staining for alpha smooth muscle actin, which is known to be absent in LIFs, and lipid droplets was performed to evaluate the pulmonary expression of this specific subset of fibroblasts. Relative mRNA expression of ADRP was significantly reduced in lungs of CDH-associated PH on E18.5 and E21.5 compared to controls. ADRP immunoreactivity and lipid staining were markedly diminished in alveolar mesenchymal cells of CDH-associated PH on E18.5 and E21.5 compared to controls. Confocal laser scanning microscopy demonstrated markedly decreased LIF expression in alveolar interstitium of CDH-associated PH on E18.5 and E21.5 compared to controls. Decreased pulmonary LIF expression during late gestation suggests impaired LIF functioning in the nitrofen-induced CDH model, which may cause disruption in fetal alveolarization and lipid homeostasis, and thus contribute to the development of PH.

Dynamic Regulation of Platelet-Derived Growth Factor Receptor α Expression in Alveolar Fibroblasts during Realveolarization

PubMed Central

Chen, Leiling; Acciani, Thomas; Le Cras, Tim; Lutzko, Carolyn

2012-01-01

Although the importance of platelet-derived growth factor receptor (PDGFR)-α signaling during normal alveogenesis is known, it is unclear whether this signaling pathway can regulate realveolarization in the adult lung. During alveolar development, PDGFR-α–expressing cells induce α smooth muscle actin (α-SMA) and differentiate to interstitial myofibroblasts. Fibroblast growth factor (FGF) signaling regulates myofibroblast differentiation during alveolarization, whereas peroxisome proliferator-activated receptor (PPAR)-γ activation antagonizes myofibroblast differentiation in lung fibrosis. Using left lung pneumonectomy, the roles of FGF and PPAR-γ signaling in differentiation of myofibroblasts from PDGFR-α–positive precursors during compensatory lung growth were assessed. FGF receptor (FGFR) signaling was inhibited by conditionally activating a soluble dominant-negative FGFR2 transgene. PPAR-γ signaling was activated by administration of rosiglitazone. Changes in α-SMA and PDGFR-α protein expression were assessed in PDGFR-α–green fluorescent protein (GFP) reporter mice using immunohistochemistry, flow cytometry, and real-time PCR. Immunohistochemistry and flow cytometry demonstrated that the cell ratio and expression levels of PDGFR-α–GFP changed dynamically during alveolar regeneration and that α-SMA expression was induced in a subset of PDGFR-α–GFP cells. Expression of a dominant-negative FGFR2 and administration of rosiglitazone inhibited induction of α-SMA in PDGFR-α–positive fibroblasts and formation of new septae. Changes in gene expression of epithelial and mesenchymal signaling molecules were assessed after left lobe pneumonectomy, and results demonstrated that inhibition of FGFR2 signaling and increase in PPAR-γ signaling altered the expression of Shh, FGF, Wnt, and Bmp4, genes that are also important for epithelial–mesenchymal crosstalk during early lung development. Our data demonstrate for the first time that a comparable epithelial–mesenchymal crosstalk regulates fibroblast phenotypes during alveolar septation. PMID:22652199

Proinflammatory and anti-inflammatory cytokine balance in gasoline exhaust induced pulmonary injury in mice.

PubMed

Sureshkumar, Veerapandian; Paul, Bholanath; Uthirappan, Mani; Pandey, Renu; Sahu, Anand Prakash; Lal, Kewal; Prasad, Arun Kumar; Srivastava, Suresh; Saxena, Ashok; Mathur, Neeraj; Gupta, Yogendra Kumar

2005-03-01

Proinflammatory and anti-inflammatory cytokine balance and associated changes in pulmonary bronchoalveolar lavage fluid (BALF) of unleaded gasoline exhaust (GE) exposed mice were investigated. Animals were exposed to GE (1 L/min of GE mixed with 14 L/min of compressed air) using a flow-past, nose-only, dynamic inhalation exposure chamber for different durations (7, 14, and 21 days). The particulate content of the GE was found to be 0.635, +/-0.10 mg PM/m3. Elevated levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were observed in BALF of GE-exposed mice, but interleukin 1beta(IL-1beta) and the anti-inflammatory cytokine interleukin-10 (IL-10) remained unaffected. GE induced higher activities of alkaline phosphatase (ALP), gamma-glutamyl transferase (gammaGT), and lactate dehydrogenase (LDH) in the BALF, indicating Type II alveolar epithelial cell injury, Clara-cell injury, and general toxicity, respectively. Total protein in the BALF increased after 14 and 21 days of exposure, indicating enhanced alveolar-capillary permeability. However, the difference in the mean was found statistically insignificant in comparison to the compressed air control. Total cell count in the BALF of GE-exposed mice ranged between 0.898 and 0.813x10(6) cells/ml, whereas the compressed air control showed 0.65x10(6) cells/mL. The histopathological changes in GE-exposed lung includes perivascular, and peribronchiolar cuffing of mononuclear cells, migration of polymorphonuclear cells in the alveolar septa, alveolar thickening, and mild alveolar edematous changes indicating inflammation. The shift in pro- and anti-inflammatory cytokine balance and elevation of the pulmonary marker enzymes indicate toxic insult of GE. This study will help in our understanding of the mechanism of pulmonary injury by GE in the light of cytokine profiles, pulmonary marker enzymes, and lung architecture.

Intraluminal fibrosis in interstitial lung disorders.

PubMed Central

Basset, F.; Ferrans, V. J.; Soler, P.; Takemura, T.; Fukuda, Y.; Crystal, R. G.

1986-01-01

The histopathologic and ultrastructural features of intraluminal organizing and fibrotic changes were studied in open lung biopsies and autopsy specimens from 373 patients with interstitial lung disorders, including hypersensitivity pneumonitis (n = 44), idiopathic pulmonary fibrosis (n = 92), collagen-vascular diseases (n = 20), chronic eosinophilic pneumonia (n = 10), pulmonary histiocytosis X (n-90), pulmonary sarcoidosis (n = 62), pneumoconioses (n = 25), Legionnaire's disease (n = 5), drug- and toxin-induced pneumonitis (n = 4), radiation-induced pneumonitis (n = 2), lymphangioleiomyomatosis (n = 11), and chronic organizing pneumonia of unknown cause (n = 8). Three patterns of intraluminal organization and fibrosis were recognized: 1) intraluminal buds, which partially filled the alveoli, alveolar ducts and/or distal bronchioles; 2) obliterative changes, in which loose connective tissue masses obliterated the lumens of alveoli, alveolar ducts or distal bronchioles, and 3) mural incorporation of previously intraluminal connective tissue masses, which fused with alveolar, alveolar ductal, or bronchiolar structures and frequently became reepithelialized. All three patterns had common morphologic features, suggesting that, regardless of their severity, they resulted from a common pathogenetic mechanism, ie, the migration of activated connective tissue cells, through defects in the epithelial lining and its basement membrane, from the interstitial into the intraluminal compartment. Intraluminal buds were observed most frequently in hypersensitivity pneumonitis, chronic eosinophilic pneumonia, and organizing pneumonia of unknown cause. Mural incorporation and, to a lesser extent, obliterative changes were observed in most interstitial disorders and were very prominent in idiopathic pulmonary fibrosis. Mural incorporation and obliterative changes play an important role in pulmonary remodeling, especially when several adjacent alveoli and/or other air spaces are involved. Under these circumstances, intraluminal organization can mediate the fusion of adjacent alveolar structures by intraluminal connective tissue. Images Figure 15 Figure 9 Figure 10 Figure 16 Figure 17 Figure 1 Figure 2 Figure 3 Figure 4 Figure 18 Figure 5 Figure 6 Figure 7 Figure 8 Figure 19 Figure 20 Figure 11 Figure 12 Figure 13 Figure 14 PMID:3953768

Alveolar hemorrhage in systemic lupus erythematosus: a cohort review.

PubMed

Andrade, C; Mendonça, T; Farinha, F; Correia, J; Marinho, A; Almeida, I; Vasconcelos, C

2016-01-01

Diffuse alveolar hemorrhage (DAH) is a rare but potentially catastrophic manifestation with a high mortality. Among rheumatologic diseases, it occurs most frequently in patients with systemic lupus erythematosus (SLE) and systemic vasculitis. Despite new diagnostic tools and therapies, it remains a diagnostic and therapeutic challenge. The aim of this work was to characterize the SLE patients with an episode of alveolar hemorrhage followed in our Clinical Immunology Unit (CIU). A retrospective chart review was carried out for all patients with SLE followed in CIU between 1984 and the end of 2013. We reviewed the following data: demographic characteristics, clinical and laboratory data, radiologic investigations, histologic studies, treatment, and outcome. We identified 10 episodes of DAH, corresponding to seven patients, all female. These represent 1.6% of SLE patients followed in our Unit. The age at DAH attack was 42.75 ± 18.9 years. The average time between diagnosis of SLE and the onset of DAH was 7.1 years. Three patients had the diagnosis of SLE and the DAH attack at the same time. Disease activity according to SLEDAI was high, ranging from 15 to 41. All patients were treated with methylprednisolone, 37.5% cyclophosphamide and 28.6% plasmapheresis. The overall mortality rate was 28.6%. © The Author(s) 2015.

Zanthoxylum piperitum reversed alveolar bone loss of periodontitis via regulation of bone remodeling-related factors.

PubMed

Kim, Mi Hye; Lee, Hye Ji; Park, Jung-Chul; Hong, Jongki; Yang, Woong Mo

2017-01-04

Zanthoxylum piperitum (ZP) has been used to prevent toothache in East Asia. In this study, we investigated the effects of ZP on periodontitis along with alveolar bone loss. Twenty-eight male Sprague-Dawley rats were assigned into 4 groups; non-ligated (NOR), ligated and treated vehicle (CTR), ligated and treated 1mg/mL ZP (ZP1), and ligated and treated 100mg/mL ZP (ZP100). Sterilized 3-0 nylon ligature was placed into the subgingival sulcus around the both sides of mandibular first molar. After topical application of 1 and 100mg/mL ZP for 2 weeks, mandibles was removed for histology. In addition, SaOS-2 osteoblast cells were treated 1, 10 and 100μg/mL ZP for 24h to analyze the expressions of alveolar bone-related markers. Several alveolar bone resorption pits, which indicate cementum demineralization were decreased by ZP treatment. Topical ZP treatment inhibited periodontitis-induced alveolar bone loss. In addition, there were significant reduction of osteoclastic activities following topical ZP treatment in periodontium. The expression of RANKL was decreased in SaOS-2 osteoblast cells by treating ZP, while that of OPG was increased. ZP treatment increased the expressions of Runx2 and Osterix in SaOS-2 cells. In summary, ZP treatment inhibited alveolar bone loss as well as maintained the integrity of periodontal structures via regulation of bone remodeling. ZP may be a therapeutic target for treating periodontitis. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

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

Baker, Anna D.; Malur, Anagha; Barna, Barbara P.

Peroxisome proliferator-activated receptor-gamma (PPAR{gamma}) is a nuclear transcription factor involved in lipid metabolism that is constitutively expressed in the alveolar macrophages of healthy individuals. PPAR{gamma} has recently been implicated in the catabolism of surfactant by alveolar macrophages, specifically the cholesterol component of surfactant while the mechanism remains unclear. Studies from other tissue macrophages have shown that PPAR{gamma} regulates cholesterol influx, efflux, and metabolism. PPAR{gamma} promotes cholesterol efflux through the liver X receptor-alpha (LXR{alpha}) and ATP-binding cassette G1 (ABCG1). We have recently shown that macrophage-specific PPAR{gamma} knockout (PPAR{gamma} KO) mice accumulate cholesterol-laden alveolar macrophages that exhibit decreased expression of LXR{alpha} andmore » ABCG1 and reduced cholesterol efflux. We hypothesized that in addition to the dysregulation of these cholesterol efflux genes, the expression of genes involved in cholesterol synthesis and influx was also dysregulated and that replacement of PPAR{gamma} would restore regulation of these genes. To investigate this hypothesis, we have utilized a Lentivirus expression system (Lenti-PPAR{gamma}) to restore PPAR{gamma} expression in the alveolar macrophages of PPAR{gamma} KO mice. Our results show that the alveolar macrophages of PPAR{gamma} KO mice have decreased expression of key cholesterol synthesis genes and increased expression of cholesterol receptors CD36 and scavenger receptor A-I (SRA-I). The replacement of PPAR{gamma} (1) induced transcription of LXR{alpha} and ABCG1; (2) corrected suppressed expression of cholesterol synthesis genes; and (3) enhanced the expression of scavenger receptors CD36. These results suggest that PPAR{gamma} regulates cholesterol metabolism in alveolar macrophages.« less

Pasteurella haemolytica A1-Derived Leukotoxin and Endotoxin Induce Intracellular Calcium Elevation in Bovine Alveolar Macrophages by Different Signaling Pathways

PubMed Central

Hsuan, S. L.; Kannan, M. S.; Jeyaseelan, S.; Prakash, Y. S.; Sieck, G. C.; Maheswaran, S. K.

1998-01-01

Leukotoxin and endotoxin derived from Pasteurella haemolytica serotype 1 are the primary virulence factors contributing to the pathogenesis of lung injury in bovine pneumonic pasteurellosis. Activation of bovine alveolar macrophages with endotoxin or leukotoxin results in the induction of cytokine gene expression, with different kinetics (H. S. Yoo, S. K. Maheswaran, G. Lin, E. L. Townsend, and T. R. Ames, Infect. Immun. 63:381–388, 1995; H. S. Yoo, B. S. Rajagopal, S. K. Maheswaran, and T. R. Ames, Microb. Pathog. 18:237–252, 1995). Furthermore, extracellular Ca2+ is required for leukotoxin-induced cytokine gene expression. However, the involvement of Ca2+ in endotoxin effects and the precise signaling mechanisms in the regulation of intracellular Ca2+ by leukotoxin and endotoxin are not known. In fura-2-acetoxymethyl ester-loaded alveolar macrophages, intracellular Ca2+ regulation by leukotoxin and endotoxin was studied by video fluorescence microscopy. Leukotoxin induced a sustained elevation of intracellular Ca2+ in a concentration-dependent fashion by influx of extracellular Ca2+ through voltage-gated channels. In the presence of fetal bovine serum, endotoxin elevated intracellular Ca2+ even in the absence of extracellular Ca2+. Leukotoxin-induced intracellular Ca2+ elevation was inhibited by pertussis toxin, inhibitors of phospholipases A2 and C, and the arachidonic acid analog 5,8,11,14-eicosatetraynoic acid. Intracellular Ca2+ elevation by endotoxin was inhibited by inhibitors of phospholipase C and protein tyrosine kinase, but not by pertussis toxin, or the arachidonic acid analog. To the best of our knowledge, this is the first report of Ca2+ signaling by leukotoxin through a G-protein-coupled mechanism involving activation of phospholipases A2 and C and release of arachidonic acid in bovine alveolar macrophages. Ca2+ signaling by endotoxin, on the other hand, involves activation of phospholipase C and requires tyrosine phosphorylation. The differences in the Ca2+ signaling mechanisms may underlie the reported temporal differences in gene expression during leukotoxin and endotoxin activation. PMID:9596757

Pasteurella haemolytica A1-derived leukotoxin and endotoxin induce intracellular calcium elevation in bovine alveolar macrophages by different signaling pathways.

PubMed

Hsuan, S L; Kannan, M S; Jeyaseelan, S; Prakash, Y S; Sieck, G C; Maheswaran, S K

1998-06-01

Leukotoxin and endotoxin derived from Pasteurella haemolytica serotype 1 are the primary virulence factors contributing to the pathogenesis of lung injury in bovine pneumonic pasteurellosis. Activation of bovine alveolar macrophages with endotoxin or leukotoxin results in the induction of cytokine gene expression, with different kinetics (H. S. Yoo, S. K. Maheswaran, G. Lin, E. L. Townsend, and T. R. Ames, Infect. Immun. 63:381-388, 1995; H. S. Yoo, B. S. Rajagopal, S. K. Maheswaran, and T. R. Ames, Microb. Pathog. 18:237-252, 1995). Furthermore, extracellular Ca2+ is required for leukotoxin-induced cytokine gene expression. However, the involvement of Ca2+ in endotoxin effects and the precise signaling mechanisms in the regulation of intracellular Ca2+ by leukotoxin and endotoxin are not known. In fura-2-acetoxymethyl ester-loaded alveolar macrophages, intracellular Ca2+ regulation by leukotoxin and endotoxin was studied by video fluorescence microscopy. Leukotoxin induced a sustained elevation of intracellular Ca2+ in a concentration-dependent fashion by influx of extracellular Ca2+ through voltage-gated channels. In the presence of fetal bovine serum, endotoxin elevated intracellular Ca2+ even in the absence of extracellular Ca2+. Leukotoxin-induced intracellular Ca2+ elevation was inhibited by pertussis toxin, inhibitors of phospholipases A2 and C, and the arachidonic acid analog 5,8,11,14-eicosatetraynoic acid. Intracellular Ca2+ elevation by endotoxin was inhibited by inhibitors of phospholipase C and protein tyrosine kinase, but not by pertussis toxin, or the arachidonic acid analog. To the best of our knowledge, this is the first report of Ca2+ signaling by leukotoxin through a G-protein-coupled mechanism involving activation of phospholipases A2 and C and release of arachidonic acid in bovine alveolar macrophages. Ca2+ signaling by endotoxin, on the other hand, involves activation of phospholipase C and requires tyrosine phosphorylation. The differences in the Ca2+ signaling mechanisms may underlie the reported temporal differences in gene expression during leukotoxin and endotoxin activation.

Bronchoalveolar inflammation after exposure to diesel exhaust: comparison between unfiltered and particle trap filtered exhaust

PubMed Central

Rudell, B.; Blomberg, A.; Helleday, R.; Ledin, M. C.; Lundback, B.; Stjernberg, N.; Horstedt, P.; Sandstrom, T.

1999-01-01

OBJECTIVES: Air pollution particulates have been identified as having adverse effects on respiratory health. The present study was undertaken to further clarify the effects of diesel exhaust on bronchoalveolar cells and soluble components in normal healthy subjects. The study was also designed to evaluate whether a ceramic particle trap at the end of the tail pipe, from an idling engine, would reduce indices of airway inflammation. METHODS: The study comprised three exposures in all 10 healthy never smoking subjects; air, diluted diesel exhaust, and diluted diesel exhaust filtered with a ceramic particle trap. The exposures were given for 1 hour in randomised order about 3 weeks apart. The diesel exhaust exposure apperatus has previously been carefully developed and evaluated. Bronchoalveolar lavage was performed 24 hours after exposures and the lavage fluids from the bronchial and bronchoalveolar region were analysed for cells and soluble components. RESULTS: The particle trap reduced the mean steady state number of particles by 50%, but the concentrations of the other measured compounds were almost unchanged. It was found that diesel exhaust caused an increase in neutrophils in airway lavage, together with an adverse influence on the phagocytosis by alveolar macrophages in vitro. Furthermore, the diesel exhaust was found to be able to induce a migration of alveolar macrophages into the airspaces, together with reduction in CD3+CD25+ cells. (CD = cluster of differentiation) The use of the specific ceramic particle trap at the end of the tail pipe was not sufficient to completely abolish these effects when interacting with the exhaust from an idling vehicle. CONCLUSIONS: The current study showed that exposure to diesel exhaust may induce neutrophil and alveolar macrophage recruitment into the airways and suppress alveolar macrophage function. The particle trap did not cause significant reduction of effects induced by diesel exhaust compared with unfiltered diesel exhaust. Further studies are warranted to evaluate more efficient treatment devices to reduce adverse reactions to diesel exhaust in the airways.   PMID:10492649

Bronchoalveolar inflammation after exposure to diesel exhaust: comparison between unfiltered and particle trap filtered exhaust.

PubMed

Rudell, B; Blomberg, A; Helleday, R; Ledin, M C; Lundbäck, B; Stjernberg, N; Hörstedt, P; Sandström, T

1999-08-01

Air pollution particulates have been identified as having adverse effects on respiratory health. The present study was undertaken to further clarify the effects of diesel exhaust on bronchoalveolar cells and soluble components in normal healthy subjects. The study was also designed to evaluate whether a ceramic particle trap at the end of the tail pipe, from an idling engine, would reduce indices of airway inflammation. The study comprised three exposures in all 10 healthy never smoking subjects; air, diluted diesel exhaust, and diluted diesel exhaust filtered with a ceramic particle trap. The exposures were given for 1 hour in randomised order about 3 weeks apart. The diesel exhaust exposure apperatus has previously been carefully developed and evaluated. Bronchoalveolar lavage was performed 24 hours after exposures and the lavage fluids from the bronchial and bronchoalveolar region were analysed for cells and soluble components. The particle trap reduced the mean steady state number of particles by 50%, but the concentrations of the other measured compounds were almost unchanged. It was found that diesel exhaust caused an increase in neutrophils in airway lavage, together with an adverse influence on the phagocytosis by alveolar macrophages in vitro. Furthermore, the diesel exhaust was found to be able to induce a migration of alveolar macrophages into the airspaces, together with reduction in CD3+CD25+ cells. (CD = cluster of differentiation) The use of the specific ceramic particle trap at the end of the tail pipe was not sufficient to completely abolish these effects when interacting with the exhaust from an idling vehicle. The current study showed that exposure to diesel exhaust may induce neutrophil and alveolar macrophage recruitment into the airways and suppress alveolar macrophage function. The particle trap did not cause significant reduction of effects induced by diesel exhaust compared with unfiltered diesel exhaust. Further studies are warranted to evaluate more efficient treatment devices to reduce adverse reactions to diesel exhaust in the airways.

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.

Short communication: Camel milk ameliorates inflammatory responses and oxidative stress and downregulates mitogen-activated protein kinase signaling pathways in lipopolysaccharide-induced acute respiratory distress syndrome in rats.

PubMed

Zhu, Wei-Wei; Kong, Gui-Qing; Ma, Ming-Ming; Li, Yan; Huang, Xiao; Wang, Li-Peng; Peng, Zhen-Yi; Zhang, Xiao-Hua; Liu, Xiang-Yong; Wang, Xiao-Zhi

2016-01-01

Acute respiratory distress syndrome (ARDS) is a complex syndrome disorder with high mortality rate. Camel milk (CM) contains antiinflammatory and antioxidant properties and protects against numerous diseases. This study aimed to demonstrate the function of CM in lipopolysaccharide (LPS)-induced ARDS in rats. Camel milk reduced the lung wet:dry weight ratio and significantly reduced LPS-induced increases in neutrophil infiltration, interstitial and intra-alveolar edema, thickness of the alveolar wall, and lung injury scores of lung tissues. It also had antiinflammatory and antioxidant effects on LPS-induced ARDS. After LPS stimulation, the levels of proinflammatory cytokines (tumor necrosis factor-α, IL-10, and IL-1β) in serum and oxidative stress markers (malondialdehyde, myeloperoxidase, and total antioxidant capacity) in lung tissue were notably attenuated by CM. Camel milk also downregulated mitogen-activated protein kinase signaling pathways. Given these results, CM is a potential complementary food for ARDS treatment. Copyright © 2016 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Vitamin E does not prevent exercise-induced increase in pulmonary clearance.

PubMed

Lorino, A M; Paul, M; Cocea, L; Scherrer-Crosbie, M; Dahan, E; Meignan, M; Atlan, G

1994-11-01

It has been observed that sustained exercise results in a prolonged increase in alveolar epithelial permeability, as assessed by the pulmonary clearance rate of aerosolized 99mTc-labeled diethylenetriaminepentaacetate (Lorino et al. J. Appl. Physiol. 67: 2055-2059, 1989). The involvement of lipid peroxidation in this increased permeability was tested in seven nonsmoking volunteers by comparing the exercise-induced increases in pulmonary 99mTc-diethylenetriaminepentaacetate clearance before and after a 3-wk supplementation with oral vitamin E (1,000 IU/day), according to a protocol designed as a single-blind crossover study. The 60-min exercise was performed on a treadmill at a constant load corresponding to 80% of maximal O2 uptake. Administration of vitamin E, a very important antioxidant, did not reduce the exercise-induced increase in lung clearance, suggesting that the exercise-induced increase in lung epithelial permeability does not primarily result from the occurrence of lipid peroxidation in the alveolar membrane. This result thus corroborates the hypothesis of an alteration of the intercellular tight junctions due to the mechanical effects of hyperventilation.

Overcoming Rapid Inactivation of Lung Surfactant: Analogies Between Competitive Adsorption and Colloid Stability

PubMed Central

Zasadzinski, Joseph A.; Stenger, Patrick C.; Shieh, Ian; Dhar, Prajnaparamita

2009-01-01

Lung surfactant (LS) is a mixture of lipids and proteins that line the alveolar air-liquid interface, lowering the interfacial tension to levels that make breathing possible. In acute respiratory distress syndrome (ARDS), inactivation of LS is believed to play an important role in the development and severity of the disease. This review examines the competitive adsorption of LS and surface-active contaminants, such as serum proteins, present in the alveolar fluids of ARDS patients, and how this competitive adsorption can cause normal amounts of otherwise normal LS to be ineffective in lowering the interfacial tension. LS and serum proteins compete for the air-water interface when both are present in solution either in the alveolar fluids or in a Langmuir trough. Equilibrium favors LS as it has the lower equilibrium surface pressure, but the smaller proteins are kinetically favored over multi-micron LS bilayer aggregates by faster diffusion. If albumin reaches the interface, it creates an energy barrier to subsequent LS adsorption that slows or prevents the adsorption of the necessary amounts of LS required to lower surface tension. This process can be understood in terms of classic colloid stability theory in which an energy barrier to diffusion stabilizes colloidal suspensions against aggregation. This analogy provides qualitative and quantitative predictions regarding the origin of surfactant inactivation. An important corollary is that any additive that promotes colloid coagulation, such as increased electrolyte concentration, multivalent ions, hydrophilic non-adsorbing polymers such as PEG, dextran, etc. or polyelectrolytes such as chitosan, added to LS, also promotes LS adsorption in the presence of serum proteins and helps reverse surfactant inactivation. The theory provides quantitative tools to determine the optimal concentration of these additives and suggests that multiple additives may have a synergistic effect. A variety of physical and chemical techniques including isotherms, fluorescence microscopy, electron microscopy and X-ray diffraction show that LS adsorption is enhanced by this mechanism without substantially altering the structure or properties of the LS monolayer. PMID:20026298

DA-Raf-Mediated Suppression of the Ras--ERK Pathway Is Essential for TGF-β1-Induced Epithelial-Mesenchymal Transition in Alveolar Epithelial Type 2 Cells.

PubMed

Watanabe-Takano, Haruko; Takano, Kazunori; Hatano, Masahiko; Tokuhisa, Takeshi; Endo, Takeshi

2015-01-01

Myofibroblasts play critical roles in the development of idiopathic pulmonary fibrosis by depositing components of extracellular matrix. One source of lung myofibroblasts is thought to be alveolar epithelial type 2 cells that undergo epithelial-mesenchymal transition (EMT). Rat RLE-6TN alveolar epithelial type 2 cells treated with transforming growth factor-β1 (TGF-β1) are converted into myofibroblasts through EMT. TGF-β induces both canonical Smad signaling and non-canonical signaling, including the Ras-induced ERK pathway (Raf-MEK-ERK). However, the signaling mechanisms regulating TGF-β1-induced EMT are not fully understood. Here, we show that the Ras-ERK pathway negatively regulates TGF-β1-induced EMT in RLE-6TN cells and that DA-Raf1 (DA-Raf), a splicing isoform of A-Raf and a dominant-negative antagonist of the Ras-ERK pathway, plays an essential role in EMT. Stimulation of the cells with fibroblast growth factor 2 (FGF2), which activated the ERK pathway, prominently suppressed TGF-β1-induced EMT. An inhibitor of MEK, but not an inhibitor of phosphatidylinositol 3-kinase, rescued the TGF-β1-treated cells from the suppression of EMT by FGF2. Overexpression of a constitutively active mutant of a component of the Ras-ERK pathway, i.e., H-Ras, B-Raf, or MEK1, interfered with EMT. Knockdown of DA-Raf expression with siRNAs facilitated the activity of MEK and ERK, which were only weakly and transiently activated by TGF-β1. Although DA-Raf knockdown abrogated TGF-β1-induced EMT, the abrogation of EMT was reversed by the addition of the MEK inhibitor. Furthermore, DA-Raf knockdown impaired the TGF-β1-induced nuclear translocation of Smad2, which mediates the transcription required for EMT. These results imply that intrinsic DA-Raf exerts essential functions for EMT by antagonizing the TGF-β1-induced Ras-ERK pathway in RLE-6TN cells.

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.

Scaling laws for oxygen transport across the space-filling system of respiratory membranes in the human lung

NASA Astrophysics Data System (ADS)

Hou, Chen

Space-filling fractal surfaces play a fundamental role in how organisms function at various levels and in how structure determines function at different levels. In this thesis, we develop a quantitative theory of oxygen transport to and across the surface of the highly branched, space-filling system of alveoli, the fundamental gas exchange unit (acinar airways), in the human lung. Oxygen transport in the acinar airways is by diffusion, and we treat the two steps---diffusion through the branched airways, and transfer across the alveolar membranes---as a stationary diffusion-reaction problem, taking into account that there may be steep concentration gradients between the entrance and remote alveoli (screening). We develop a renormalization treatment of this screening effect and derive an analytic formula for the oxygen current across the cumulative alveolar membrane surface, modeled as a fractal, space-filling surface. The formula predicts the current from a minimum of morphological data of the acinus and appropriate values of the transport parameters, through a number of power laws (scaling laws). We find that the lung at rest operates near the borderline between partial screening and no screening; that it switches to no screening under exercise; and that the computed currents agree with measured values within experimental uncertainties. From an analysis of the computed current as a function of membrane permeability, we find that the space-filling structure of the gas exchanger is simultaneously optimal with respect to five criteria. The exchanger (i) generates a maximum oxygen current at minimum permeability; (ii) 'wastes' a minimum of surface area; (iii) maintains a minimum residence time of oxygen in the acinar airways; (iv) has a maximum fault tolerance to loss of permeability; and (v) generates a maximum current increase when switching from rest to exercise.

Ulinastatin post-treatment attenuates lipopolysaccharide-induced acute lung injury in rats and human alveolar epithelial cells

PubMed Central

Luo, Yunpeng; Che, Wen; Zhao, Mingyan

2017-01-01

Ulinastatin (UTI), a serine protease inhibitor, possesses anti-inflammatory properties and has been suggested to modulate lipopolysaccharide (LPS)-induced acute lung injury (ALI). High-mobility group box 1 (HMGB1), a nuclear DNA-binding protein, plays a key role in the development of ALI. The aim of this study was to investigate whether UTI attenuates ALI through the inhibition of HMGB1 expression and to elucidate the underlying molecular mechanisms. ALI was induced in male rats by the intratracheal instillation of LPS (5 mg/kg). UTI was administered intraperitoneally 30 min following exposure to LPS. A549 alveolar epithelial cells were incubated with LPS in the presence or absence of UTI. An enzyme-linked immunosorbent assay was used to detect the levels of inflammatory cytokines. Western blot analysis was performed to detect the changes in the expression levels of Toll-like receptor 2/4 (TLR2/4) and the activation of nuclear factor-κB (NF-κB). The results revealed that UTI significantly protected the animals from LPS-induced ALI, as evidenced by the decrease in the lung wet to dry weight ratio, total cells, neutrophils, macrophages and myeloperoxidase activity, associated with reduced lung histological damage. We also found that UTI post-treatment markedly inhibited the release of HMGB1 and other pro-inflammatory cytokines. Furthermore, UTI significantly inhibited the LPS-induced increase in TLR2/4 protein expression and NF-κB activation in lung tissues. In vitro, UTI markedly inhibited the expression of TLR2/4 and the activation of NF-κB in LPS-stimulated A549 alveolar epithelial cells. The findings of our study indicate that UTI attenuates LPS-induced ALI through the inhibition of HMGB1 expression in rats. These benefits are associated with the inhibition of the activation of the TLR2/4-NF-κB pathway by UTI. PMID:27959396

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

Malaviya, Rama; Venosa, Alessandro; Hall, LeRoy

Nitrogen mustard (NM) is a toxic vesicant known to cause damage to the respiratory tract. Injury is associated with increased expression of inducible nitric oxide synthase (iNOS). In these studies we analyzed the effects of transient inhibition of iNOS using aminoguanidine (AG) on NM-induced pulmonary toxicity. Rats were treated intratracheally with 0.125 mg/kg NM or control. Bronchoalveolar lavage fluid (BAL) and lung tissue were collected 1 d–28 d later and lung injury, oxidative stress and fibrosis assessed. NM exposure resulted in progressive histopathological changes in the lung including multifocal lesions, perivascular and peribronchial edema, inflammatory cell accumulation, alveolar fibrin deposition,more » bronchiolization of alveolar septal walls, and fibrosis. This was correlated with trichrome staining and expression of proliferating cell nuclear antigen (PCNA). Expression of heme oxygenase (HO)-1 and manganese superoxide dismutase (Mn-SOD) was also increased in the lung following NM exposure, along with levels of protein and inflammatory cells in BAL, consistent with oxidative stress and alveolar-epithelial injury. Both classically activated proinflammatory (iNOS{sup +} and cyclooxygenase-2{sup +}) and alternatively activated profibrotic (YM-1{sup +} and galectin-3{sup +}) macrophages appeared in the lung following NM administration; this was evident within 1 d, and persisted for 28 d. AG administration (50 mg/kg, 2 ×/day, 1 d–3 d) abrogated NM-induced injury, oxidative stress and inflammation at 1 d and 3 d post exposure, with no effects at 7 d or 28 d. These findings indicate that nitric oxide generated via iNOS contributes to acute NM-induced lung toxicity, however, transient inhibition of iNOS is not sufficient to protect against pulmonary fibrosis. -- Highlights: ► Nitrogen mustard (NM) induces acute lung injury and fibrosis. ► Pulmonary toxicity is associated with increased expression of iNOS. ► Transient inhibition of iNOS attenuates acute lung injury induced by NM.« less

Reversal of nicotine-induced alveolar lipofibroblast-to-myofibroblast transdifferentiation by stimulants of parathyroid hormone-related protein signaling.

PubMed

Rehan, Virender K; Sakurai, Reiko; Wang, Ying; Santos, Jamie; Huynh, Kyle; Torday, John S

2007-01-01

Nicotine exposure disrupts the parathyroid hormone-related protein (PTHrP)-driven alveolar epithelial-mesenchymal paracrine-signaling pathway, resulting in the transdifferentiation of pulmonary lipofibroblasts (LIFs) to myofibroblasts (MYFs), which seems to be central to altered pulmonary development and function in infants born to mothers who smoke during pregnancy. Modulation of PTHrP-driven signaling can almost completely prevent nicotine-induced LIF-to-MYF transdifferentiation. However, once this process has occurred, whether it can be reversed is not known. Our objective was to determine if nicotine-induced LIF-to-MYF transdifferentiation could be reversed by specifically targeting the PTHrP-mediated alveolar epithelial-mesenchymal paracrine signaling. WI38 cells, a human embryonic pulmonary fibroblast cell line, were initially treated with nicotine for 7 days and LIF-to-MYF transdifferentiation was confirmed by determining the downregulation of the key lipogenic marker, peroxisome proliferator-activated receptor gamma (PPARgamma) and upregulation of the key myogenic marker, alpha-smooth muscle actin (alphaSMA). Because downregulation of the PPARgamma signaling pathway is the key determinant of LIF-to-MYF transdifferentiation, cells were treated with three agonists of this pathway, PTHrP, dibutryl cAMP (DBcAMP), or rosiglitazone (RGZ) for 7 days, and the expression of the PTHrP receptor, PPARgamma, alphaSMA, and calponin was determined by Western analysis and immunohistochemistry. Simultaneously, fibroblast function was characterized by measuring their capacity to take up triglycerides. Nicotine-induced LIF-to-MYF transdifferentiation was almost completely reversed by treatment with RGZ, PTHrP, or DBcAMP, as determined by protein and functional assays. Using a specific molecular approach and targeting specific molecular intermediates in the PTHrP signaling pathway, to our knowledge, this for the first time, demonstrates the reversibility of nicotine-induced LIF-to-MYF transdifferentiation, suggesting not only the possibility of prevention but also the potential for reversal of nicotine-induced lung injury.

EGR-1 regulates Ho-1 expression induced by cigarette smoke

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

Chen, Huaqun, E-mail: chenhuaqun@njnu.edu.cn; Wang, Lijuan; Gong, Tao

2010-05-28

As an anti-oxidant molecule, heme oxygenase-1 (HO-1) has been implicated in the protection of lung injury by cigarette smoke (CS). The mechanisms regulating its expression have not been defined. In this report, the role of early growth response 1 (EGR-1) in the regulation of Ho-1 expression was investigated. In C57BL/6 mice with CS exposure, HO-1 was greatly increased in bronchial epithelial cells and alveolar inflammatory cells. In primary cultured mouse lung fibroblasts and RAW264.7 cells exposed to cigarette smoke water extract (CSE), an increase in HO-1 protein level was detected. In addition, CSE induced HO-1 expression was decreased in Egr-1more » deficient mouse embryo fibroblasts (Egr-1{sup -/-} MEFs). Nuclear localization of EGR-1 was examined in mouse lung fibroblasts after exposure to CSE. Luciferase reporter activity assays showed that the enhancer region of the Ho-1 gene containing a proposed EGR-1 binding site was responsible for the induction of HO-1. A higher increase of alveolar mean linear intercept (Lm) was observed in lung tissues, and a larger increase in the number of total cells and monocytes/macrophages from bronchial alveolar lavage fluid was found in CS-exposed mice by loss of function of EGR-1 treatment. In summary, the present data demonstrate that EGR-1 plays a critical role in HO-1 production induced by CS.« less

Mitogenic stimulation accelerates influenza-induced mortality by increasing susceptibility of alveolar type II cells to infection

PubMed Central

Noel, John G.; Pitstick, Lori B.; Gardner, Jason C.; Uehara, Yasuaki; Wu, Huixing; Saito, Atsushi; Lewnard, Kara E.; Liu, Huan; White, Mitchell R.; Hartshorn, Kevan L.; McCormack, Francis X.

2017-01-01

Development of pneumonia is the most lethal consequence of influenza, increasing mortality more than 50-fold compared with uncomplicated infection. The spread of viral infection from conducting airways to the alveolar epithelium is therefore a pivotal event in influenza pathogenesis. We found that mitogenic stimulation with keratinocyte growth factor (KGF) markedly accelerated mortality after infectious challenge with influenza A virus (IAV). Coadministration of KGF with IAV markedly accelerated the spread of viral infection from the airways to alveoli compared with challenge with IAV alone, based on spatial and temporal analyses of viral nucleoprotein staining of lung tissue sections and dissociated lung cells. To better define the temporal relationship between KGF administration and susceptibility to IAV infection in vivo, we administered KGF 120, 48, 24, and 0 h before intrapulmonary IAV challenge and assessed the percentages of proliferating and IAV-infected, alveolar type II (AECII) cells in dispersed lung cell populations. Peak AECII infectivity coincided with the timing of KGF administration that also induced peak AECII proliferation. AECII from mice that were given intrapulmonary KGF before isolation and then infected with IAV ex vivo exhibited the same temporal pattern of proliferation and infectious susceptibility. KGF-induced increases in mortality, AECII proliferation, and enhanced IAV susceptibility were all reversed by pretreatment of the animals with the mTOR inhibitor rapamycin before mitogenic stimulation. Taken together, these data suggest mTOR signaling-dependent, mitogenic conditioning of AECII is a determinant of host susceptibility to infection with IAV. PMID:28739896

Mitogenic stimulation accelerates influenza-induced mortality by increasing susceptibility of alveolar type II cells to infection.

PubMed

Nikolaidis, Nikolaos M; Noel, John G; Pitstick, Lori B; Gardner, Jason C; Uehara, Yasuaki; Wu, Huixing; Saito, Atsushi; Lewnard, Kara E; Liu, Huan; White, Mitchell R; Hartshorn, Kevan L; McCormack, Francis X

2017-08-08

Development of pneumonia is the most lethal consequence of influenza, increasing mortality more than 50-fold compared with uncomplicated infection. The spread of viral infection from conducting airways to the alveolar epithelium is therefore a pivotal event in influenza pathogenesis. We found that mitogenic stimulation with keratinocyte growth factor (KGF) markedly accelerated mortality after infectious challenge with influenza A virus (IAV). Coadministration of KGF with IAV markedly accelerated the spread of viral infection from the airways to alveoli compared with challenge with IAV alone, based on spatial and temporal analyses of viral nucleoprotein staining of lung tissue sections and dissociated lung cells. To better define the temporal relationship between KGF administration and susceptibility to IAV infection in vivo, we administered KGF 120, 48, 24, and 0 h before intrapulmonary IAV challenge and assessed the percentages of proliferating and IAV-infected, alveolar type II (AECII) cells in dispersed lung cell populations. Peak AECII infectivity coincided with the timing of KGF administration that also induced peak AECII proliferation. AECII from mice that were given intrapulmonary KGF before isolation and then infected with IAV ex vivo exhibited the same temporal pattern of proliferation and infectious susceptibility. KGF-induced increases in mortality, AECII proliferation, and enhanced IAV susceptibility were all reversed by pretreatment of the animals with the mTOR inhibitor rapamycin before mitogenic stimulation. Taken together, these data suggest mTOR signaling-dependent, mitogenic conditioning of AECII is a determinant of host susceptibility to infection with IAV.

Perfluorocarbon induces alveolar epithelial cell response through structural and mechanical remodeling.

PubMed

André Dias, Sofia; Planus, Emmanuelle; Angely, Christelle; Lotteau, Luc; Tissier, Renaud; Filoche, Marcel; Louis, Bruno; Pelle, Gabriel; Isabey, Daniel

2018-02-15

During total liquid ventilation, lung cells are exposed to perfluorocarbon (PFC) whose chemophysical properties highly differ from standard aqueous cell feeding medium (DMEM). We herein perform a systematic study of structural and mechanical properties of A549 alveolar epithelial cells in order to characterize their response to PFC exposure, using DMEM as control condition. Changes in F-actin structure, focal adhesion density and glycocalyx distribution are evaluated by confocal fluorescent microscopy. Changes in cell mechanics and adhesion are measured by multiscale magnetic twisting cytometry (MTC). Two different microrheological models (single Voigt and power law) are used to analyze the cell mechanics characterized by cytoskeleton (CSK) stiffness and characteristic relaxation times. Cell-matrix adhesion is analyzed using a stochastic multibond deadhesion model taking into account the non-reversible character of the cell response, allowing us to quantify the adhesion weakness and the number of associated bonds. The roles of F-actin structure and glycocalyx layer are evaluated by depolymerizing F-actin and degrading glycocalyx, respectively. Results show that PFC exposure consistently induces F-actin remodeling, CSK softening and adhesion weakening. These results demonstrate that PFC triggers an alveolar epithelial cell response herein evidenced by a decay in intracellular CSK tension, an adhesion weakening and a glycocalyx layer redistribution. These PFC-induced cell adjustments are consistent with the hypothesis that cells respond to a decrease in adhesion energy at cell surface. This adhesion energy can be even further reduced in the presence of surfactant adsorbed at the cell surface.

Inhibiting Bruton's Tyrosine Kinase Rescues Mice from Lethal Influenza Induced Acute Lung Injury.

PubMed

Florence, Jon M; Krupa, Agnieszka; Booshehri, Laela M; Davis, Sandra A; Matthay, Michael A; Kurdowska, Anna K

2018-03-08

Infection with seasonal influenza A virus (IAV) leads to lung inflammation and respiratory failure, a main cause of death in influenza infected patients. Previous experiments in our laboratory indicated that Bruton's tyrosine kinase (Btk) plays a substantial role in regulating inflammation in the respiratory region during acute lung injury (ALI) in mice, therefore we sought to determine if blocking Btk activity had a protective effect in the lung during influenza induced inflammation. A Btk inhibitor (Btk Inh.) Ibrutinib (also known as PCI-32765) was administered intranasally to mice starting 72h after lethal infection with IAV. Our data indicates that treatment with the Btk inhibitor not only reduced weight loss and led to survival, but had a dramatic effect on morphological changes to the lungs of IAV infected mice. Attenuation of lung inflammation indicative of ALI such as alveolar hemorrhage, interstitial thickening, and the presence of alveolar exudate, together with reduced levels of inflammatory mediators TNFα, IL-1β, IL-6, KC, and MCP-1 strongly suggest amelioration of the pathological immune response in the lungs to promote resolution of the infection. Finally, we observed that blocking Btk specifically in the alveolar compartment led to significant attenuation of neutrophil extracellular traps (NET)s released into the lung in vivo, and NET formation in vitro. Our innovative findings suggest that Btk may be a new drug target for influenza induced lung injury, and in general immunomodulatory treatment may be key in treating lung dysfunction driven by excessive inflammation.

Diffusion of hyperpolarized 129Xe in the lung: a simplified model of 129Xe septal uptake and experimental results

NASA Astrophysics Data System (ADS)

Patz, Samuel; Muradyan, Iga; Hrovat, Mirko I.; Dabaghyan, Mikayel; Washko, George R.; Hatabu, Hiroto; Butler, James P.

2011-01-01

We used hyperpolarized 129Xe NMR to measure pulmonary alveolar surface area per unit gas volume SA/Vgas, alveolar septal thickness h and capillary transit time τ, three critical determinants of the lung's primary role as a gas exchange organ. An analytical solution for a simplified diffusion model is described, together with a modification of the xenon transfer contrast imaging technique utilizing 90° radio-frequency pulses applied to the dissolved phase, rather than traditional 180° pulses. With this approach, three-dimensional (3D) maps of SA/Vgas were obtained. We measured global SA/Vgas, h and τ in four normal subjects, two subjects with mild interstitial lung disease (ILD) and two subjects with mild chronic obstructive pulmonary disease (COPD). In normals, SA/Vgas decreased with increasing lung volume from ~320 to 80 cm-1 both h~13 μm and τ~1.5 s were relatively constant. For the two ILD subjects, h was, respectively, 36 and 97% larger than normal, quantifying an increased gas/blood tissue barrier; SA/Vgas and τ were normal. The two COPD subjects had SA/Vgas values ~25% that of normals, quantifying septal surface loss in emphysema; h and τ were normal. These are the first noninvasive, non-radiation-based, quantitative measurements of h and τ in patients with pulmonary disease.

Alveolar Ridge Augmentation with Three-Dimensional Printed Hydroxyapatite Devices: A Preclinical Study.

PubMed

Fiorellini, Joseph P; Norton, Michael R; Luan, Kevin WanXin; Kim, David Minjoon; Wada, Kei; Sarmiento, Hector L

2018-02-14

The objective of this study was to evaluate the effectiveness of precise three-dimensional hydroxyapatite printed micro- and macrochannel devices for alveolar ridge augmentation in a canine model. All grafts induced minimal inflammatory and fibrotic reactions. Examination of undecalcified sections revealed that both types of grafts demonstrated bone ingrowth. The majority of the bone growth into the block graft was into the channels, though a portion grew directly into the construct in the form of small bony spicules. In conclusion, bone ingrowth was readily demonstrated in the middle of the implanted printed devices.

Alveolar macrophages are critical for broadly-reactive antibody-mediated protection against influenza A virus in mice.

PubMed

He, Wenqian; Chen, Chi-Jene; Mullarkey, Caitlin E; Hamilton, Jennifer R; Wong, Christine K; Leon, Paul E; Uccellini, Melissa B; Chromikova, Veronika; Henry, Carole; Hoffman, Kevin W; Lim, Jean K; Wilson, Patrick C; Miller, Matthew S; Krammer, Florian; Palese, Peter; Tan, Gene S

2017-10-10

The aim of candidate universal influenza vaccines is to provide broad protection against influenza A and B viruses. Studies have demonstrated that broadly reactive antibodies require Fc-Fc gamma receptor interactions for optimal protection; however, the innate effector cells responsible for mediating this protection remain largely unknown. Here, we examine the roles of alveolar macrophages, natural killer cells, and neutrophils in antibody-mediated protection. We demonstrate that alveolar macrophages play a dominant role in conferring protection provided by both broadly neutralizing and non-neutralizing antibodies in mice. Our data also reveal the potential mechanisms by which alveolar macrophages mediate protection in vivo, namely antibody-induced inflammation and antibody-dependent cellular phagocytosis. This study highlights the importance of innate effector cells in establishing a broad-spectrum antiviral state, as well as providing a better understanding of how multiple arms of the immune system cooperate to achieve an optimal antiviral response following influenza virus infection or immunization.Broadly reactive antibodies that recognize influenza A virus HA can be protective, but the mechanism is not completely understood. Here, He et al. show that the inflammatory response and phagocytosis mediated by the interaction between protective antibodies and macrophages are essential for protection.

Effect of Vernonia cinerea in improvement of respiratory tissue in chronic nicotine treatment.

PubMed

Promputta, Chamaibhorn; Anupunpisit, Vipavee; Panyarachun, Busaba; Sawatpanich, Tarinee; Watthanachaiyingcharoen, Rith; Paeratakul, Ornlaksana; Kamkaen, Narisa; Petpiboolthai, Hattaya

2012-12-01

To demonstrate the effect of Vernonia cinerea (VC) on rat respiratory tissue in chronic nicotine condition. Pathology of rat respiratory tissue was induced by intraperitoneally injection with 1 mg/kg BW of rat. Male Wistar rats were divided into three groups, control group (C), nicotine treated group (N) and nicotine treated with Vernonia cinerea (VC) supplementation (NV, 100 mg/kg BW of rat) for 3 and 6 months. The animals were sacrificed and the respiratory tissues were removed and further processed for paraffin embedment and stained with Hematoxylin & Eosin (H&E), Periodic Acid Schiff (PAS), and Masson's trichrome techniques. The histopathology of lung tissue and trachea occurred in a chronic nicotine treatment. The thickness of alveolar walls and proliferation of alveolar type 2 cell were found. There was remarkable increasing of various inflammatory cells, alveolar macrophages, lymphocytes and plasma cells after nicotine treatment for 6 months. A large number of small blood vessels appeared in the alveolar wall. Nicotine also caused fibrosis which dispersed throughout the lung parenchyma in perivascular peribronchiole and alveolar wall regions. Moreover there was the appearance of epithelial cell injury and goblet cell hyperplasia in the trachea. Regarding the VC supplementation, the result of a recovery of alveolar walls, i.e. decreasing of various inflammatory cells and alveolar type 2 cells was clearly demonstrated. In addition, the fibrosis and goblet cell hyperplasia were almost disappeared in the lung tissue after VC treatment. Administration of VC in a chronic nicotine treatment resulted in an improvement of respiratory tissue. The recovery of the respiratory tract, especially trachea and lung tissue was characterized by the remarkable decrease of various inflammatory cells, fibrotic areas, and goblet cell hyperplasia. The VC, therefore shows the potential effect to be a new herbal therapeutic agent for alleviate the symptoms of the respiratory tract caused by nicotine from heavy cigarette smoke.

Pirfenidone ameliorates lipopolysaccharide-induced pulmonary inflammation and fibrosis by blocking NLRP3 inflammasome activation.

PubMed

Li, Yi; Li, Haitao; Liu, Shuai; Pan, Pinhua; Su, Xiaoli; Tan, Hongyi; Wu, Dongdong; Zhang, Lemeng; Song, Chao; Dai, Minhui; Li, Qian; Mao, Zhi; Long, Yuan; Hu, Yongbin; Hu, Chengping

2018-05-18

Acute respiratory distress syndrome(ARDS)is a severe clinical disorder characterized by its acute onset, diffuse alveolar damage, intractable hypoxemia, and non-cardiogenic pulmonary edema. Acute lung injury(ALI) can trigger persistent lung inflammation and fibrosis through activation of the NLRP3 inflammasome and subsequent secretion of mature IL-1β, suggesting that the NLRP3 inflammasome is a potential therapeutic target for ALI, for which new therapeutic approaches are needed. Our present study aims to assess whether pirfenidone,with anti-fibrotic and anti-inflammatory properties, can improve LPS-induced inflammation and fibrosis by inhibiting NLRP3 inflammasome activation. Male C57BL/6 J mice were intratracheally injected with LPS to induce ALI. Mice were administered pirfenidone by oral gavage throughout the entire experimental course. The mouse macrophage cell line (J774 A.1) was incubated with LPS and ATP, with or without PFD pre-treatment. We demonstrated that PFD remarkably ameliorated LPS-induced pulmonary inflammation and fibrosis and reduced IL-1β and TGF-β1 levels in bronchoalveolar lavage fluid(BALF). Pirfenidone substantially reduced NLRP3 and ASC expression and inhibited caspase-1 activation and IL-1β maturation in lung tissues. In vitro, the experiments revealed that PFD significantly suppressed LPS/ATP-induced production of reactive oxygen species (ROS) and decreased caspase-1 activation and the level of IL-1β in J774 A.1 cells. Taken together, the administration of PFD reduced LPS-induced lung inflammation and fibrosis by blocking NLRP3 inflammasome activation and subsequent IL-1β secretion. These findings indicated that PFD can down-regulate NLRP3 inflammasome activation and that it may offer a promising therapeutic approach for ARDS patients. Copyright © 2018 Elsevier Ltd. All rights reserved.

Deconvoluting lung evolution: from phenotypes to gene regulatory networks

PubMed Central

Torday, John S.; Rehan, Virender K.; Hicks, James W.; Wang, Tobias; Maina, John; Weibel, Ewald R.; Hsia, Connie C.W.; Sommer, Ralf J.; Perry, Steven F.

2007-01-01

Speakers in this symposium presented examples of respiratory regulation that broadly illustrate principles of evolution from whole organ to genes. The swim bladder and lungs of aquatic and terrestrial organisms arose independently from a common primordial “respiratory pharynx” but not from each other. Pathways of lung evolution are similar between crocodiles and birds but a low compliance of mammalian lung may have driven the development of the diaphragm to permit lung inflation during inspiration. To meet the high oxygen demands of flight, bird lungs have evolved separate gas exchange and pump components to achieve unidirectional ventilation and minimize dead space. The process of “screening” (removal of oxygen from inspired air prior to entering the terminal units) reduces effective alveolar oxygen tension and potentially explains why nonathletic large mammals possess greater pulmonary diffusing capacities than required by their oxygen consumption. The “primitive” central admixture of oxygenated and deoxygenated blood in the incompletely divided reptilian heart is actually co-regulated with other autonomic cardiopulmonary responses to provide flexible control of arterial oxygen tension independent of ventilation as well as a unique mechanism for adjusting metabolic rate. Some of the most ancient oxygen-sensing molecules, i.e., hypoxia-inducible factor-1alpha and erythropoietin, are up-regulated during mammalian lung development and growth under apparently normoxic conditions, suggesting functional evolution. Normal alveolarization requires pleiotropic growth factors acting via highly conserved cell–cell signal transduction, e.g., parathyroid hormone-related protein transducing at least partly through the Wingless/int pathway. The latter regulates morphogenesis from nematode to mammal. If there is commonality among these diverse respiratory processes, it is that all levels of organization, from molecular signaling to structure to function, co-evolve progressively, and optimize an existing gas-exchange framework. PMID:20607138

Immunomodulatory Role of Stem Cells from Human Exfoliated Deciduous Teeth on Periodontal Regeneration.

PubMed

Gao, Xianling; Shen, Zongshan; Guan, Meiliang; Huang, Qiting; Chen, Lingling; Qin, Wei; Ge, Xiaohu; Chen, Haijia; Xiao, Yin; Lin, Zhengmei

2018-05-09

Periodontitis is initiated by the infection of periodontal bacteria and subsequent tissue inflammation due to immunoreaction, eventually leading to periodontal apparatus loss. Stem cells from human exfoliated deciduous teeth (SHEDs) have exhibited beneficial characteristics in dental tissue regeneration. However, the immunomodulatory functions of SHEDs have not been elucidated in the context of periodontitis treatment. In this study, we investigated the potential immunomodulatory effects of SHEDs on experimental periodontitis and demonstrated that multidose delivery of SHEDs led to periodontal tissue regeneration. SHEDs and monocytes/macrophages were cocultured in transwell systems and SHEDs were found to be capable of promoting monocyte/macrophage conversion to CD206 + M2-like phenotype. Bioluminescence imaging (BLI) was employed to assess the survival and distribution of SHEDs after delivery in periodontal tissues in an induced periodontitis model, and BLI revealed that SHEDs survived for ∼7 days in periodontal tissues with little tissue diffusion. Then, multidose SHED delivery was applied to treat periodontitis at 7-day intervals. Results showed that mutidose SHEDs altered the cytokine expression profile in gingival crevicular fluid, reduced gum bleeding, increased new attachment of periodontal ligament, and decreased osteoclast differentiation. Micro-computed tomography analysis showed SHED administration significantly increased periodontal regeneration and alveolar bone volume, and decreased distance of cementoenamel junction to alveolar bone crest. Furthermore, an increase in the number of CD206 + M2 macrophages was observed in periodontal tissues following the delivery of SHEDs, which aligned well with the promoted conversion to CD206 + M2-like cells from monocytes/macrophages in vitro after stimulation by SHEDs. This study demonstrated in a rat periodontitis model that local delivery of SHEDs attributed to the induction of M2 macrophage polarization, reduction of periodontal tissue inflammation, and enhancement of periodontal regeneration.

Impact of hydrogel nanoparticle size and functionalization on in vivo behavior for lung imaging and therapeutics

PubMed Central

Liu, Yongjian; Ibricevic-Richardson, Aida; Cohen, Joel A.; Cohen, Jessica L.; Gunsten, Sean P.; Fréchet, Jean M. J.; Walter, Michael J.; Welch, Michael J.; Brody, Steven L.

2009-01-01

Polymer chemistry offers the possibility of synthesizing multifunctional nanoparticles which incorporate moieties that enhance diagnostic and therapeutic targeting of cargo delivery to the lung. However, since rules for predicting particle behavior following modification are not well defined, it is essential that probes for tracking fate in vivo are also included. Accordingly, we designed polyacrylamide-based hydrogel particles of differing sizes, functionalized with a nona-arginine cell-penetrating peptide (Arg9), and labeled with imaging components to assess lung retention and cellular uptake after intratracheal administration. Radiolabeled microparticles (1–5 µm diameter) and nanoparticles (20–40 nm diameter) without and with Arg9 showed diffuse airspace distribution by positron emission tomography imaging. Biodistribution studies revealed that particle clearance and extrapulmonary distribution was, in part, size dependent. Microparticles were rapidly cleared by mucociliary routes but unexpectedly, also through the circulation. In contrast, nanoparticles had prolonged lung retention enhanced by Arg9 and were significantly restricted to the lung. For all particle types, uptake was predominant in alveolar macrophages, and, to a lesser extent, lung epithelial cells. In general, particles did not induce local inflammatory responses, with the exception of microparticles bearing Arg9. Whereas microparticles may be advantageous for short-term applications, nano-sized particles constitute an efficient high-retention and non-inflammatory vehicle for the delivery of diagnostic imaging agents and therapeutics to lung airspaces and alveolar macrophages that can be enhanced by Arg9. Importantly, our results show that minor particle modifications may significantly impact in vivo behavior within the complex environments of the lung, underscoring the need for animal modeling. PMID:19852512

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

Pulmonary Administration of GW0742, a High-Affinity Peroxisome Proliferator-Activated Receptor Agonist, Repairs Collapsed Alveoli in an Elastase-Induced Mouse Model of Emphysema.

PubMed

Ozawa, Chihiro; Horiguchi, Michiko; Akita, Tomomi; Oiso, Yuki; Abe, Kaori; Motomura, Tomoki; Yamashita, Chikamasa

2016-01-01

Pulmonary emphysema is a disease in which lung alveoli are irreversibly damaged, thus compromising lung function. Our previous study revealed that all-trans-retinoic acid (ATRA) induces the differentiation of human lung alveolar epithelial type 2 progenitor cells and repairs the alveoli of emphysema model mice. ATRA also reportedly has the ability to activate peroxisome proliferator-activated receptor (PPAR) β/δ. A selective PPARβ/δ ligand has been reported to induce the differentiation of human keratinocytes during wound repair. Here, we demonstrate that treatment using a high-affinity PPARβ/δ agonist, GW0742, reverses the lung tissue damage induced by elastase in emphysema-model mice and improves respiratory function. Mice treated with elastase, which collapsed their alveoli, were then treated with either 10% dimethyl sulfoxide (DMSO) in saline (control group) or GW0742 (1.0 mg/kg twice a week) by pulmonary administration. Treatment with GW0742 for 2 weeks increased the in vivo expression of surfactant proteins A and D, which are known alveolar type II epithelial cell markers. GW0742 treatment also shortened the average distance between alveolar walls in the lungs of emphysema model mice, compared with a control group treated with 10% DMSO in saline. Treatment with GW0742 for 3 weeks also improved tissue elastance (cm H2O/mL), as well as the ratio of the forced expiratory volume in the first 0.05 s to the forced vital capacity (FEV 0.05/FVC). In each of these experiments, GW0742 treatment reversed the damage caused by elastase. In conclusion, PPARβ/δ agonists are potential therapeutic agents for pulmonary emphysema.

Burkholderia mallei and Burkholderia pseudomallei stimulate differential inflammatory responses from human alveolar type II cells (ATII) and macrophages.

PubMed

Lu, Richard; Popov, Vsevolod; Patel, Jignesh; Eaves-Pyles, Tonyia

2012-01-01

Alveolar type II pneumocytes (ATII) and alveolar macrophages (AM) play a crucial role in the lung's innate immune response. Burkholderia pseudomallei (BP) and Burkholderia mallei (BM) are facultative Gram-negative bacilli that cause melioidosis and glanders, respectively. The inhalation of these pathogens can cause lethal disease and death in humans. We sought to compare the pathogenesis of and host responses to BP and BM through contact with human primary ATII cells and monocytes-derived macrophages (MDM). We hypothesized that because BP and BM induce different disease outcomes, each pathogen would induce distinct, unique host immune responses from resident pulmonary cells. Our findings showed that BP adhered readily to ATII cells compared to BM. BP, but not BM, was rapidly internalized by macrophages where it replicated to high numbers. Further, BP-induced significantly higher levels of pro-inflammatory cytokine secretion from ATII cells (IL-6, IL-8) and macrophages (IL-6, TNFα) at 6 h post-infection compared to BM (p < 0.05). Interestingly, BM-induced the anti-inflammatory cytokine, IL-10, in ATII cells and macrophages at 6 h post-infection, with delayed induction of inflammatory cytokines at 24 h post-infection. Because BP is flagellated and produces LPS, we confirmed that it stimulated both Toll-like receptor (TLR) 4 and TLR5 via NF-κb activation while the non-flagellated BM stimulated only TLR4. These data show the differences in BP and BM pathogenicity in the lung when infecting human ATII cells and macrophages and demonstrate the ability of these pathogens to elicit distinct immune responses from resident lung cells which may open new targets for therapeutic intervention to fight against these pathogens.

Inhibition of the alveolar macrophage oxidative burst by a diffusible component from the surface of the spores of the fungus Aspergillus fumigatus.

PubMed Central

Slight, J.; Nicholson, W. J.; Mitchell, C. G.; Pouilly, N.; Beswick, P. H.; Seaton, A.; Donaldson, K.

1996-01-01

BACKGROUND: Aspergillus fumigatus is a fungus that grows on dead and decaying organic matter in the environment and whose spores are present ubiquitously in the air. The fungus causes a range of diseases in the human lung. A study was undertaken to demonstrate and partially characterise an inhibitor of the macrophage respiratory burst from the surface of A fumigatus spores that could be an important factor in allowing the fungus to colonise the lung. METHODS: The spore-derived inhibitor of the respiratory burst of rat alveolar macrophages, as measured by generation of superoxide anion, was demonstrated in Hank's balanced salt solution extracts of four clinical isolates and an environmental isolate of A fumigatus. The time course of the release of the inhibitor into aqueous solution was assessed and the cytotoxic potential of the spore-derived inhibitor towards macrophages was tested using the propidium iodide method. An oxygen electrode was used to confirm the superoxide anion measurements. Molecular weight cutoff filters were used to determine the size of the inhibitor as assessed in the respiratory burst assay and also by its ability to inhibit macrophage spreading on glass. The crude diffusate from the spore surface was fractionated by reversed phase high pressure liquid chromatography (HPLC) and the fractions analysed for inhibitory activity, protein, and carbohydrate content. RESULTS: A small molecular weight (< 10 kD) heat stable toxin was released from the spores of clinical and environmental isolates of A fumigatus within minutes of deposition in aqueous solution. The key effect of the toxin demonstrated here was its ability to inhibit the oxidative burst of macrophages as measured by superoxide anion release. The inhibition was not due to cell death or detectable loss of membrane integrity as measured by permeability to propidium iodide. The toxin was not a scavenger of superoxide anion. Oxygen electrode studies suggested indirectly that the inhibitor acted to inhibit the assembly of the macrophage NADPH-oxidase complex. Fractions of < 10 kD also inhibited the spreading of alveolar macrophages, confirming that the toxin had an additional effect on macrophages that leads to loss of adherence or impairment of cytoskeletal function. In reversed phase HPLC fractions the inhibitory activity eluted with an associated carbohydrate, although the exact chemical nature of the toxin remains to be elucidated. CONCLUSIONS: This spore toxin may, through its ability to diffuse rapidly into lung lining fluid, diminish the macrophage respiratory burst and play a part in allowing A fumigatus to persist in the lung and manifest its well known pathogenic effects. Future research will be focused on further molecular characterisation of the toxin and elaboration of the effect of the toxin on intracellular signalling pathways involved in the activation of alveolar macrophages. PMID:8733491

Paclitaxel-induced lung injury and its amelioration by parecoxib sodium.

PubMed

Liu, Wen-jie; Zhong, Zhong-jian; Cao, Long-hui; Li, Hui-ting; Zhang, Tian-hua; Lin, Wen-qian

2015-08-10

To investigate the mechanism of paclitaxel-induced lung injury and its amelioration by parecoxib sodium. In this study, rats were randomly divided into: the control group (Con); the paclitaxel chemotherapy group (Pac); the paclitaxel+ parecoxib sodium intervention group (Pac + Pare); and the parecoxib sodium group (Pare). We observed changes in alveolar ventilation function, alveolar-capillary membrane permeability, lung tissue pathology and measured the levels of inflammatory cytokines and cyclooxygenase-2 (Cox-2) in lung tissue, the expression of tight junction proteins (Zo-1 and Claudin-4). Compared with the Con group, the lung tissue of the Pac group showed significantly increased expression of Cox-2 protein (p < 0.01), significant lung tissue inflammatory changes, significantly increased expression of inflammatory cytokines, decreased expression of Zo-1 and Claudin-4 proteins (p < 0.01), increased alveolar-capillary membrane permeability (p < 0.01), and reduced ventilation function (p < 0.01). Notably, in Pac + Pare group, intraperitoneal injection of parecoxib sodium led to decreased Cox-2 and ICAM-1 levels and reduced inflammatory responses, the recovered expression of Zo-1 and Claudin-4, reduced level of indicators reflecting the high permeability state, and close-to-normal levels of ventilation function. Intervention by the Cox-2-specific inhibitor parecoxib sodium can block this damage.

Paclitaxel-induced lung injury and its amelioration by parecoxib sodium

PubMed Central

Liu, Wen-jie; Zhong, Zhong-jian; Cao, Long-hui; Li, Hui-ting; Zhang, Tian-hua; Lin, Wen-qian

2015-01-01

To investigate the mechanism of paclitaxel-induced lung injury and its amelioration by parecoxib sodium. In this study, rats were randomly divided into: the control group (Con); the paclitaxel chemotherapy group (Pac); the paclitaxel+ parecoxib sodium intervention group (Pac + Pare); and the parecoxib sodium group (Pare). We observed changes in alveolar ventilation function, alveolar-capillary membrane permeability, lung tissue pathology and measured the levels of inflammatory cytokines and cyclooxygenase-2 (Cox-2) in lung tissue, the expression of tight junction proteins (Zo-1 and Claudin-4). Compared with the Con group, the lung tissue of the Pac group showed significantly increased expression of Cox-2 protein (p < 0.01), significant lung tissue inflammatory changes, significantly increased expression of inflammatory cytokines, decreased expression of Zo-1 and Claudin-4 proteins (p < 0.01), increased alveolar-capillary membrane permeability (p < 0.01), and reduced ventilation function (p < 0.01). Notably, in Pac + Pare group, intraperitoneal injection of parecoxib sodium led to decreased Cox-2 and ICAM-1 levels and reduced inflammatory responses, the recovered expression of Zo-1 and Claudin-4, reduced level of indicators reflecting the high permeability state, and close-to-normal levels of ventilation function. Intervention by the Cox-2-specific inhibitor parecoxib sodium can block this damage. PMID:26256764

Diesel exhaust particles induce the over expression of tumor necrosis factor-alpha (TNF-alpha) gene in alvelor machrophage and failed to induce apoptosis through activation of nuclear factor-kappaB (NF-kappaB)

EPA Science Inventory

Exposure to particulate matter (PM2.5-10), including diesel exhaust particles (DEP) has been reported to induce lung injury and exacerbation of asthma and chronic obstructive pulmonary disease. Alveolar macrophages play a major role in the lung's response to inhaled particles and...

The role of inducible nitric oxide synthase for interstitial remodeling of alveolar septa in surfactant protein D-deficient mice

PubMed Central

Atochina-Vasserman, Elena N.; Massa, Christopher B.; Birkelbach, Bastian; Guo, Chang-Jiang; Scott, Pamela; Haenni, Beat; Beers, Michael F.; Ochs, Matthias; Gow, Andrew J.

2015-01-01

Surfactant protein D (SP-D) modulates the lung's immune system. Its absence leads to NOS2-independent alveolar lipoproteinosis and NOS2-dependent chronic inflammation, which is critical for early emphysematous remodeling. With aging, SP-D knockout mice develop an additional interstitial fibrotic component. We hypothesize that this age-related interstitial septal wall remodeling is mediated by NOS2. Using invasive pulmonary function testing such as the forced oscillation technique and quasistatic pressure-volume perturbation and design-based stereology, we compared 29-wk-old SP-D knockout (Sftpd−/−) mice, SP-D/NOS2 double-knockout (DiNOS) mice, and wild-type mice (WT). Structural changes, including alveolar epithelial surface area, distribution of septal wall thickness, and volumes of septal wall components (alveolar epithelium, interstitial tissue, and endothelium) were quantified. Twenty-nine-week-old Sftpd−/− mice had preserved lung mechanics at the organ level, whereas elastance was increased in DiNOS. Airspace enlargement and loss of surface area of alveolar epithelium coexist with increased septal wall thickness in Sftpd−/− mice. These changes were reduced in DiNOS, and compared with Sftpd−/− mice a decrease in volumes of interstitial tissue and alveolar epithelium was found. To understand the effects of lung pathology on measured lung mechanics, structural data were used to inform a computational model, simulating lung mechanics as a function of airspace derecruitment, septal wall destruction (loss of surface area), and septal wall thickening. In conclusion, NOS2 mediates remodeling of septal walls, resulting in deposition of interstitial tissue in Sftpd−/−. Forward modeling linking structure and lung mechanics describes the complex mechanical properties by parenchymatous destruction (emphysema), interstitial remodeling (septal wall thickening), and altered recruitability of acinar airspaces. PMID:26320150

Surfactant Protein–C Chromatin-Bound Green Fluorescence Protein Reporter Mice Reveal Heterogeneity of Surfactant Protein C–Expressing Lung Cells

PubMed Central

Lee, Joo-Hyeon; Kim, Jonghwan; Gludish, David; Roach, Rebecca R.; Saunders, Arven H.; Barrios, Juliana; Woo, Andrew Jonghan; Chen, Huaiyong; Conner, David A.; Fujiwara, Yuko; Stripp, Barry R.

2013-01-01

The regeneration of alveolar epithelial cells is a critical aspect of alveolar reorganization after lung injury. Although alveolar Type II (AT2) cells have been described as progenitor cells for alveolar epithelia, more remains to be understood about how their progenitor cell properties are regulated. A nuclear, chromatin-bound green fluorescence protein reporter (H2B-GFP) was driven from the murine surfactant protein–C (SPC) promoter to generate SPC H2B-GFP transgenic mice. The SPC H2B-GFP allele allowed the FACS-based enrichment and gene expression profiling of AT2 cells. Approximately 97% of AT2 cells were GFP-labeled on Postnatal Day 1, and the percentage of GFP-labeled AT2 cells decreased to approximately 63% at Postnatal Week 8. Isolated young adult SPC H2B-GFP+ cells displayed proliferation, differentiation, and self-renewal capacity in the presence of lung fibroblasts in a Matrigel-based three-dimensional culture system. Heterogeneity within the GFP+ population was revealed, because cells with distinct alveolar and bronchiolar gene expression arose in three-dimensional cultures. CD74, a surface marker highly enriched on GFP+ cells, was identified as a positive selection marker, providing 3-fold enrichment for AT2 cells. In vivo, GFP expression was induced within other epithelial cell types during maturation of the distal lung. The utility of the SPC H2B-GFP murine model for the identification of AT2 cells was greatest in early postnatal lungs and more limited with age, when some discordance between SPC and GFP expression was observed. In adult mice, this allele may allow for the enrichment and future characterization of other SPC-expressing alveolar and bronchiolar cells, including putative stem/progenitor cell populations. PMID:23204392

The fraction of NO in exhaled air and estimates of alveolar NO in adolescents with asthma: methodological aspects.

PubMed

Heijkenskjöld-Rentzhog, Charlotte; Alving, Kjell; Kalm-Stephens, Pia; Lundberg, Jon O; Nordvall, Lennart; Malinovschi, Andrei

2012-10-01

This study investigated the oral contribution to exhaled NO in young people with asthma and its potential effects on estimated alveolar NO (Calv(NO) ), a proposed marker of inflammation in peripheral airways. Secondary aims were to investigate the effects of various exhalation flow-rates and the feasibility of different proposed adjustments of (Calv(NO) ) for trumpet model and axial diffusion (TMAD). Exhaled NO at flow rates of 50-300 ml/sec, and salivary nitrite was measured before and after antibacterial mouthwash in 29 healthy young people (10-20 years) and 29 with asthma (10-19 years). Calv(NO) was calculated using the slope-intercept model with and without TMAD adjustment. Exhaled NO at 50 ml/sec decreased significantly after mouthwash, to a similar degree in asthmatic and healthy subjects (8.8% vs. 9.8%, P = 0.49). The two groups had similar salivary nitrite levels (56.4 vs. 78.4 µM, P = 0.25). Calv(NO) was not significantly decreased by mouthwash. Calv(NO) levels were similar when flow-rates between 50-200 or 100-300 ml/sec were used (P = 0.34 in asthmatics and P = 0.90 in healthy subjects). A positive association was found between bronchial and alveolar NO in asthmatic subjects and this disappeared after the TMAD-adjustment. Negative TMAD-adjusted Calv(NO) values were found in a minority of the subjects. Young people with and without asthma have similar salivary nitrite levels and oral contributions to exhaled NO and therefore no antibacterial mouthwash is necessary in routine use. TMAD corrections of alveolar NO could be successfully applied in young people with asthma and yielded negative results only in a minority of subjects. Copyright © 2012 Wiley Periodicals, Inc.

The NS1 Glycoprotein Can Generate Dramatic Antibody-Enhanced Dengue Viral Replication in Normal Out-Bred Mice Resulting in Lethal Multi-Organ Disease

PubMed Central

Falconar, Andrew K. I.; Martinez, Fernando

2011-01-01

Antibody-enhanced replication (AER) of dengue type-2 virus (DENV-2) strains and production of antibody-enhanced disease (AED) was tested in out-bred mice. Polyclonal antibodies (PAbs) generated against the nonstructural-1 (NS1) glycoprotein candidate vaccine of the New Guinea-C (NG-C) or NSx strains reacted strongly and weakly with these antigens, respectively. These PAbs contained the IgG2a subclass, which cross-reacted with the virion-associated envelope (E) glycoprotein of the DENV-2 NSx strain, suggesting that they could generate its AER via all mouse Fcγ-receptor classes. Indeed, when these mice were challenged with a low dose (<0.5 LD50) of the DENV-2 NSx strain, but not the NG-C strain, they all generated dramatic and lethal DENV-2 AER/AED. These AER/AED mice developed life-threatening acute respiratory distress syndrome (ARDS), displayed by diffuse alveolar damage (DAD) resulting from i) dramatic interstitial alveolar septa-thickening with mononuclear cells, ii) some hyperplasia of alveolar type-II pneumocytes, iii) copious intra-alveolar protein secretion, iv) some hyaline membrane-covered alveolar walls, and v) DENV-2 antigen-positive alveolar macrophages. These mice also developed meningo-encephalitis, with greater than 90,000-fold DENV-2 AER titers in microglial cells located throughout their brain parenchyma, some of which formed nodules around dead neurons. Their spleens contained infiltrated megakaryocytes with DENV-2 antigen-positive red-pulp macrophages, while their livers displayed extensive necrosis, apoptosis and macro- and micro-steatosis, with DENV-2 antigen-positive Kuppfer cells and hepatocytes. Their infections were confirmed by DENV-2 isolations from their lungs, spleens and livers. These findings accord with those reported in fatal human “severe dengue” cases. This DENV-2 AER/AED was blocked by high concentrations of only the NG-C NS1 glycoprotein. These results imply a potential hazard of DENV NS1 glycoprotein-based vaccines, particularly against DENV strains that contain multiple mutations or genetic recombination within or between their DENV E and NS1 glycoprotein-encoding genes. The model provides potential for assessing DENV strain pathogenicity and anti-DENV therapies in normal mice. PMID:21731643

Reduction in membrane component of diffusing capacity is associated with the extent of acute pulmonary embolism

PubMed Central

Piirilä, Päivi; Laiho, Mia; Mustonen, Pirjo; Graner, Marit; Piilonen, Anneli; Raade, Merja; Sarna, Seppo; Harjola, Veli-Pekka; Sovijärvi, Anssi

2011-01-01

Acute pulmonary embolism (PE) often decreases pulmonary diffusing capacity for carbon monoxide (DL,CO), but data on the mechanisms involved are inconsistent. We wanted to investigate whether reduction in diffusing capacity of alveolo-capillary membrane (DM) and pulmonary capillary blood volume (Vc) is associated with the extent of PE or the presence and severity of right ventricular dysfunction (RVD) induced by PE and how the possible changes are corrected after 7-month follow-up. Forty-seven patients with acute non-massive PE in spiral computed tomography (CT) were included. The extent of PE was assessed by scoring mass of embolism. DL,CO, Vc, DM and alveolar volume (VA) were measured by using a single breath method with carbon monoxide and oxygen both at the acute phase and 7 months later. RVD was evaluated with transthoracic echocardiography and electrocardiogram. Fifteen healthy subjects were included as controls. DL,CO, DL, CO/VA, DM, vital capacity (VC) and VA were significantly lower in the patients with acute PE than in healthy controls (P<0·001). DM/Vc relation was significantly lower in patients with RVD than in healthy controls (P = 0·004). DM correlated inversely with central mass of embolism (r = −0·312; P = 0·047) whereas Vc did not. DM, DL,CO, VC and VA improved significantly within 7 months. In all patients (P = 0·001, P = 0·001) and persistent RVD (P = 0·020, P = 0·012), DM and DL,CO remained significantly lower than in healthy controls in the follow-up. DM was inversely related to central mass of embolism. Reduction in DM mainly explains the sustained decrease in DL,CO in PE after 7 months despite modern treatment of PE. PMID:21143754

The effect of hyperbaric oxygen treatment on aspiration pneumonia.

PubMed

Sahin, Sevtap Hekimoglu; Kanter, Mehmet; Ayvaz, Suleyman; Colak, Alkin; Aksu, Burhan; Guzel, Ahmet; Basaran, Umit Nusret; Erboga, Mustafa; Ozcan, Ali

2011-08-01

We have studied whether hyperbaric oxygen (HBO) prevents different pulmonary aspiration materials-induced lung injury in rats. The experiments were designed in 60 Sprague-Dawley rats, ranging in weight from 250 to 300 g, randomly allotted into one of six groups (n = 10): saline control, Biosorb Energy Plus (BIO), hydrochloric acid (HCl), saline + HBO treated, BIO + HBO treated, and HCl + HBO treated. Saline, BIO, HCl were injected into the lungs in a volume of 2 ml/kg. A total of seven HBO sessions were performed at 2,4 atm 100% oxygen for 90 min at 6-h intervals. Seven days later, rats were sacrificed, and both lungs in all groups were examined biochemically and histopathologically. Our findings show that HBO inhibits the inflammatory response reducing significantly (P < 0.05) peribronchial inflammatory cell infiltration, alveolar septal infiltration, alveolar edema, alveolar exudate, alveolar histiocytes, interstitial fibrosis, granuloma, and necrosis formation in different pulmonary aspiration models. Pulmonar aspiration significantly increased the tissue HP content, malondialdehyde (MDA) levels and decreased (P < 0.05) the antioxidant enzyme (SOD, GSH-Px) activities. HBO treatment significantly (P < 0.05) decreased the elevated tissue HP content, and MDA levels and prevented inhibition of SOD, and GSH-Px (P < 0.05) enzymes in the tissues. Furthermore, there is a significant reduction in the activity of inducible nitric oxide synthase, TUNEL and arise in the expression of surfactant protein D in lung tissue of different pulmonary aspiration models with HBO therapy. It was concluded that HBO treatment might be beneficial in lung injury, therefore, shows potential for clinical use.

Novel role of NPY in neuroimmune interaction and lung growth after intrauterine growth restriction.

PubMed

Thangaratnarajah, Chansutha; Dinger, Katharina; Vohlen, Christina; Klaudt, Christian; Nawabi, Jawed; Lopez Garcia, Eva; Kwapiszewska, Grazyna; Dobner, Julia; Nüsken, Kai D; van Koningsbruggen-Rietschel, Silke; von Hörsten, Stephan; Dötsch, Jörg; Alejandre Alcázar, Miguel A

2017-09-01

Individuals with intrauterine growth restriction (IUGR) are at risk for chronic lung disease. Using a rat model, we showed in our previous studies that altered lung structure is related to IL-6/STAT3 signaling. As neuropeptide Y (NPY), a coneurotransmitter of the sympathetic nervous system, regulates proliferation and immune response, we hypothesized that dysregulated NPY after IUGR is linked to IL-6, impaired myofibroblast function, and alveolar growth. IUGR was induced in rats by isocaloric low-protein diet; lungs were analyzed on embryonic day (E) 21, postnatal day (P) 3, P12, and P23. Finally, primary neonatal lung myofibroblasts (pnF) and murine embryonic fibroblasts (MEF) were used to assess proliferation, apoptosis, migration, and IL-6 expression. At E21, NPY and IL-6 expression was decreased, and AKT/PKC and STAT3/AMPKα signaling was reduced. Early reduction of NPY/IL-6 was associated with increased chord length in lungs after IUGR at P3, indicating reduced alveolar formation. At P23, however, IUGR rats exhibited a catch-up of body weight and alveolar growth coupled with more proliferating myofibroblasts. These structural findings after IUGR were linked to activated NPY/PKC, IL-6/AMPKα signaling. Complementary, IUGR-pnF showed increased survival, impaired migration, and reduced IL-6 compared with control-pnF (Co-pnF). In contrast, NPY induced proliferation, migration, and increased IL-6 synthesis in fibroblasts. Additionally, NPY -/- mice showed reduced IL-6 signaling and less proliferation of lung fibroblasts. Our study presents a novel role of NPY during alveolarization: NPY regulates 1 ) IL-6 and lung STAT3/AMPKα signaling, and 2 ) proliferation and migration of myofibroblasts. These new insights in pulmonary neuroimmune interaction offer potential strategies to enable lung growth. Copyright © 2017 the American Physiological Society.

Cytotoxicity, cytokine release and ER stress-autophagy gene expression in endothelial cells and alveolar-endothelial co-culture exposed to pristine and carboxylated multi-walled carbon nanotubes.

PubMed

Chang, Shiwei; Zhao, Xuqi; Li, Siyu; Liao, Tuqiang; Long, Jimin; Yu, Zhiqiang; Cao, Yi

2018-06-18

Recently we found that direct exposure of human umbilical vein endothelial cells (HUVECs) to multi-walled carbon nanotubes (MWCNTs) might induce toxicological responses through the modulation of ER stress gene expression, but whether this signal could be transferred from other cells to endothelial cells (ECs) is unknown. This study investigated the toxicity of pristine and carboxylated MWCNTs to HUVECs and alveolar-endothelial co-culture, the later of which could mimic the possible signaling communications between ECs and MWCNT exposed alveolar cells. The results showed that direct contact with high levels of MWCNTs induced cytotoxicity and modulated expression of genes associated with ER stress (HSPA5, DDIT3 and XBP-1s) and autophagy (BECN1 and ATG12) both in A549-THP-1 macrophages cultured in the upper chambers as well as HUVECs. However, most of these responses were minimal or negligible in HUVECs cultured in the lower chambers. Moreover, significantly increased cytokine release (interleukin-6 and soluble vascular cell adhesion molecule-1) was only observed in MWCNT exposed HUVECs (p < 0.01) but not HUVECs cultured in the lower chambers (p > 0.05). The minimal or even absent response was likely due to relatively low translocation of MWCNTs from upper chambers to lower chambers, whereas A549-macrophages cultured in the upper chambers internalized large amount MWCNTs. The results indicated that ER stress-autophagy signaling might not be able to transfer from alveolar cells to endothelial cells unless sufficient MWCNTs are translocated. Copyright © 2018 Elsevier Inc. All rights reserved.

Alveolar macrophage phagocytosis is enhanced after blunt chest trauma and alters the posttraumatic mediator release.

PubMed

Seitz, Daniel H; Palmer, Annette; Niesler, Ulrike; Fröba, Janine S; Heidemann, Vera; Rittlinger, Anne; Braumüller, Sonja T; Zhou, Shaoxia; Gebhard, Florian; Knöferl, Markus W

2011-12-01

Blunt chest trauma is known to induce a pulmonary invasion of short-lived polymorphonuclear neutrophils and apoptosis of alveolar epithelial type 2 (AT2) cells. Apoptotic cells are removed by alveolar macrophages (AMΦ). We hypothesized that chest trauma alters the phagocytic response of AMΦ as well as the mediator release of AMΦ during phagocytosis. To study this, male Sprague-Dawley rats were subjected to blunt chest trauma. Phagocytosis assays were performed in AMΦ isolated 2 or 24 h after trauma with apoptotic cells or opsonized beads. Phagocytosis of apoptotic AT2 cells by unstimulated AMΦ was significantly increased 2 h after trauma. At 24 h, AMΦ from traumatized animals, stimulated with phorbol-12-myristate-13-acetate, ingested significantly more apoptotic polymorphonuclear neutrophils than AMΦ from sham animals. Alveolar macrophages after trauma released significantly higher levels of tumor necrosis factor α, macrophage inflammatory protein 1α, and cytokine-induced neutrophil chemoattractant 1 when they incorporated latex beads, but significantly lower levels of interleukin 1β and macrophage inflammatory protein 1α when they ingested apoptotic cells. In vivo, phagocytosis of intratracheally instilled latex beads was decreased in traumatized rats. The bronchoalveolar lavage concentrations of the phagocytosis-supporting surfactant proteins A and D after blunt chest trauma were slightly decreased, whereas surfactant protein D mRNA expression in AT2 cells was significantly increased after 2 h. These findings indicate that chest trauma augments the phagocytosis of apoptotic cells by AMΦ. Phagocytosis of opsonized beads enhances and ingestion of apoptotic cells downregulates the immunologic response following lung contusion. Our data emphasize the important role of phagocytosis during posttraumatic inflammation after lung contusion.

Ibuprofen-induced patent ductus arteriosus closure: physiologic, histologic, and biochemical effects on the premature lung.

PubMed

McCurnin, Donald; Seidner, Steven; Chang, Ling-Yi; Waleh, Nahid; Ikegami, Machiko; Petershack, Jean; Yoder, Brad; Giavedoni, Luis; Albertine, Kurt H; Dahl, Mar Janna; Wang, Zheng-ming; Clyman, Ronald I

2008-05-01

The goal was to study the pulmonary, biochemical, and morphologic effects of a persistent patent ductus arteriosus in a preterm baboon model of bronchopulmonary dysplasia. Preterm baboons (treated prenatally with glucocorticoids) were delivered at 125 days of gestation (term: 185 days), given surfactant, and ventilated for 14 days. Twenty-four hours after birth, newborns were randomly assigned to receive either ibuprofen (to close the patent ductus arteriosus; n = 8) or no drug (control; n = 13). After treatment was started, the ibuprofen group had significantly lower pulmonary/systemic flow ratio, higher systemic blood pressure, and lower left ventricular end diastolic diameter, compared with the control group. There were no differences in cardiac performance indices between the groups. Ventilation index and dynamic compliance were significantly improved with ibuprofen. The improved pulmonary mechanics in ibuprofen-treated newborns were not attributable to changes in levels of surfactant protein B, C, or D, saturated phosphatidylcholine, or surfactant inhibitory proteins. There were no differences in tracheal concentrations of cytokines commonly associated with the development of bronchopulmonary dysplasia. The groups had similar messenger RNA expression of genes that regulate inflammation and remodeling in the lung. Lungs from ibuprofen-treated newborns were significantly drier (lower wet/dry ratio) and expressed 2.5 times more epithelial sodium channel protein than did control lungs. By 14 days after delivery, control newborns had morphologic features of arrested alveolar development (decreased alveolar surface area and complexity), compared with age-matched fetuses. In contrast, there was no evidence of alveolar arrest in the ibuprofen-treated newborns. Ibuprofen-induced patent ductus arteriosus closure improved pulmonary mechanics, decreased total lung water, increased epithelial sodium channel expression, and decreased the detrimental effects of preterm birth on alveolarization.

Effects of β-Glucans Ingestion on Alveolar Bone Loss, Intestinal Morphology, Systemic Inflammatory Profile, and Pancreatic β-Cell Function in Rats with Periodontitis and Diabetes

PubMed Central

Silva, Viviam de O.; Lobato, Raquel V.; Orlando, Débora R.; Borges, Bruno D.B.; de Sousa, Raimundo V.

2017-01-01

This study aimed to evaluate the effects of β-glucan ingestion (Saccharomyces cerevisiae) on the plasmatic levels of tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10), alveolar bone loss, and pancreatic β-cell function (HOMA-BF) in diabetic rats with periodontal disease (PD). Besides, intestinal morphology was determined by the villus/crypt ratio. A total of 48 Wistar rats weighing 203 ± 18 g were used. Diabetes was induced by the intraperitoneal injection of streptozotocin (80 mg/kg) and periodontal inflammation, by ligature. The design was completely randomized in a factorial scheme 2 × 2 × 2 (diabetic or not, with or without periodontitis, and ingesting β-glucan or not). The animals received β-glucan by gavage for 28 days. Alveolar bone loss was determined by scanning electron microscopy (distance between the cementoenamel junction and alveolar bone crest) and histometric analysis (bone area between tooth roots). β-glucan reduced plasmatic levels of TNF-α in diabetic animals with PD and of IL-10 in animals with PD (p < 0.05). β-glucan reduced bone loss in animals with PD (p < 0.05). In diabetic animals, β-glucan improved β-cell function (p < 0.05). Diabetic animals had a higher villus/crypt ratio (p < 0.05). In conclusion, β-glucan ingestion reduced the systemic inflammatory profile, prevented alveolar bone loss, and improved β-cell function in diabetic animals with PD. PMID:28906456

Type XVIII collagen degradation products in acute lung injury

PubMed Central

Perkins, Gavin D; Nathani, Nazim; Richter, Alex G; Park, Daniel; Shyamsundar, Murali; Heljasvaara, Ritva; Pihlajaniemi, Taina; Manji, Mav; Tunnicliffe, W; McAuley, Danny; Gao, Fang; Thickett, David R

2009-01-01

Introduction In acute lung injury, repair of the damaged alveolar-capillary barrier is an essential part of recovery. Endostatin is a 20 to 28 kDa proteolytic fragment of the basement membrane collagen XVIII, which has been shown to inhibit angiogenesis via action on endothelial cells. We hypothesised that endostatin may have a role in inhibiting lung repair in patients with lung injury. The aims of the study were to determine if endostatin is elevated in the plasma/bronchoalveolar lavage fluid of patients with acute lung injury and ascertain whether the levels reflect the severity of injury and alveolar inflammation, and to assess if endostatin changes occur early after the injurious lung stimuli of one lung ventilation and lipopolysaccharide (LPS) challenge. Methods Endostatin was measured by ELISA and western blotting. Results Endostatin is elevated within the plasma and bronchoalveolar lavage fluid of patients with acute lung injury. Lavage endostatin reflected the degree of alveolar neutrophilia and the extent of the loss of protein selectivity of the alveolar-capillary barrier. Plasma levels of endostatin correlated with the severity of physiological derangement. Western blotting confirmed elevated type XVIII collagen precursor levels in the plasma and lavage and multiple endostatin-like fragments in the lavage of patients. One lung ventilation and LPS challenge rapidly induce increases in lung endostatin levels. Conclusions Endostatin may adversely affect both alveolar barrier endothelial and epithelial cells, so its presence within both the circulation and the lung may have a pathophysiological role in acute lung injury that warrants further evaluation. PMID:19358707

Use of Aminocaproic Acid in Combination With Extracorporeal Membrane Oxygenation in a Case of Leptospirosis Pulmonary Hemorrhage Syndrome.

PubMed

Pardinas, Miguel; Mendirichaga, Rodrigo; Budhrani, Gaurav; Garg, Rajan; Rosario, Luis; Rico, Rene; Panos, Anthony; Baier, Horst; Krick, Stefanie

2017-01-01

A 32-year-old man presented with a 10-day history of fever, chills, nausea, vomiting, myalgia, nonproductive cough, and worsening dyspnea after freshwater swimming in the Caribbean 1 week prior to presentation. Shortly after arrival at the hospital, the patient developed severe respiratory distress with massive hemoptysis. Based on serologic workup, he was diagnosed with leptospirosis pulmonary hemorrhage syndrome leading to diffuse alveolar hemorrhage, severe hypoxemic respiratory failure, and multiorgan failure. He received appropriate antibiotic coverage along with hemodynamic support with norepinephrine and vasopressin, mechanical ventilation, and renal replacement therapy in an intensive care unit. Introduction of extracorporeal membrane oxygenation was initiated to provide lung-protective ventilation supporting the recovery of his pulmonary function. Aminocaproic acid was used to stop and prevent further alveolar hemorrhage. He fully recovered thereafter; however, it is uncertain whether it was the use of aminocaproic acid that led to the resolution of his disease.

Use of Aminocaproic Acid in Combination With Extracorporeal Membrane Oxygenation in a Case of Leptospirosis Pulmonary Hemorrhage Syndrome

PubMed Central

Pardinas, Miguel; Mendirichaga, Rodrigo; Budhrani, Gaurav; Garg, Rajan; Rosario, Luis; Rico, Rene; Panos, Anthony; Baier, Horst; Krick, Stefanie

2017-01-01

A 32-year-old man presented with a 10-day history of fever, chills, nausea, vomiting, myalgia, nonproductive cough, and worsening dyspnea after freshwater swimming in the Caribbean 1 week prior to presentation. Shortly after arrival at the hospital, the patient developed severe respiratory distress with massive hemoptysis. Based on serologic workup, he was diagnosed with leptospirosis pulmonary hemorrhage syndrome leading to diffuse alveolar hemorrhage, severe hypoxemic respiratory failure, and multiorgan failure. He received appropriate antibiotic coverage along with hemodynamic support with norepinephrine and vasopressin, mechanical ventilation, and renal replacement therapy in an intensive care unit. Introduction of extracorporeal membrane oxygenation was initiated to provide lung-protective ventilation supporting the recovery of his pulmonary function. Aminocaproic acid was used to stop and prevent further alveolar hemorrhage. He fully recovered thereafter; however, it is uncertain whether it was the use of aminocaproic acid that led to the resolution of his disease. PMID:28469503

The lung in amyloidosis.

PubMed

Milani, Paolo; Basset, Marco; Russo, Francesca; Foli, Andrea; Palladini, Giovanni; Merlini, Giampaolo

2017-09-30

Amyloidosis is a disorder caused by misfolding of autologous protein and its extracellular deposition as fibrils, resulting in vital organ dysfunction and eventually death. Pulmonary amyloidosis may be localised or part of systemic amyloidosis.Pulmonary interstitial amyloidosis is symptomatic only if the amyloid deposits severely affect gas exchange alveolar structure, thus resulting in serious respiratory impairment. Localised parenchymal involvement may be present as nodular amyloidosis or as amyloid deposits associated with localised lymphomas. Finally, tracheobronchial amyloidosis, which is usually not associated with evident clonal proliferation, may result in airway stenosis.Because the treatment options for amyloidosis are dependent on the fibril protein type, the workup of all new cases should include accurate determination of the amyloid protein. Most cases are asymptomatic and need only a careful follow-up. Diffuse alveolar-septal amyloidosis is treated according to the underlying systemic amyloidosis. Nodular pulmonary amyloidosis is usually localised, conservative excision is usually curative and the long-term prognosis is excellent. Tracheobronchial amyloidosis is usually treated with bronchoscopic interventions or external beam radiation therapy. Copyright ©ERS 2017.

IRON-BINDING AND STORAGE PROTEINS IN SPUTUM

EPA Science Inventory

Induced sputum (IS) and bronchoalveolar lavage (BAL) sample different lung compartments, with IS obtaining secretions from the surfaces of the bronchial airways and BAL sampling secretions from the alveolar airspaces. Deposition of iron-containing particulate matter occurs prefer...

Seawater inhalation induces acute lung injury via ROS generation and the endoplasmic reticulum stress pathway

PubMed Central

Li, Cong-Cong; Lu, Xi; Qian, Wei-Sheng; Li, Yu-Juan; Jin, Fa-Guang; Mu, De-Guang

2018-01-01

Seawater (SW) inhalation can induce acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). In the present study, SW induced apoptosis of rat alveolar epithelial cells and histopathological alterations to lung tissue. Furthermore, SW administration increased generation of reactive oxygen species (ROS), whereas pretreatment with the ROS scavenger, N-acetyl-L-cysteine (NAC), significantly decreased ROS generation, apoptosis and histopathological alterations. In addition, SW exposure upregulated the expression levels of glucose-regulated protein 78 (GRP78) and CCAAT/enhancer binding protein homologous protein (CHOP), which are critical proteins in the endoplasmic reticulum (ER) stress response, thus indicating that SW may activate ER stress. Conversely, blocking ER stress with 4-phenylbutyric acid (4-PBA) significantly improved SW-induced apoptosis and histopathological alterations, whereas an ER stress inducer, thapsigargin, had the opposite effect. Furthermore, blocking ROS with NAC inhibited SW-induced ER stress, as evidenced by the downregulation of GRP78, phosphorylated (p)-protein kinase R-like ER kinase (PERK), p-inositol-requiring kinase 1α (IRE1α), p-50 activating transcription factor 6α and CHOP. In addition, blocking ER stress with 4-PBA decreased ROS generation. In conclusion, the present study indicated that ROS and ER stress pathways, which are involved in alveolar epithelial cell apoptosis, are important in the pathogenesis of SW-induced ALI. PMID:29436612

Targeting the Ron-Dek Signaling Axis in Breast Cancer

DTIC Science & Technology

2015-09-01

deficient alveolar myeloid cells exacerbate LPS-induced acute lung injury in the murine lung. Innate immunity. 2011; 17:499–507. 25. Stuart WD, Kulkarni...induced Ron activation in human and murine breast cancer cell lines induces the accumulation of Dek protein. This accumulation of Dek is significant as...Dek overexpression in breast cancer cell lines leads to increases in cell growth and migration while Dek depletion in breast cancer cells leads to

Administration of intrapulmonary sodium polyacrylate to induce lung injury for the development of a porcine model of early acute respiratory distress syndrome.

PubMed

Henderson, William R; Barnbrook, Julian; Dominelli, Paolo B; Griesdale, Donald Eg; Arndt, Tara; Molgat-Seon, Yannick; Foster, Glen; Ackland, Gareth L; Xu, James; Ayas, Najib T; Sheel, Andrew W

2014-12-01

The loss of alveolar epithelial and endothelial integrity is a central component in acute respiratory distress syndrome (ARDS); however, experimental models investigating the mechanisms of epithelial injury are lacking. The purpose of the present study was to design and develop an experimental porcine model of ARDS by inducing lung injury with intrapulmonary administration of sodium polyacrylate (SPA). The present study was performed at the Centre for Comparative Medicine, University of British Columbia, Vancouver, British Columbia. Human alveolar epithelial cells were cultured with several different concentrations of SPA; a bioluminescence technique was used to assess cell death associated with each concentration. In the anesthetized pig model (female Yorkshire X pigs (n = 14)), lung injury was caused in 11 animals (SPA group) by injecting sequential aliquots (5 mL) of 1% SPA gel in aqueous solution into the distal airway via a rubber catheter through an endotracheal tube. The SPA was dispersed throughout the lungs by manual bag ventilation. Three control animals (CON group) underwent all experimental procedures and measurements with the exception of SPA administration. The mean (± SD) ATP concentration after incubation of human alveolar epithelial cells with 0.1% SPA (0.92 ± 0.27 μM/well) was approximately 15% of the value found for the background control (6.30 ± 0.37 μM/well; p < 0.001). Elastance of the respiratory system (E RS) and the lung (E L) increased in SPA-treated animals after injury (p = 0.003 and p < 0.001, respectively). Chest wall elastance (E CW) did not change in SPA-treated animals. There were no differences in E RS, E L, or E CW in the CON group when pre- and post-injury values were compared. Analysis of bronchoalveolar lavage fluid showed a significant shift toward neutrophil predominance from before to after injury in SPA-treated animals (p < 0.001) but not in the CON group (p = 0.38). Necropsy revealed marked consolidation and congestion of the dorsal lung lobes in SPA-treated animals, with light-microscopy evidence of bronchiolar and alveolar spaces filled with neutrophilic infiltrate, proteinaceous debris, and fibrin deposition. These findings were absent in animals in the CON group. Electron microscopy of lung tissue from SPA-treated animals revealed injury to the alveolar epithelium and basement membranes, including intra-alveolar neutrophils and fibrin on the alveolar surface and intravascular fibrin (microthrombosis). In this particular porcine model, the nonimmunogenic polymer SPA caused a rapid exudative lung injury. This model may be useful to study ARDS caused by epithelial injury and inflammation.

Reference values for pulmonary diffusing capacity for adult native Finns.

PubMed

Kainu, Annette; Toikka, Jyri; Vanninen, Esko; Timonen, Kirsi L

2017-04-01

Measurement standards for pulmonary diffusing capacity were updated in 2005 by the ATS/ERS Task Force. However, in Finland reference values published in 1982 by Viljanen et al. have been used to date. The main aim of this study was to produce updated reference models for single-breath diffusing capacity for carbon monoxide for Finnish adults. Single-breath diffusing capacity for carbon monoxide was measured in 631 healthy non-smoking volunteers (41.5% male). Reference values for diffusing capacity (DLCO), alveolar volume (VA), diffusing capacity per unit of lung volume (DLCO/VA), and lung volumes were calculated using a linear regression model. Previously used Finnish reference values were found to produce too low predicted values, with mean predicted DLCO 111.0 and 104.4%, and DLCO/VA of 103.5 and 102.7% in males and females, respectively. With the European Coalition for Steel and Coal (ECSC) reference values there was a significant sex difference in DLCO/VA with mean predicted 105.4% in males and 92.8% in females (p < .001). New reference values for DLCO, DLCO/VA, VA, vital capacity (VC), inspiratory vital capacity (IVC), and inspiratory capacity (IC) are suggested for clinical use to replace technically outdated reference values for clinical applications.

Lung Morphometry with Hyperpolarized 129Xe: Theoretical Background

PubMed Central

Sukstanskii, A.L.; Yablonskiy, D.A.

2011-01-01

The 3He lung morphometry technique, based on MRI measurements of hyperpolarized 3He gas diffusion in lung airspaces, provides unique information on the lung microstructure at the alveolar level. In vivo 3D tomographic images of standard morphological parameters (airspace chord length, lung parenchyma surface-to-volume ratio, number of alveoli per unit volume) can be generated from a rather short (several seconds) MRI scan. The technique is based on a theory of gas diffusion in lung acinar airways and experimental measurements of diffusion attenuated MRI signal. The present work aims at developing the theoretical background of a similar technique based on hyperpolarized 129Xe gas. As the diffusion coefficient and gyromagnetic ratio of 129Xe gas are substantially different from those of 3He gas, the specific details of the theory and experimental measurements with 129Xe should be amended. We establish phenomenological relationships between acinar airway geometrical parameters and the diffusion attenuated MR signal for human and small animal lungs, both normal lungs and lungs with mild emphysema. Optimal diffusion times are shown to be about 5 ms for human and 1.3 ms for small animals. The expected uncertainties in measuring main morphometrical parameters of the lungs are estimated in the framework of Bayesian probability theory. PMID:21713985

Hypotonic Shock Modulates Na+ Current via a Cl- and Ca2+/Calmodulin Dependent Mechanism in Alveolar Epithelial Cells

PubMed Central

Tatur, Sabina; Brochiero, Emmanuelle; Grygorczyk, Ryszard; Berthiaume, Yves

2013-01-01

Alveolar epithelial cells are involved in Na+ absorption via the epithelial Na+ channel (ENaC), an important process for maintaining an appropriate volume of liquid lining the respiratory epithelium and for lung oedema clearance. Here, we investigated how a 20% hypotonic shock modulates the ionic current in these cells. Polarized alveolar epithelial cells isolated from rat lungs were cultured on permeant filters and their electrophysiological properties recorded. A 20% bilateral hypotonic shock induced an immediate, but transient 52% rise in total transepithelial current and a 67% increase in the amiloride-sensitive current mediated by ENaC. Amiloride pre-treatment decreased the current rise after hypotonic shock, showing that ENaC current is involved in this response. Since Cl- transport is modulated by hypotonic shock, its contribution to the basal and hypotonic-induced transepithelial current was also assessed. Apical NPPB, a broad Cl- channel inhibitor and basolateral DIOA a potassium chloride co-transporter (KCC) inhibitor reduced the total and ENaC currents, showing that transcellular Cl- transport plays a major role in that process. During hypotonic shock, a basolateral Cl- influx, partly inhibited by NPPB is essential for the hypotonic-induced current rise. Hypotonic shock promoted apical ATP secretion and increased intracellular Ca2+. While apyrase, an ATP scavenger, did not inhibit the hypotonic shock current response, W7 a calmodulin antagonist completely prevented the hypotonic current rise. These results indicate that a basolateral Cl- influx as well as Ca2+/calmodulin, but not ATP, are involved in the acute transepithelial current rise elicited by hypotonic shock. PMID:24019969

Lead intoxication under environmental hypoxia impairs oral health.

PubMed

Terrizzi, Antonela R; Fernandez-Solari, Javier; Lee, Ching M; Martínez, María Pilar; Conti, María Ines

2014-01-01

We have reported that chronic lead intoxication under hypoxic environment induces alveolar bone loss that can lead to periodontal damage with the subsequent loss of teeth. The aim of the present study was to assess the modification of oral inflammatory parameters involved in the pathogenesis of periodontitis in the same experimental model. In gingival tissue, hypoxia increased inducible nitric oxid synthase (iNOS) activity (p < .01) and meanwhile lead decreased prostaglandin E2 (PGE2) content (p < .05). In submandibular gland (SMG), iNOS activity was enhanced by lead and PGE2 content was increased by both lead and hypoxia (p < .01) and even more by combined treatments (p < .001). In the SMG, hypoxia stimulated angiogenesis (p < .01) with blood extravasation. Adrenal glands were 22% bigger in those animals exposed to lead under hypoxic conditions. Results suggest a wide participation of inflammatory markers that mediate alveolar bone loss induced by these environmental conditions. The lack of information regarding oral health in lead-contaminated populations that coexist with hypoxia induced us to evaluate the alteration of inflammatory parameters in rat oral tissues to elucidate the link between periodontal damage and these environmental conditions.

An improved method for the isolation of rat alveolar type II lung cells: Use in the Comet assay to determine DNA damage induced by cigarette smoke.

PubMed

Dalrymple, Annette; Ordoñez, Patricia; Thorne, David; Dillon, Debbie; Meredith, Clive

2015-06-01

Smoking is a cause of serious diseases, including lung cancer, emphysema, chronic bronchitis and heart disease. DNA damage is thought to be one of the mechanisms by which cigarette smoke (CS) initiates disease in the lung. Indeed, CS induced DNA damage can be measured in vitro and in vivo. The potential of the Comet assay to measure DNA damage in isolated rat lung alveolar type II epithelial cells (AEC II) was explored as a means to include a genotoxicity end-point in rodent sub-chronic inhalation studies. In this study, published AEC II isolation methods were improved to yield viable cells suitable for use in the Comet assay. The improved method reduced the level of basal DNA damage and DNA repair in isolated AEC II. CS induced DNA damage could also be quantified in isolated cells following a single or 5 days CS exposure. In conclusion, the Comet assay has the potential to determine CS or other aerosol induced DNA damage in AEC II isolated from rodents used in sub-chronic inhalation studies. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Cannabidiol decreases bone resorption by inhibiting RANK/RANKL expression and pro-inflammatory cytokines during experimental periodontitis in rats.

PubMed

Napimoga, Marcelo H; Benatti, Bruno B; Lima, Flavia O; Alves, Polyanna M; Campos, Alline C; Pena-Dos-Santos, Diego R; Severino, Fernando P; Cunha, Fernando Q; Guimarães, Francisco S

2009-02-01

Cannabidiol (CBD) is a cannabinoid component from Cannabis sativa that does not induce psychotomimetic effects and possess anti-inflammatory properties. In the present study we tested the effects of CBD in a periodontitis experimental model in rats. We also investigated possible mechanisms underlying these effects. Periodontal disease was induced by a ligature placed around the mandible first molars of each animal. Male Wistar rats were divided into 3 groups: control animals; ligature-induced animals treated with vehicle and ligature-induced animals treated with CBD (5 mg/kg, daily). Thirty days after the induction of periodontal disease the animals were sacrificed and mandibles and gingival tissues removed for further analysis. Morphometrical analysis of alveolar bone loss demonstrated that CBD-treated animals presented a decreased alveolar bone loss and a lower expression of the activator of nuclear factor-kappaB ligand RANKL/RANK. Moreover, gingival tissues from the CBD-treated group showed decreased neutrophil migration (MPO assay) associated with lower interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha production. These results indicate that CBD may be useful to control bone resorption during progression of experimental periodontitis in rats.

Effects of peroxisome proliferator-activated receptor-β/δ on sepsis induced acute lung injury.

PubMed

Wang, Cairui; Zhou, Guopeng; Zeng, Zeng

2014-01-01

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the first steps in the development of multiple organ failure induced by sepsis. A systemic excessive inflammatory reaction is currently the accepted mechanism of the pathogenesis of sepsis. Several studies have suggested a protective role of the peroxisome proliferator activated receptor-β/δ (PPAR-β/δ) in related inflammatory diseases. But the role of PPARβ/δ in ALI remains uncertain. The aim of this study was to investigate the role and possible mechanism of PPARβ/δ in ALI induced by sepsis. Cecal ligation and puncture (CLP) was used as a sepsis model. Rats were randomly divided into four groups, the control group (CON, n = 6), sham-operation group (SHAM, n = 12), cecal ligation and puncture group (CLP, n = 30), GW501516 group (CLP+GW, n = 25), which underwent CLP and were subcutaneously injected with the PPAR-β/δ agonist GW501516 (0.05 mg/100 g body weight). Survival was monitored to 24 hours after operation. Blood pressure, serum creatinine, blood urea nitrogen, aspartate aminotrasferase and alanine aminotrasferase were measured after CLP. Concentrations of tumor necrosis factor α (TNF-α) and interleukin (IL)-1β in serum were detected by enzyme linked immunosorbent assay (ELISA) kits. Lung tissue samples were stained with H&E and scored according to the degree of inflammation. Bacterial colonies were counted in the peritoneal fluid. Alveolar macrophages were cultured and incubated with GW501516 (0.15 µmol/L) and PPARβ/δ adenovirus and then treated with Lipopolysaccharide (2 µg/ml) for 2 hours. The TNF-α, IL-1β and IL-6 RNA in lung and alveolar macrophages were determined by real-time PCR. Phosphorylation of signal transducer and activator of transcription 3 (STAT3) in lung and alveolar macrophages was detected by Western blotting. GW501516 significantly increased the survival of septic rats, decreased histological damage of the lungs, reduced inflammatory cytokines in serum and lung tissues of septic rats and did not increase counts of peritoneal bacteria. In vitro, GW501516 and over-expression of PPARβ/δ attenuated gene expression of TNF-α, IL-1β and IL-6 in alveolar macrophages. Both in vivo and in vitro, PPARβ/δ inhibited the phosphorylation of STAT3. PPARβ/δ plays a protective role in sepsis induced ALI via suppressing excessive inflammation.

Regulation of ENaC-mediated alveolar fluid clearance by insulin via PI3K/Akt pathway in LPS-induced acute lung injury.

PubMed

Deng, Wang; Li, Chang-Yi; Tong, Jin; Zhang, Wei; Wang, Dao-Xin

2012-03-30

Stimulation of epithelial sodium channel (ENaC) increases Na(+) transport, a driving force of alveolar fluid clearance (AFC) to keep alveolar spaces free of edema fluid that is beneficial for acute lung injury (ALI). It is well recognized that regulation of ENaC by insulin via PI3K pathway, but the mechanism of this signaling pathway to regulate AFC and ENaC in ALI remains unclear. The aim of this study was to investigate the effect of insulin on AFC in ALI and clarify the pathway in which insulin regulates the expression of ENaC in vitro and in vivo. A model of ALI (LPS at a dose of 5.0 mg/kg) with non-hyperglycemia was established in Sprague-Dawley rats receiving continuous exogenous insulin by micro-osmotic pumps and wortmannin. The lungs were isolated for measurement of bronchoalveolar lavage fluid(BALF), total lung water content(TLW), and AFC after ALI for 8 hours. Alveolar epithelial type II cells were pre-incubated with LY294002, Akt inhibitor and SGK1 inhibitor 30 minutes before insulin treatment for 2 hours. The expressions of α-,β-, and γ-ENaC were detected by immunocytochemistry, reverse transcriptase polymerase chain reaction (RT-PCR) and western blotting. In vivo, insulin decreased TLW, enchanced AFC, increased the expressions of α-,β-, and γ-ENaC and the level of phosphorylated Akt, attenuated lung injury and improved the survival rate in LPS-induced ALI, the effects of which were blocked by wortmannin. Amiloride, a sodium channel inhibitor, significantly reduced insulin-induced increase in AFC. In vitro, insulin increased the expressions of α-,β-, and γ-ENaC as well as the level of phosphorylated Akt but LY294002 and Akt inhibitor significantly prevented insulin-induced increase in the expression of ENaC and the level of phosphorylated Akt respectively. Immunoprecipitation studies showed that levels of Nedd4-2 binding to ENaC were decreased by insulin via PI3K/Akt pathway. Our study demonstrated that insulin alleviated pulmonary edema and enhanced AFC by increasing the expression of ENaC that dependent upon PI3K/Akt pathway by inhibition of Nedd4-2.

Effects of Cinnamoyloxy-mammeisin from Geopropolis on Osteoclast Differentiation and Porphyromonas gingivalis-Induced Periodontitis.

PubMed

da Cunha, Marcos Guilherme; Ramos-Junior, Erivan Schnaider; Franchin, Marcelo; Taira, Thaise Mayumi; Beutler, John A; Franco, Gilson Cesar Nobre; Ikegaki, Masaharu; de Alencar, Severino Matias; Fukada, Sandra Yasuyo; Rosalen, Pedro Luiz

2017-06-23

Bone-loss-related diseases such as rheumatoid arthritis, osteomyelitis, osteoporosis, and periodontitis are associated with high rates of morbidity worldwide. These disorders are characterized by an imbalance between the formation and activity of osteoblasts and osteoclasts, leading to bone loss. In this context, we evaluated the effect of cinnamoyloxy-mammeisin (CNM), an anti-inflammatory coumarin found in Melipona scutellaris geopropolis, on key targets related to bone remodeling. In the present study we investigated the in vitro effects of CNM on osteoclast differentiation and M-CSF+RANKL-induced osteoclastogenic marker expression. Additionally, the interference of CNM treatment on osteoclast activity was evaluated by zymography and resorption area. Finally, we assessed the capacity of the compound to mitigate alveolar bone loss in vivo in experimental murine periodontitis induced by Porphyromonas gingivalis. We observed that treatment with CNM impaired osteoclast differentiation, as evidenced by a reduced number of tartrate-resistant acid-phosphatase-positive multinucleated cells (TRAP+) as well as the expression of osteoclastogenic markers upon M-CSF+RANKL-induced stimulation. Similarly, we observed reduced gelatinolytic and resorption capacity in M-CSF+RANKL-induced cells in vitro. Lastly, CNM attenuated alveolar bone loss in an experimental murine periodontitis model. These findings indicate that CNM may be considered a promising treatment for bone loss diseases.

Attenuation of endoplasmic reticulum stress by caffeine ameliorates hyperoxia-induced lung injury

PubMed Central

Jing, Xigang; Michalkiewicz, Teresa; Afolayan, Adeleye J.; Wu, Tzong-Jin; Konduri, Girija G.

2017-01-01

Rodent pups exposed to hyperoxia develop lung changes similar to bronchopulmonary dysplasia (BPD) in extremely premature infants. Oxidative stress from hyperoxia can injure developing lungs through endoplasmic reticulum (ER) stress. Early caffeine treatment decreases the rate of BPD, but the mechanisms remain unclear. We hypothesized that caffeine attenuates hyperoxia-induced lung injury through its chemical chaperone property. Sprague-Dawley rat pups were raised either in 90 (hyperoxia) or 21% (normoxia) oxygen from postnatal day 1 (P1) to postnatal day 10 (P10) and then recovered in 21% oxygen until P21. Caffeine (20 mg/kg) or normal saline (control) was administered intraperitoneally daily starting from P2. Lungs were inflation-fixed for histology or snap-frozen for immunoblots. Blood caffeine levels were measured in treated pups at euthanasia and were found to be 18.4 ± 4.9 μg/ml. Hyperoxia impaired alveolar formation and increased ER stress markers and downstream effectors; caffeine treatment attenuated these changes at P10. Caffeine also attenuated the hyperoxia-induced activation of cyclooxygenase-2 and markers of apoptosis. In conclusion, hyperoxia-induced alveolar growth impairment is mediated, in part, by ER stress. Early caffeine treatment protects developing lungs from hyperoxia-induced injury by attenuating ER stress. PMID:28213471

Augmenting autophagy for prognosis based intervention of COPD-pathophysiology.

PubMed

Bodas, Manish; Vij, Neeraj

2017-05-04

Chronic obstructive pulmonary disease (COPD) is foremost among the non-reversible fatal ailments where exposure to tobacco/biomass-smoke and aging are the major risk factors for the initiation and progression of the obstructive lung disease. The role of smoke-induced inflammatory-oxidative stress, apoptosis and cellular senescence in driving the alveolar damage that mediates the emphysema progression and severe lung function decline is apparent, although the central mechanism that regulates these processes was unknown. To fill in this gap in knowledge, the central role of proteostasis and autophagy in regulating chronic lung disease causing mechanisms has been recently described. Recent studies demonstrate that cigarette/nicotine exposure induces proteostasis/autophagy-impairment that leads to perinuclear accumulation of polyubiquitinated proteins as aggresome-bodies, indicative of emphysema severity. In support of this concept, autophagy inducing FDA-approved anti-oxidant drugs control tobacco-smoke induced inflammatory-oxidative stress, apoptosis, cellular senescence and COPD-emphysema progression in variety of preclinical models. Hence, we propose that precise and early detection of aggresome-pathology can allow the timely assessment of disease severity in COPD-emphysema subjects for prognosis-based intervention. While intervention with autophagy-inducing drugs is anticipated to reduce alveolar damage and lung function decline, resulting in a decrease in the current mortality rates in COPD-emphysema subjects.

Impact of Different Tidal Volume Levels at Low Mechanical Power on Ventilator-Induced Lung Injury in Rats.

PubMed

Moraes, Lillian; Silva, Pedro L; Thompson, Alessandra; Santos, Cintia L; Santos, Raquel S; Fernandes, Marcos V S; Morales, Marcelo M; Martins, Vanessa; Capelozzi, Vera L; de Abreu, Marcelo G; Pelosi, Paolo; Rocco, Patricia R M

2018-01-01

Tidal volume (V T ) has been considered the main determinant of ventilator-induced lung injury (VILI). Recently, experimental studies have suggested that mechanical power transferred from the ventilator to the lungs is the promoter of VILI. We hypothesized that, as long as mechanical power is kept below a safe threshold, high V T should not be injurious. The present study aimed to investigate the impact of different V T levels and respiratory rates (RR) on lung function, diffuse alveolar damage (DAD), alveolar ultrastructure, and expression of genes related to inflammation [interleukin (IL)-6], alveolar stretch (amphiregulin), epithelial [club cell secretory protein (CC)16] and endothelial [intercellular adhesion molecule (ICAM)-1] cell injury, and extracellular matrix damage [syndecan-1, decorin, and metalloproteinase (MMP)-9] in experimental acute respiratory distress syndrome (ARDS) under low-power mechanical ventilation. Twenty-eight Wistar rats received Escherichia coli lipopolysaccharide intratracheally. After 24 h, 21 animals were randomly assigned to ventilation (2 h) with low mechanical power at three different V T levels ( n = 7/group): (1) V T = 6 mL/kg and RR adjusted to normocapnia; (2) V T = 13 mL/kg; and 3) V T = 22 mL/kg. In the second and third groups, RR was adjusted to yield low mechanical power comparable to that of the first group. Mechanical power was calculated as [(Δ[Formula: see text]/Est, L )/2]× RR (ΔP, L = transpulmonary driving pressure, Est, L = static lung elastance). Seven rats were not mechanically ventilated (NV) and were used for molecular biology analysis. Mechanical power was comparable among groups, while V T gradually increased. ΔP, L and mechanical energy were higher in V T = 22 mL/kg than V T = 6 mL/kg and V T = 13 mL/kg ( p < 0.001 for both). Accordingly, DAD score increased in V T = 22 mL/kg compared to V T = 6 mL/kg and V T = 13 mL/kg [23(18.5-24.75) vs. 16(12-17.75) and 16(13.25-18), p < 0.05, respectively]. V T = 22 mL/kg was associated with higher IL-6, amphiregulin, CC16, MMP-9, and syndecan-1 mRNA expression and lower decorin expression than V T = 6 mL/kg. Multiple linear regression analyses indicated that V T was able to predict changes in IL-6 and CC16, whereas ΔP, L predicted pHa, oxygenation, amphiregulin, and syndecan-1 expression. In the model of ARDS used herein, even at low mechanical power, high V T resulted in VILI. V T control seems to be more important than RR control to mitigate VILI.

The integrity of PRRSV nucleocapsid protein is necessary for up-regulation of optimal interleukin-10 through NF-κB and p38 MAPK pathways in porcine alveolar macrophages.

PubMed

Yu, Jiang; Liu, Yanyan; Zhang, Yuyu; Zhu, Xiwang; Ren, Sufang; Guo, Lihui; Liu, Xing; Sun, Wenbo; Chen, Zhi; Cong, Xiaoyan; Chen, Lei; Shi, Jianli; Du, Yijun; Li, Jun; Wu, Jiaqiang; Wang, Jinbao

2017-08-01

Porcine reproductive and respiratory syndrome (PRRS), a highly contagious disease, has been constantly causing huge economic losses all over the world. PRRS virus (PRRSV) infection results in immunosuppression and IL-10 up-regulation. The relationship between them is still in dispute. Previous studies demonstrated the protein of PRRSV nucleocapsid (N) protein is able to up-regulate IL-10, yet the underlying molecular mechanisms remain unknown. In this study, the expression kinetics of IL-10 up-regulation induced by PRRSV N protein were analyzed in immortalized porcine alveolar macrophages (PAMs). N protein induced IL-10 expression in a time- and dose-dependent manner. Inhibition experiments of signaling pathways suggested NF-κB and p38 MAPK pathways are both involved in N protein-induced IL-10 up-regulation. Besides, the integrity of N protein is essential for significant IL-10 up-regulation. This research is beneficial for further understanding of the interplay between PRRSV and host immune system. Copyright © 2017. Published by Elsevier Ltd.

Meconium increases type 1 angiotensin II receptor expression and alveolar cell death.

PubMed

Rosenfeld, Charles R; Zagariya, Alexander M; Liu, Xiao-Tie; Willis, Brigham C; Fluharty, Steven; Vidyasagar, Dharmapuri

2008-03-01

The pulmonary renin-angiotensin system (RAS) contributes to inflammation and epithelial apoptosis in meconium aspiration. It is unclear if both angiotensin II receptors (ATR) contribute, where they are expressed and if meconium modifies subtype expression. We examined ATR subtypes in 2 wk rabbit pup lungs before and after meconium exposure and with and without captopril pretreatment or type 1 receptor (AT1R) inhibition with losartan, determining expression and cellular localization with immunoblots, RT-PCR and immunohistochemistry, respectively. Responses of cultured rat alveolar type II pneumocytes were also examined. Type 2 ATR were undetected in newborn lung before and after meconium instillation. AT1R were expressed in pulmonary vascular and bronchial smooth muscle and alveolar and bronchial epithelium. Meconium increased total lung AT1R protein approximately 3-fold (p = 0.006), mRNA 29% (p = 0.006) and immunostaining in bronchial and alveolar epithelium and smooth muscle, which were unaffected by captopril and losartan. Meconium also increased AT1R expression >3-fold in cultured type II pneumocytes and caused concentration-dependent cell death inhibited by losartan. Meconium increases AT1R expression in newborn rabbit lung and cultured type II pneumocytes and induces AT1R-mediated cell death. The pulmonary RAS contributes to the pathogenesis of meconium aspiration through increased receptor expression.

Quantification of lung microstructure with hyperpolarized 3He diffusion MRI

PubMed Central

Sukstanskii, Alexander L.; Woods, Jason C.; Gierada, David S.; Quirk, James D.; Hogg, James C.; Cooper, Joel D.; Conradi, Mark S.

2009-01-01

The structure and integrity of pulmonary acinar airways and their changes in different diseases are of great importance and interest to a broad range of physiologists and clinicians. The introduction of hyperpolarized gases has opened a door to in vivo studies of lungs with MRI. In this study we demonstrate that MRI-based measurements of hyperpolarized 3He diffusivity in human lungs yield quantitative information on the value and spatial distribution of lung parenchyma surface-to-volume ratio, number of alveoli per unit lung volume, mean linear intercept, and acinar airway radii—parameters that have been used by lung physiologists for decades and are accepted as gold standards for quantifying emphysema. We validated our MRI-based method in six human lung specimens with different levels of emphysema against direct unbiased stereological measurements. We demonstrate for the first time MRI images of these lung microgeometric parameters in healthy lungs and lungs with different levels of emphysema (mild, moderate, and severe). Our data suggest that decreases in lung surface area per volume at the initial stages of emphysema are due to dramatic decreases in the depth of the alveolar sleeves covering the alveolar ducts and sacs, implying dramatic decreases in the lung's gas exchange capacity. Our novel methods are sufficiently sensitive to allow early detection and diagnosis of emphysema, providing an opportunity to improve patient treatment outcomes, and have the potential to provide safe and noninvasive in vivo biomarkers for monitoring drug efficacy in clinical trials. PMID:19661452

Effects of ZCR-2060 on allergic airway inflammation and cell activation in guinea-pigs.

PubMed

Abe, T; Yoshida, K; Omata, T; Segawa, Y; Matsuda, K; Nagai, H

1994-11-01

The effects of 2-(2-(4-(diphenylmethyl)-1-piperadinyl) ethoxy) benzoic acid malate (ZCR-2060) on allergic airway inflammation and inflammatory cell activation in guinea-pigs were studied. Allergic airway inflammation was induced by inhalation of antigen into actively-sensitized animals and the increase in inflammatory cells into bronchoalveolar lavage fluid (BALF) was measured. Aeroantigen-induced infiltration of inflammatory cells, especially eosinophils and neutrophils, in BALF gradually increased, and reached a peak at 6 or 9 h after the challenge. ZCR-2060 (1 mg kg-1 p.o.) clearly inhibited the increase of eosinophil numbers in BALF. Moreover, the effect of ZCR-2060 on inflammatory cell activation in terms of chemotaxis and superoxide generation in-vitro was studied. ZCR-2060 (10(-6)-10(-4) M) inhibited the platelet-activating factor (PAF)-induced chemotaxis of eosinophils and neutrophils, but did not inhibit the leukotriene B4-induced chemotaxis of eosinophils and the formyl-Met-Leu-Phe-induced chemotaxis of neutrophils. PAF-induced superoxide anion generation by eosinophils, neutrophils and alveolar macrophages was inhibited by ZCR-2060 (10(-6)-10(-4) M). However, ZCR-2060 did not affect phorbol myristate acetate-induced superoxide anion generation by eosinophils, neutrophils and alveolar macrophages. These results indicate that ZCR-2060 inhibits allergic airway inflammation, and PAF-induced inflammatory cell activation in guinea-pigs. ZCR-2060 may prove useful for the treatment of allergic airway inflammation or allergic disorders, especially inflammatory cell infiltration and activation.

An ultra fast detection method reveals strain-induced Ca(2+) entry via TRPV2 in alveolar type II cells.

PubMed

Fois, Giorgio; Wittekindt, Oliver; Zheng, Xing; Felder, Erika Tatiana; Miklavc, Pika; Frick, Manfred; Dietl, Paul; Felder, Edward

2012-09-01

A commonly used technique to investigate strain-induced responses of adherent cells is culturing them on an elastic membrane and globally stretching the membrane. However, it is virtually impossible to acquire microscopic images immediately after the stretch with this method. Using a newly developed technique, we recorded the strain-induced increase of the cytoplasmic Ca(2+) concentration ([Ca(2+)](c)) in rat primary alveolar type II (ATII) cells at an acquisition rate of 30ms and without any temporal delay. We can show that the onset of the mechanically induced rise in [Ca(2+)](c) was very fast (<30 ms), and Ca(2+) entry was immediately abrogated when the stimulus was withdrawn. This points at a direct mechanical activation of an ion channel. RT-PCR revealed high expression of TRPV2 in ATII cells, and silencing TRPV2, as well as blocking TRPV channels with ruthenium red, significantly reduced the strain-induced Ca(2+) response. Moreover, the usually homogenous pattern of the strain-induced [Ca(2+)](c) increase was converted into a point-like response after both treatments. Also interfering with actin/myosin and integrin binding inhibited the strain-induced increase of [Ca(2)](c). We conclude that TRPV2 participates in strain-induced Ca(2+) entry in ATII cells and suggest a direct mechanical activation of the channel that depends on FAs and actin/myosin. Furthermore, our results underline the importance of cell strain systems that allow high temporal resolution.

Time-based understanding of DLCO and DLNO.

PubMed

Kang, Min-Yeong; Sapoval, Bernard

2016-05-01

Capture of CO and NO by blood requires molecules to travel by diffusion from alveolar gas to haemoglobin molecules inside RBCs and then to react. One can attach to these processes two times, a time for diffusion and a time for reaction. This reaction time is known from chemical kinetics and, therefore, constitutes a unique physical clock. This paper presents a time-based bottom-up theory that yields a simple expression for DLCO and DLNO that produces quantitative predictions which compare successfully with experiments. Specifically, when this new approach is applied to DLCO experiments, it can be used to determine the value of the characteristic diffusion time, and the value of capillary volume (Vc). The new theory also provides a simple explanation for still unexplained correlations such as the observed proportionality between the so-called membrane conductance DM and Vc of Roughton and Forster's interpretation. This new theory indicates that DLCO should be proportional to the haematocrit as found in several experiments. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

The cytoprotective role of DJ-1 and p45 NFE2 against human primary alveolar type II cell injury and emphysema.

PubMed

Tan, Li Hui; Bahmed, Karim; Lin, Chih-Ru; Marchetti, Nathaniel; Bolla, Sudhir; Criner, Gerard J; Kelsen, Steven; Madesh, Muniswamy; Kosmider, Beata

2018-02-23

Emphysema is characterized by irreversibly enlarged airspaces and destruction of alveolar walls. One of the factors contributing to this disease pathogenesis is an elevation in extracellular matrix (ECM) degradation in the lung. Alveolar type II (ATII) cells produce and secrete pulmonary surfactants and proliferate to restore the epithelium after damage. We isolated ATII cells from control non-smokers, smokers and patients with emphysema to determine the role of NFE2 (nuclear factor, erythroid-derived 2). NFE2 is a heterodimer composed of two subunits, a 45 kDa (p45 NFE2) and 18 kDa (p18 NFE2) polypeptides. Low expression of p45 NFE2 in patients with emphysema correlated with a high ECM degradation. Moreover, we found that NFE2 knockdown increased cell death induced by cigarette smoke extract. We also studied the cross talk between p45 NFE2 and DJ-1. DJ-1 protein is a redox-sensitive chaperone that protects cells from oxidative stress. We detected that cigarette smoke significantly increased p45 NFE2 levels in DJ-1 KO mice compared to wild-type mice. Our results indicate that p45 NFE2 expression is induced by exposure to cigarette smoke, has a cytoprotective activity against cell injury, and its downregulation in human primary ATII cells may contribute to emphysema pathogenesis.

CSF1R inhibition prevents radiation pulmonary fibrosis by depletion of interstitial macrophages.

PubMed

Meziani, Lydia; Mondini, Michele; Petit, Benoît; Boissonnas, Alexandre; Thomas de Montpreville, Vincent; Mercier, Olaf; Vozenin, Marie-Catherine; Deutsch, Eric

2018-03-01

Radiation-induced lung fibrosis (RIF) is a delayed side-effect of chest radiotherapy, frequently associated with macrophage infiltration.We aimed to characterise the role of pulmonary macrophages in RIF using human lung biopsies from patients receiving radiotherapy for thorax malignancies and a RIF model developed in C57BL/6 mice after 16-Gy thorax irradiation.High numbers of macrophages (both interstitial and alveolar) were detected in clinical and preclinical RIF. In the preclinical model, upregulation of T-helper (Th)2 cytokines was measured, whereas Th1 cytokines were downregulated in RIF tissue lysate. Bronchoalveolar lavage demonstrated upregulation of both types of cytokines. At steady state, tissue-infiltrating macrophages (IMs) expressed 10-fold more arginase (Arg)-1 than alveolar macrophages (AMs), and a 40-fold upregulation of Arg-1 was found in IMs isolated from RIF. IMs, but not AMs, were able to induce myofibroblast activation in vitro In addition, whereas depletion of AMs using Clodrosome didn't affect RIF score, depletion of IMs using a clinically available colony-stimulating factor receptor-1 (CSF1R) neutralising antibody was antifibrotic.These findings suggest differential contributions of alveolar versus interstitial macrophages in RIF, highlighting the fibrogenic role of IMs. The CSF1/CSF1R pathway was identified as a new therapeutic target to inhibit RIF. Copyright ©ERS 2018.

Inhibitory effects of a bisphosphonate (risedronate) on experimental periodontitis in rats.

PubMed

Shoji, K; Horiuchi, H; Shinoda, H

1995-07-01

The present study was designed to examine whether systemic administration of a bisphosphonate, risedronate, could prevent alveolar bone resorption in rats with experimental periodontitis. On Day 1, an elastic ring was placed around the neck of the right mandibular 1st molar to induce inflammatory periodontitis. The animals were given daily injections of either 0.9% NaCl (control group), or 0.8, 1.6 or 3.2 mumoles/kg (s.c.) of risedronate (experimental groups) from Days 1 to 7, and were killed on Day 8. Histological examinations and determination of bone mineral density in the interdental area between the 1st and 2nd molars with an image analyzer revealed that the presence of the elastic ring induced a loss of attachment and bone resorption in the control group. Vigorous bone resorption, with appearance of a large number of osteoclasts, was observed in the interdental and bifurcation areas. In the experimental groups, however, the resorption of alveolar bone and the loss of bone mineral content in these areas were prevented in a dose-dependent fashion, especially at doses of 1.6 and 3.2 mumoles/kg. Many osteoclasts were detached from the surface of the alveolar bone and had degenerated appearances, such as rounded shapes, loss of polarity and pyknosis. These results suggest that administration of risedronate is effective in preventing bone resorption in periodontitis.

Phagocytosis of microparticles by alveolar macrophages during acute lung injury requires MerTK.

PubMed

Mohning, Michael P; Thomas, Stacey M; Barthel, Lea; Mould, Kara J; McCubbrey, Alexandria L; Frasch, S Courtney; Bratton, Donna L; Henson, Peter M; Janssen, William J

2018-01-01

Microparticles are a newly recognized class of mediators in the pathophysiology of lung inflammation and injury, but little is known about the factors that regulate their accumulation and clearance. The primary objective of our study was to determine whether alveolar macrophages engulf microparticles and to elucidate the mechanisms by which this occurs. Alveolar microparticles were quantified in bronchoalveolar fluid of mice with lung injury induced by LPS and hydrochloric acid. Microparticle numbers were greatest at the peak of inflammation and declined as inflammation resolved. Isolated, fluorescently labeled particles were placed in culture with macrophages to evaluate ingestion in the presence of endocytosis inhibitors. Ingestion was blocked with cytochalasin D and wortmannin, consistent with a phagocytic process. In separate experiments, mice were treated intratracheally with labeled microparticles, and their uptake was assessed though microscopy and flow cytometry. Resident alveolar macrophages, not recruited macrophages, were the primary cell-ingesting microparticles in the alveolus during lung injury. In vitro, microparticles promoted inflammatory signaling in LPS primed epithelial cells, signifying the importance of microparticle clearance in resolving lung injury. Microparticles were found to have phosphatidylserine exposed on their surfaces. Accordingly, we measured expression of phosphatidylserine receptors on macrophages and found high expression of MerTK and Axl in the resident macrophage population. Endocytosis of microparticles was markedly reduced in MerTK-deficient macrophages in vitro and in vivo. In conclusion, microparticles are released during acute lung injury and peak in number at the height of inflammation. Resident alveolar macrophages efficiently clear these microparticles through MerTK-mediated phagocytosis.

Locally Produced BDNF Promotes Sclerotic Change in Alveolar Bone after Nerve Injury

PubMed Central

Ida-Yonemochi, Hiroko; Yamada, Yurie; Yoshikawa, Hiroyuki

2017-01-01

Brain-derived neurotrophic factor (BDNF), which is released due to nerve injury, is known to promote the natural healing of injured nerves. It is often observed that damage of mandibular canal induces local sclerotic changes in alveolar bone. We reported that peripheral nerve injury promotes the local production of BDNF; therefore, it was possible to hypothesize that peripheral nerve injury affects sclerotic changes in the alveolar bone. This study aimed to evaluate the effect of BDNF on osteogenesis using in vitro osteoblast-lineage cell culture and an in vivo rat osteotomy model. MC3T3-E1 cells were cultured with BDNF and were examined for cell proliferative activity, chemotaxis and mRNA expression levels of osteoblast differentiation markers. For in vivo study, inferior alveolar nerve (IAN) injury experiments and mandibular cortical osteotomy were performed using a rat model. In the osteotomy model, exogenous BDNF was applied to bone surfaces after corticotomy of the mandible, and we morphologically analyzed the new bone formation. As a result, mRNA expression of osteoblast differentiation marker, osteocalcin, was significantly increased by BDNF, although cell proliferation and migration were not affected. In the in vivo study, osteopontin-positive new bone formation was significantly accelerated in the BDNF-grafted groups, and active bone remodeling, involving trkB-positive osteoblasts and osteocytes, continued after 28 days. In conclusion, BDNF stimulated the differentiation of MC3T3-E1 cells and it promoted new bone formation and maturation. These results suggested that local BDNF produced by peripheral nerve injury contributes to accelerating sclerotic changes in the alveolar bone. PMID:28072837

Intrauterine growth restriction decreases pulmonary alveolar and vessel growth and causes pulmonary artery endothelial cell dysfunction in vitro in fetal sheep

PubMed Central

Seedorf, Gregory J.; Brown, Alicia; Roe, Gates; O'Meara, Meghan C.; Gien, Jason; Tang, Jen-Ruey; Abman, Steven H.

2011-01-01

Intrauterine growth restriction (IUGR) increases the risk for bronchopulmonary dysplasia (BPD). Abnormal lung structure has been noted in animal models of IUGR, but whether IUGR adversely impacts fetal pulmonary vascular development and pulmonary artery endothelial cell (PAEC) function is unknown. We hypothesized that IUGR would decrease fetal pulmonary alveolarization, vascular growth, and in vitro PAEC function. Studies were performed in an established model of severe placental insufficiency and IUGR induced by exposing pregnant sheep to elevated temperatures. Alveolarization, quantified by radial alveolar counts, was decreased 20% (P < 0.005) in IUGR fetuses. Pulmonary vessel density was decreased 44% (P < 0.01) in IUGR fetuses. In vitro, insulin increased control PAEC migration, tube formation, and nitric oxide (NO) production. This response was absent in IUGR PAECs. VEGFA stimulated tube formation, and NO production also was absent. In control PAECs, insulin increased cell growth by 68% (P < 0.0001). Cell growth was reduced in IUGR PAECs by 29% at baseline (P < 0.01), and the response to insulin was attenuated (P < 0.005). Despite increased basal and insulin-stimulated Akt phosphorylation in IUGR PAECs, endothelial NO synthase (eNOS) protein expression as well as basal and insulin-stimulated eNOS phosphorylation were decreased in IUGR PAECs. Both VEGFA and VEGFR2 also were decreased in IUGR PAECs. We conclude that fetuses with IUGR are characterized by decreased alveolar and vascular growth and PAEC dysfunction in vitro. This may contribute to the increased risk for adverse respiratory outcomes and BPD in infants with IUGR. PMID:21873446

Rapid Host Defense against Aspergillus fumigatus Involves Alveolar Macrophages with a Predominance of Alternatively Activated Phenotype

PubMed Central

Bhatia, Shikha; Fei, Mingjian; Yarlagadda, Manohar; Qi, Zengbiao; Akira, Shizuo; Saijo, Shinobu; Iwakura, Yoichiro; van Rooijen, Nico; Gibson, Gregory A.; St. Croix, Claudette M.; Ray, Anuradha; Ray, Prabir

2011-01-01

The ubiquitous fungus Aspergillus fumigatus is associated with chronic diseases such as invasive pulmonary aspergillosis in immunosuppressed patients and allergic bronchopulmonary aspergillosis (ABPA) in patients with cystic fibrosis or severe asthma. Because of constant exposure to this fungus, it is critical for the host to exercise an immediate and decisive immune response to clear fungal spores to ward off disease. In this study, we observed that rapidly after infection by A. fumigatus, alveolar macrophages predominantly express Arginase 1 (Arg1), a key marker of alternatively activated macrophages (AAMs). The macrophages were also found to express Ym1 and CD206 that are also expressed by AAMs but not NOS2, which is expressed by classically activated macrophages. The expression of Arg1 was reduced in the absence of the known signaling axis, IL-4Rα/STAT6, for AAM development. While both Dectin-1 and TLR expressed on the cell surface have been shown to sense A. fumigatus, fungus-induced Arg1 expression in CD11c+ alveolar macrophages was not dependent on either Dectin-1 or the adaptor MyD88 that mediates intracellular signaling by most TLRs. Alveolar macrophages from WT mice efficiently phagocytosed fungal conidia, but those from mice deficient in Dectin-1 showed impaired fungal uptake. Depletion of macrophages with clodronate-filled liposomes increased fungal burden in infected mice. Collectively, our studies suggest that alveolar macrophages, which predominantly acquire an AAM phenotype following A. fumigatus infection, have a protective role in defense against this fungus. PMID:21246055

Antenatal phosphodiesterase 4 inhibition restores postnatal growth and pulmonary development in a model of chorioamnionitis in rabbits.

PubMed

Homer, L; Launay, E; Joram, N; Jacqueline, C; Jarreau, P-H; Caillon, J; Moyon, T; Branger, B; Potel, G; Roze, J C; Méhats, C; Gras-Leguen, C

2012-03-01

Chorioamnionitis is implicated in the pathophysiology of bronchopulmonary disease, and the associated inflammatory response is responsible for adverse effects on alveolar development. The aim of this work was to analyze the effects of a phosphodiesterase 4 (PDE4)-selective inhibitor, rolipram (a modulator of the inflammatory response), in an experimental model of chorioamnionitis on pulmonary development and on the processes of infection and inflammation. Rabbit mothers were assigned to four groups: 1) saline serum inoculation (controls); 2) Escherichia coli intrauterine inoculation (C+); 3) rolipram infusion (R+); and 4) E. coli inoculation + rolipram infusion (C+R+). High rates of morbility and mortality were noticed in mothers and pups (5 of 13 pregnant rabbits in groups with rolipram). Alveolar development, inflammation, and infection were analyzed in pups at day 0 and day 5. At day 0, in the context of chorioamnionitis, rolipram significantly decreased birth weight (p < 0.01) relative to that of controls (p < 0.05). At day 5, weight normalized in group C+R+ but not in group C+ relative to controls (p < 0.001); moreover, alveolar airspace volume was preserved in group C+R+ but not in group C+ (p < 0.05). Interstitial volume decreased in group C+ versus controls (p < 0.05) but was preserved in group C+R+. Specific alveolar area was not significantly modified by rolipram. No significant difference was found concerning bronchoalveolar lavage cellularity, and all blood cultures remained sterile. In this model of impaired alveologenesis, rolipram significantly preserved specific alveolar density. However, PDE4 inhibition induced antenatal fetal demise and growth retardation.

Seawater inhalation induces acute lung injury via ROS generation and the endoplasmic reticulum stress pathway.

PubMed

Li, Peng-Cheng; Wang, Bo-Rong; Li, Cong-Cong; Lu, Xi; Qian, Wei-Sheng; Li, Yu-Juan; Jin, Fa-Guang; Mu, De-Guang

2018-05-01

Seawater (SW) inhalation can induce acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). In the present study, SW induced apoptosis of rat alveolar epithelial cells and histopathological alterations to lung tissue. Furthermore, SW administration increased generation of reactive oxygen species (ROS), whereas pretreatment with the ROS scavenger, N‑acetyl‑L‑cysteine (NAC), significantly decreased ROS generation, apoptosis and histopathological alterations. In addition, SW exposure upregulated the expression levels of glucose‑regulated protein 78 (GRP78) and CCAAT/enhancer binding protein homologous protein (CHOP), which are critical proteins in the endoplasmic reticulum (ER) stress response, thus indicating that SW may activate ER stress. Conversely, blocking ER stress with 4‑phenylbutyric acid (4‑PBA) significantly improved SW‑induced apoptosis and histopathological alterations, whereas an ER stress inducer, thapsigargin, had the opposite effect. Furthermore, blocking ROS with NAC inhibited SW‑induced ER stress, as evidenced by the downregulation of GRP78, phosphorylated (p)‑protein kinase R‑like ER kinase (PERK), p‑inositol‑requiring kinase 1α (IRE1α), p‑50 activating transcription factor 6α and CHOP. In addition, blocking ER stress with 4‑PBA decreased ROS generation. In conclusion, the present study indicated that ROS and ER stress pathways, which are involved in alveolar epithelial cell apoptosis, are important in the pathogenesis of SW‑induced ALI.

Effect of exposure to diesel exhaust particles on the susceptibility of the lung to infection.

PubMed

Castranova, V; Ma, J Y; Yang, H M; Antonini, J M; Butterworth, L; Barger, M W; Roberts, J; Ma, J K

2001-08-01

There are at least three mechanisms by which alveolar macrophages play a critical role in protecting the lung from bacterial or viral infections: production of inflammatory cytokines that recruit and activate lung phagocytes, production of antimicrobial reactive oxidant species, and production of interferon (an antiviral agent). In this article we summarize data concerning the effect of exposure to diesel exhaust particles on these alveolar macrophage functions and the role of adsorbed organic chemicals compared to the carbonaceous core in the toxicity of diesel particles. In vitro exposure of rat alveolar macrophages to diesel exhaust particles decreased the ability of lipopolysaccharide (LPS), a bacterial product] to stimulate the production of inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha). Methanol extract exhibited this potential but methanol-washed diesel particles did not. Exposure of rats to diesel exhaust particles by intratracheal instillation also decreased LPS-induced TNF-alpha and IL-1 production from alveolar macrophages. In contrast, carbon black did not exhibit this inhibitory effect. Exposure of rats to diesel exhaust particles by inhalation decreased the ability of alveolar macrophages to produce antimicrobial reactive oxidant species in response to zymosan (a fungal component). In contrast, exposure to coal dust increased zymosan-stimulated oxidant production. In vivo exposure to diesel exhaust particles but not to carbon black decreased the ability of the lungs to clear bacteria. Inhalation exposure of mice to diesel exhaust particles but not to coal dust depressed the ability of the lung to produce the antiviral agent interferon and increased viral multiplication in the lung. These results support the hypothesis that exposure to diesel exhaust particles increases the susceptibility of the lung to infection by depressing the antimicrobial potential of alveolar macrophages. This inhibitory effect appears to be due to adsorbed organic chemicals rather than the carbonaceous core of the diesel particles.

Effect of exposure to diesel exhaust particles on the susceptibility of the lung to infection.

PubMed Central

Castranova, V; Ma, J Y; Yang, H M; Antonini, J M; Butterworth, L; Barger, M W; Roberts, J; Ma, J K

2001-01-01

There are at least three mechanisms by which alveolar macrophages play a critical role in protecting the lung from bacterial or viral infections: production of inflammatory cytokines that recruit and activate lung phagocytes, production of antimicrobial reactive oxidant species, and production of interferon (an antiviral agent). In this article we summarize data concerning the effect of exposure to diesel exhaust particles on these alveolar macrophage functions and the role of adsorbed organic chemicals compared to the carbonaceous core in the toxicity of diesel particles. In vitro exposure of rat alveolar macrophages to diesel exhaust particles decreased the ability of lipopolysaccharide (LPS), a bacterial product] to stimulate the production of inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha). Methanol extract exhibited this potential but methanol-washed diesel particles did not. Exposure of rats to diesel exhaust particles by intratracheal instillation also decreased LPS-induced TNF-alpha and IL-1 production from alveolar macrophages. In contrast, carbon black did not exhibit this inhibitory effect. Exposure of rats to diesel exhaust particles by inhalation decreased the ability of alveolar macrophages to produce antimicrobial reactive oxidant species in response to zymosan (a fungal component). In contrast, exposure to coal dust increased zymosan-stimulated oxidant production. In vivo exposure to diesel exhaust particles but not to carbon black decreased the ability of the lungs to clear bacteria. Inhalation exposure of mice to diesel exhaust particles but not to coal dust depressed the ability of the lung to produce the antiviral agent interferon and increased viral multiplication in the lung. These results support the hypothesis that exposure to diesel exhaust particles increases the susceptibility of the lung to infection by depressing the antimicrobial potential of alveolar macrophages. This inhibitory effect appears to be due to adsorbed organic chemicals rather than the carbonaceous core of the diesel particles. PMID:11544172

Dietary boron does not affect tooth strength, micro-hardness, and density, but affects tooth mineral composition and alveolar bone mineral density in rabbits fed a high-energy diet.

PubMed

Hakki, Sema S; SiddikMalkoc; Dundar, Niyazi; Kayis, Seyit Ali; Hakki, Erdogan E; Hamurcu, Mehmet; Baspinar, Nuri; Basoglu, Abdullah; Nielsen, Forrest H; Götz, Werner

2015-01-01

The objective of this study was to determine whether dietary boron (B) affects the strength, density and mineral composition of teeth and mineral density of alveolar bone in rabbits with apparent obesity induced by a high-energy diet. Sixty female, 8-month-old, New Zealand rabbits were randomly assigned for 7 months into five groups as follows: (1) control 1, fed alfalfa hay only (5.91 MJ/kg and 57.5 mg B/kg); (2) control 2, high energy diet (11.76 MJ and 3.88 mg B/kg); (3) B10, high energy diet + 10 mg B gavage/kg body weight/96 h; (4) B30, high energy diet + 30 mg B gavage/kg body weight/96 h; (5) B50, high energy diet + 50 mg B gavage/kg body weight/96 h. Maxillary incisor teeth of the rabbits were evaluated for compression strength, mineral composition, and micro-hardness. Enamel, dentin, cementum and pulp tissue were examined histologically. Mineral densities of the incisor teeth and surrounding alveolar bone were determined by using micro-CT. When compared to controls, the different boron treatments did not significantly affect compression strength, and micro-hardness of the teeth, although the B content of teeth increased in a dose-dependent manner. Compared to control 1, B50 teeth had decreased phosphorus (P) concentrations. Histological examination revealed that teeth structure (shape and thickness of the enamel, dentin, cementum and pulp) was similar in the B-treated and control rabbits. Micro CT evaluation revealed greater alveolar bone mineral density in B10 and B30 groups than in controls. Alveolar bone density of the B50 group was not different than the controls. Although the B treatments did not affect teeth structure, strength, mineral density and micro-hardness, increasing B intake altered the mineral composition of teeth, and, in moderate amounts, had beneficial effects on surrounding alveolar bone.

Estrogen Signaling Contributes to Sex Differences in Macrophage Polarization during Asthma.

PubMed

Keselman, Aleksander; Fang, Xi; White, Preston B; Heller, Nicola M

2017-09-01

Allergic asthma is a chronic Th2 inflammation in the lungs that constricts the airways and presents as coughing and wheezing. Asthma mostly affects boys in childhood and women in adulthood, suggesting that shifts in sex hormones alter the course of the disease. Alveolar macrophages have emerged as major mediators of allergic lung inflammation in animal models as well as humans. Whether sex differences exist in macrophage polarization and the molecular mechanism(s) that drive differential responses are not well understood. We found that IL-4-stimulated bone marrow-derived and alveolar macrophages from female mice exhibited greater expression of M2 genes in vitro and after allergen challenge in vivo. Alveolar macrophages from female mice exhibited greater expression of the IL-4Rα and estrogen receptor (ER) α compared with macrophages from male mice following allergen challenge. An ERα-specific agonist enhanced IL-4-induced M2 gene expression in macrophages from both sexes, but more so in macrophages from female mice. Furthermore, IL-4-stimulated macrophages from female mice exhibited more transcriptionally active histone modifications at M2 gene promoters than did macrophages from male mice. We found that supplementation of estrogen into ovariectomized female mice enhanced M2 polarization in vivo upon challenge with allergen and that macrophage-specific deletion of ERα impaired this M2 polarization. The effects of estrogen are long-lasting; bone marrow-derived macrophages from ovariectomized mice implanted with estrogen exhibited enhanced IL-4-induced M2 gene expression compared with macrophages from placebo-implanted littermates. Taken together, our findings suggest that estrogen enhances IL-4-induced M2 gene expression and thereby contributes to sex differences observed in asthma. Copyright © 2017 by The American Association of Immunologists, Inc.

Pasteurella haemolytica leukotoxin and endotoxin induced cytokine gene expression in bovine alveolar macrophages requires NF-kappaB activation and calcium elevation.

PubMed

Hsuan, S L; Kannan, M S; Jeyaseelan, S; Prakash, Y S; Malazdrewich, C; Abrahamsen, M S; Sieck, G C; Maheswaran, S K

1999-05-01

In bovine alveolar macrophages (BAMs), exposure to leukotoxin (Lkt) and endotoxin (LPS) from Pasteurella haemolytica results in expression of inflammatory cytokine genes and intracellular calcium ([Ca2+]i) elevation. Leukotoxin from P. haemolytica interacts only with leukocytes and platelets from ruminant species. Upregulation of cytokine genes in different cells by LPS involves activation of the transcription factor NF-kappaB (NF-kappaB), resulting in its translocation from the cytoplasm to the nucleus. Using immunocytochemical staining and confocal imaging, we studied whether NF-kappaB activation represents a common mechanism for the expression of multiple cytokine genes in BAMs (Lkt-susceptible cells) stimulated with Lkt and LPS. Bovine pulmonary artery endothelial cells and porcine alveolar macrophages were used as nonsusceptible cells. The role of Ca2+ and tyrosine kinases in NF-kappaB activation and inflammatory cytokine gene expression was studied, since an inhibitor of tyrosine kinases attenuates LPS-induced [Ca2+]i elevation in BAMs. The results are summarized as follows: (a) Lkt induced NF-kappaB activation and [Ca2+]i elevation only in BAMs, while LPS effects were demonstrable in all cell types; (b) chelation of [Ca2+]i blocked NF-kappaB activation and IL-1beta, TNFalpha, and IL-8 mRNA expression; and (c) tyrosine kinase inhibitor herbimycin A blocked expression of all three cytokine genes in BAMs stimulated with Lkt, while only the expression of IL-1beta was blocked in BAMs stimulated with LPS. We conclude that cytokine gene expression in BAMs requires NF-kappaB activation and [Ca2+]i elevation, and Lkt effects exhibit cell type- and species specificity. Copyright 1999 Academic Press.

Vitamin D treatment improves survival and infant lung structure after intra-amniotic endotoxin exposure in rats: potential role for the prevention of bronchopulmonary dysplasia

PubMed Central

Seedorf, Gregory; Gien, Jason; Abman, Steven H.

2013-01-01

Vitamin D (vit D) has anti-inflammatory properties and modulates lung growth, but whether vit D can prevent lung injury after exposure to antenatal inflammation is unknown. We hypothesized that early and sustained vit D treatment could improve survival and preserve lung growth in an experimental model of bronchopulmonary dysplasia induced by antenatal exposure to endotoxin (ETX). Fetal rats (E20) were exposed to ETX (10 μg), ETX + Vit D (1 ng/ml), or saline (control) via intra-amniotic (IA) injections and delivered 2 days later. Newborn pups exposed to IA ETX received daily intraperitoneal injections of vit D (1 ng/g) or saline for 14 days. Vit D treatment improved oxygen saturations (78 vs. 87%; P < 0.001) and postnatal survival (84% vs. 57%; P < 0.001) after exposure to IA ETX compared with IA ETX alone. Postnatal vit D treatment improved alveolar and vascular growth at 14 days by 45% and 25%, respectively (P < 0.05). Vit D increased fetal sheep pulmonary artery endothelial cell (PAEC) growth and tube formation by 64% and 44%, respectively (P < 0.001), and prevented ETX-induced reductions of PAEC growth and tube formation. Vit D directly increased fetal alveolar type II cell (ATIIC) growth by 26% (P < 0.001) and enhanced ATIIC growth in the presence of ETX-induced growth suppression by 73% (P < 0.001). We conclude that antenatal vit D therapy improved oxygenation and survival in newborn rat pups and enhanced late lung structure after exposure to IA ETX in vivo, which may partly be due to direct effects on vascular and alveolar growth. PMID:24414254

Diallylsulfide attenuates excessive collagen production and apoptosis in a rat model of bleomycin induced pulmonary fibrosis through the involvement of protease activated receptor-2

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

Kalayarasan, Srinivasan, E-mail: kalaivasanbio@gmail.com; Sriram, Narayanan; Soumyakrishnan, Syamala

Pulmonary fibrosis (PF) can be a devastating lung disease. It is primarily caused by inflammation leading to severe damage of the alveolar epithelial cells. The pathophysiology of PF is not yet been clearly defined, but studying lung parenchymal injury by involving reactive oxygen species (ROS) through the activation of protease activated receptor-2 (PAR-2) may provide promising results. PAR-2 is a G-protein coupled receptor is known to play an important role in the development of PF. In this study, we investigated the inhibitory role of diallylsulfide (DAS) against ROS mediated activation of PAR-2 and collagen production accompanied by epithelial cell apoptosis.more » Bleomycin induced ROS levels may prompt to induce the expression of PAR-2 as well as extracellular matrix proteins (ECM), such as MMP 2 and 9, collagen specific proteins HSP-47, α-SMA, and cytokines IL-6, and IL-8RA. Importantly DAS treatment effectively decreased the expression of all these proteins. The inhibitory effect of DAS on profibrotic molecules is mediated by blocking the ROS level. To identify apoptotic signaling as a mediator of PF induction, we performed apoptotic protein expression, DNA fragmentation analysis and ultrastructural details of the lung tissue were performed. DAS treatment restored all these changes to near normalcy. In conclusion, treatment of PF bearing rats with DAS results in amelioration of the ROS production, PAR-2 activation, ECM production, collagen synthesis and alveolar epithelial cell apoptosis during bleomycin induction. We attained the first evidence that treatment of DAS decreases the ROS levels and may provide a potential therapeutic effect attenuating bleomycin induced PF. - Highlights: • DAS inhibits PAR-2 activity; bleomycin stimulates PAR-2 activity. • Increase in PAR-2 activity is correlated with pulmonary fibrosis • DAS reduces pro-inflammatory activity linked to facilitating pulmonary fibrosis. • DAS inhibits apoptosis of alveolar epithelial cells.« less

Pituitary Adenylate Cyclase-Activating Polypeptide Reverses Ammonium Metavanadate-Induced Airway Hyperresponsiveness in Rats

PubMed Central

Tlili, Mounira; Sriha, Badreddine; Ben Rhouma, Khémais; Sakly, Mohsen; Wurtz, Olivier

2015-01-01

The rate of atmospheric vanadium is constantly increasing due to fossil fuel combustion. This environmental pollution favours vanadium exposure in particular to its vanadate form, causing occupational bronchial asthma and bronchitis. Based on the well admitted bronchodilator properties of the pituitary adenylate cyclase-activating polypeptide (PACAP), we investigated the ability of this neuropeptide to reverse the vanadate-induced airway hyperresponsiveness in rats. Exposure to ammonium metavanadate aerosols (5 mg/m3/h) for 15 minutes induced 4 hours later an array of pathophysiological events, including increase of bronchial resistance and histological alterations, activation of proinflammatory alveolar macrophages, and increased oxidative stress status. Powerfully, PACAP inhalation (0.1 mM) for 10 minutes alleviated many of these deleterious effects as demonstrated by a decrease of bronchial resistance and histological restoration. PACAP reduced the level of expression of mRNA encoding inflammatory chemokines (MIP-1α, MIP-2, and KC) and cytokines (IL-1α and TNF-α) in alveolar macrophages and improved the antioxidant status. PACAP reverses the vanadate-induced airway hyperresponsiveness not only through its bronchodilator activity but also by counteracting the proinflammatory and prooxidative effects of the metal. Then, the development of stable analogs of PACAP could represent a promising therapeutic alternative for the treatment of inflammatory respiratory disorders. PMID:26199679

A novel minimal invasive mouse model of extracorporeal circulation.

PubMed

Luo, Shuhua; Tang, Menglin; Du, Lei; Gong, Lina; Xu, Jin; Chen, Youwen; Wang, Yabo; Lin, Ke; An, Qi

2015-01-01

Extracorporeal circulation (ECC) is necessary for conventional cardiac surgery and life support, but it often triggers systemic inflammation that can significantly damage tissue. Studies of ECC have been limited to large animals because of the complexity of the surgical procedures involved, which has hampered detailed understanding of ECC-induced injury. Here we describe a minimally invasive mouse model of ECC that may allow more extensive mechanistic studies. The right carotid artery and external jugular vein of anesthetized adult male C57BL/6 mice were cannulated to allow blood flow through a 1/32-inch external tube. All animals (n = 20) survived 30 min ECC and subsequent 60 min observation. Blood analysis after ECC showed significant increases in levels of tumor necrosis factor α, interleukin-6, and neutrophil elastase in plasma, lung, and renal tissues, as well as increases in plasma creatinine and cystatin C and decreases in the oxygenation index. Histopathology showed that ECC induced the expected lung inflammation, which included alveolar congestion, hemorrhage, neutrophil infiltration, and alveolar wall thickening; in renal tissue, ECC induced intracytoplasmic vacuolization, acute tubular necrosis, and epithelial swelling. Our results suggest that this novel, minimally invasive mouse model can recapitulate many of the clinical features of ECC-induced systemic inflammatory response and organ injury.

A Novel Minimal Invasive Mouse Model of Extracorporeal Circulation

PubMed Central

Luo, Shuhua; Tang, Menglin; Du, Lei; Gong, Lina; Xu, Jin; Chen, Youwen; Wang, Yabo; Lin, Ke; An, Qi

2015-01-01

Extracorporeal circulation (ECC) is necessary for conventional cardiac surgery and life support, but it often triggers systemic inflammation that can significantly damage tissue. Studies of ECC have been limited to large animals because of the complexity of the surgical procedures involved, which has hampered detailed understanding of ECC-induced injury. Here we describe a minimally invasive mouse model of ECC that may allow more extensive mechanistic studies. The right carotid artery and external jugular vein of anesthetized adult male C57BL/6 mice were cannulated to allow blood flow through a 1/32-inch external tube. All animals (n = 20) survived 30 min ECC and subsequent 60 min observation. Blood analysis after ECC showed significant increases in levels of tumor necrosis factor α, interleukin-6, and neutrophil elastase in plasma, lung, and renal tissues, as well as increases in plasma creatinine and cystatin C and decreases in the oxygenation index. Histopathology showed that ECC induced the expected lung inflammation, which included alveolar congestion, hemorrhage, neutrophil infiltration, and alveolar wall thickening; in renal tissue, ECC induced intracytoplasmic vacuolization, acute tubular necrosis, and epithelial swelling. Our results suggest that this novel, minimally invasive mouse model can recapitulate many of the clinical features of ECC-induced systemic inflammatory response and organ injury. PMID:25705092

Integrative Conductance of Oxygen During Exercise at Altitude.

PubMed

Calbet, José A L; Lundby, Carsten; Boushel, Robert

2016-01-01

In the oxygen (O2) cascade downstream steps can never achieve higher flows of O2 than the preceding ones. At the lung the transfer of O2 is determined by the O2 gradient between the alveolar space and the lung capillaries and the O2 diffusing capacity (DLO2). While DLO2 may be increased several times during exercise by recruiting more lung capillaries and by increasing the oxygen carrying capacity of blood due to higher peripheral extraction of O2, the capacity to enhance the alveolocapillary PO2 gradient is more limited. The transfer of oxygen from the alveolar space to the hemoglobin (Hb) must overcome first the resistance offered by the alveolocapillary membrane (1/DM) and the capillary blood (1/θVc). The fractional contribution of each of these two components to DLO2 remains unknown. During exercise these resistances are reduced by the recruitment of lung capillaries. The factors that reduce the slope of the oxygen dissociation curve of the Hb (ODC) (i.e., lactic acidosis and hyperthermia) increase 1/θVc contributing to limit DLO2. These effects are accentuated in hypoxia. Reducing the size of the active muscle mass improves pulmonary gas exchange during exercise and reduces the rightward shift of the ODC. The flow of oxygen from the muscle capillaries to the mitochondria is pressumably limited by muscle O2 conductance (DmcO2) (an estimation of muscle oxygen diffusing capacity). However, during maximal whole body exercise in normoxia, a higher flow of O2 is achieved at the same pressure gradients after increasing blood [Hb], implying that in healthy humans exercising in normoxia there is a functional reserve in DmcO2. This conclusion is supported by the fact that during small muscle exercise in chronic hypoxia, peak exercise DmcO2 is similar to that observed during exercise in normoxia despite a markedly lower O2 pressure gradient driving diffusion.

OXIDATIVE STRESS AND LIPID MEDIATORS INDUCED IN ALVEOLAR MACHROPHAGES BY ULTRAFINE PARTICLES

EPA Science Inventory

In ambient aerosols, ultrafine particles (UFP) and their agglomerates are considered to be major factors contributing to adverse health effects. Reactivity of agglomerated UFP of elemental carbon (EC), Printex 90, Printex G, and diesel exhaust particles (DEP) was evaluated by the...

Airway epithelial cell response to human metapneumovirus infection

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

Bao, X.; Liu, T.; Spetch, L.

2007-11-10

Human metapneumovirus (hMPV) is a major cause of lower respiratory tract infections (LRTIs) in infants, elderly and immunocompromised patients. In this study, we show that hMPV can infect in a similar manner epithelial cells representative of different tracts of the airways. hMPV-induced expression of chemokines IL-8 and RANTES in primary small alveolar epithelial cells (SAE) and in a human alveolar type II-like epithelial cell line (A549) was similar, suggesting that A549 cells can be used as a model to study lower airway epithelial cell responses to hMPV infection. A549 secreted a variety of CXC and CC chemokines, cytokines and typemore » I interferons, following hMPV infection. hMPV was also a strong inducer of transcription factors belonging to nuclear factor (NF)-{kappa}B, interferon regulatory factors (IRFs) and signal transducers and activators of transcription (STATs) families, which are known to orchestrate the expression of inflammatory and immunomodulatory mediators.« less

Distribution of perfusion.

PubMed

Glenny, Robb; Robertson, H Thomas

2011-01-01

Local driving pressures and resistances within the pulmonary vascular tree determine the distribution of perfusion in the lung. Unlike other organs, these local determinants are significantly influenced by regional hydrostatic and alveolar pressures. Those effects on blood flow distribution are further magnified by the large vertical height of the human lung and the relatively low intravascular pressures in the pulmonary circulation. While the distribution of perfusion is largely due to passive determinants such as vascular geometry and hydrostatic pressures, active mechanisms such as vasoconstriction induced by local hypoxia can also redistribute blood flow. This chapter reviews the determinants of regional lung perfusion with a focus on vascular tree geometry, vertical gradients induced by gravity, the interactions between vascular and surrounding alveolar pressures, and hypoxic pulmonary vasoconstriction. While each of these determinants of perfusion distribution can be examined in isolation, the distribution of blood flow is dynamically determined and each component interacts with the others so that a change in one region of the lung influences the distribution of blood flow in other lung regions. © 2011 American Physiological Society.

Asbestos exposure induces alveolar epithelial cell plasticity through MAPK/Erk signaling.

PubMed

Tamminen, Jenni A; Myllärniemi, Marjukka; Hyytiäinen, Marko; Keski-Oja, Jorma; Koli, Katri

2012-07-01

The inhalation of asbestos fibers is considered to be highly harmful, and lead to fibrotic and/or malignant disease. Epithelial-to-mesenchymal transition (EMT) is a common pathogenic mechanism in asbestos associated fibrotic (asbestosis) and malignant lung diseases. The characterization of molecular pathways contributing to EMT may provide new possibilities for prognostic and therapeutic applications. The role of asbestos as an inducer of EMT has not been previously characterized. We exposed cultured human lung epithelial cells to crocidolite asbestos and analyzed alterations in the expression of epithelial and mesenchymal marker proteins and cell morphology. Asbestos was found to induce downregulation of E-cadherin protein levels in A549 lung carcinoma cells in 2-dimensional (2D) and 3D cultures. Similar findings were made in primary small airway epithelial cells cultured in 3D conditions where the cells retained alveolar type II cell phenotype. A549 cells also exhibited loss of cell-cell contacts, actin reorganization and expression of α-smooth muscle actin (α-SMA) in 2D cultures. These phenotypic changes were not associated with increased transforming growth factor (TGF)-β signaling activity. MAPK/Erk signaling pathway was found to mediate asbestos-induced downregulation of E-cadherin and alterations in cell morphology. Our results suggest that asbestos can induce epithelial plasticity, which can be interfered by blocking the MAPK/Erk kinase activity. Copyright © 2012 Wiley Periodicals, Inc.

Pathology of lethal and sublethal doses of aerosolized ricin in rhesus macaques.

PubMed

Bhaskaran, Manoj; Didier, Peter J; Sivasubramani, Satheesh K; Doyle, Lara A; Holley, Jane; Roy, Chad J

2014-01-01

Ricin toxin, a type 2 ribosome-inactivating protein and a category B bioterrorism agent, is produced from the seeds of castor oil plant (Ricinus communis). Chronic pathological changes in survivors of aerosolized ricin exposure have not been reported in primates. Here we compare and contrast the pathological changes manifested between rhesus macaques (RM) that succumbed to lethal dose of ricin (group I) and survivor RM exposed to low dose of ricin (group II). All animals in group I exhibited severe diffuse, necrotizing bronchiolitis and alveolitis with fibrinopurulent bronchointerstitial pneumonia, massive alveolar, perivascular and peribronchial/bronchiolar edema with hemorrhage, and necropurulent and hemorrhagic tracheobronchial lymphadenitis. All animals from group II had multifocal, fibrosing interstitial pneumonia with prominent alveolar histiocytosis and type II pneumocyte hyperplasia. Subacute changes like infiltration by lymphocytes and plasma cells and persistence of edematous fluid were occasionally present in lung and tracheobronchial lymph nodes. The changes appear to be a continuum wherein the inflammatory response shifts from an acute to subacute/chronic reparative process if the animals can survive the initial insult.

Longitudinal assessment of bleomycin-induced lung fibrosis by Micro-CT correlates with histological evaluation in mice.

PubMed

Ruscitti, Francesca; Ravanetti, Francesca; Essers, Jeroen; Ridwan, Yanto; Belenkov, Sasha; Vos, Wim; Ferreira, Francisca; KleinJan, Alex; van Heijningen, Paula; Van Holsbeke, Cedric; Cacchioli, Antonio; Villetti, Gino; Stellari, Franco Fabio

2017-01-01

The intratracheal instillation of bleomycin in mice induces early damage to alveolar epithelial cells and development of inflammation followed by fibrotic tissue changes and represents the most widely used model of pulmonary fibrosis to investigate human IPF. Histopathology is the gold standard for assessing lung fibrosis in rodents, however it precludes repeated and longitudinal measurements of disease progression and does not provide information on spatial and temporal distribution of tissue damage. Here we investigated the use of the Micro-CT technique to allow the evaluation of disease onset and progression at different time-points in the mouse bleomycin model of lung fibrosis. Micro-CT was throughout coupled with histological analysis for the validation of the imaging results. In bleomycin-instilled and control mice, airways and lung morphology changes were assessed and reconstructed at baseline, 7, 14 and 21 days post-treatment based on Micro-CT images. Ashcroft score, percentage of collagen content and percentage of alveolar air area were detected on lung slides processed by histology and subsequently compared with Micro-CT parameters. Extent (%) of fibrosis measured by Micro-CT correlated with Ashcroft score, the percentage of collagen content and the percentage of alveolar air area ( r 2  = 0.91; 0.77; 0.94, respectively). Distal airway radius also correlated with the Ashcroft score, the collagen content and alveolar air area percentage ( r 2  = 0.89; 0.78; 0.98, respectively). Micro-CT data were in good agreement with histological read-outs as micro-CT was able to quantify effectively and non-invasively disease progression longitudinally and to reduce the variability and number of animals used to assess the damage. This suggests that this technique is a powerful tool for understanding experimental pulmonary fibrosis and that its use could translate into a more efficient drug discovery process, also helping to fill the gap between preclinical setting and clinical practice.

Evaluating the oxysterol combination of 22(S)-hydroxycholesterol and 20(S)-hydroxycholesterol in periodontal regeneration using periodontal ligament stem cells and alveolar bone healing models.

PubMed

Lee, Jin-Sun; Kim, EunJi; Han, Seonggu; Kang, Kyung Lhi; Heo, Jung Sun

2017-12-06

Oxysterols, oxygenated by-products of cholesterol biosynthesis, play roles in various physiological and pathological systems. However, the effects of oxysterols on periodontal regeneration are unknown. This study investigated the effects of the specific oxysterol combination of 22(S)-hydroxycholesterol and 20(S)-hydroxycholesterol (SS) on the regeneration of periodontal tissues using in-vitro periodontal ligament stem cells (PDLSCs) and in-vivo models of alveolar bone defect. To evaluate the effects of the combined oxysterols on PDLSC biology, we studied the SS-induced osteogenic differentiation of PDLSCs by assessing alkaline phosphatase activity, intracellular calcium levels [Ca 2+ ] i , matrix mineralization, and osteogenic marker mRNA expression and protein levels. To verify the effect of oxysterols on alveolar bone regeneration, we employed tooth extraction bone defect models. Oxysterols increased the osteogenic activity of PDLSCs compared with the control group. The expression of liver X receptor (LXR) α and β, the nuclear receptors for oxysterols, and their target gene, ATP-binding cassette transporter A1 (ABCA1), increased significantly during osteogenesis. Oxysterols also increased protein levels of the hedgehog (Hh) receptor Smo and the transcription factor Gli1. We further confirmed the reciprocal reaction between the LXRs and Hh signaling. Transfection of both LXRα and LXRβ siRNAs decreased Smo and Gli1 protein levels. In contrast, the inhibition of Hh signaling attenuated the LXRα and LXRβ protein levels. Subsequently, SS-induced osteogenic activity of PDLSCs was suppressed by the inhibition of LXRs or Hh signaling. The application of SS also enhanced bone formation in the defect sites of in-vivo models, showing equivalent efficacy to recombinant human bone morphogenetic protein-2. These findings suggest that a specific combination of oxysterols promoted periodontal regeneration by regulating PDLSC activity and alveolar bone regeneration.

Histophilus somni Stimulates Expression of Antiviral Proteins and Inhibits BRSV Replication in Bovine Respiratory Epithelial Cells

PubMed Central

Lin, C.; Agnes, J. T.; Behrens, N.; Tagawa, Y.; Gershwin, L. J.; Corbeil, L. B.

2016-01-01

Our previous studies showed that bovine respiratory syncytial virus (BRSV) followed by Histophilus somni causes more severe bovine respiratory disease and a more permeable alveolar barrier in vitro than either agent alone. However, microarray analysis revealed the treatment of bovine alveolar type 2 (BAT2) epithelial cells with H. somni concentrated culture supernatant (CCS) stimulated up-regulation of four antiviral protein genes as compared with BRSV infection or dual treatment. This suggested that inhibition of viral infection, rather than synergy, may occur if the bacterial infection occurred before the viral infection. Viperin (or radical S-adenosyl methionine domain containing 2—RSAD2) and ISG15 (IFN-stimulated gene 15—ubiquitin-like modifier) were most up-regulated. CCS dose and time course for up-regulation of viperin protein levels were determined in treated bovine turbinate (BT) upper respiratory cells and BAT2 lower respiratory cells by Western blotting. Treatment of BAT2 cells with H. somni culture supernatant before BRSV infection dramatically reduced viral replication as determined by qRT PCR, supporting the hypothesis that the bacterial infection may inhibit viral infection. Studies of the role of the two known H. somni cytotoxins showed that viperin protein expression was induced by endotoxin (lipooligosaccharide) but not by IbpA, which mediates alveolar permeability and H. somni invasion. A naturally occurring IbpA negative asymptomatic carrier strain of H. somni (129Pt) does not cause BAT2 cell retraction or permeability of alveolar cell monolayers, so lacks virulence in vitro. To investigate initial steps of pathogenesis, we showed that strain 129Pt attached to BT cells and induced a strong viperin response in vitro. Thus colonization of the bovine upper respiratory tract with an asymptomatic carrier strain lacking virulence may decrease viral infection and the subsequent enhancement of bacterial respiratory infection in vivo. PMID:26859677

Histophilus somni Stimulates Expression of Antiviral Proteins and Inhibits BRSV Replication in Bovine Respiratory Epithelial Cells.

PubMed

Lin, C; Agnes, J T; Behrens, N; Shao, M; Tagawa, Y; Gershwin, L J; Corbeil, L B

2016-01-01

Our previous studies showed that bovine respiratory syncytial virus (BRSV) followed by Histophilus somni causes more severe bovine respiratory disease and a more permeable alveolar barrier in vitro than either agent alone. However, microarray analysis revealed the treatment of bovine alveolar type 2 (BAT2) epithelial cells with H. somni concentrated culture supernatant (CCS) stimulated up-regulation of four antiviral protein genes as compared with BRSV infection or dual treatment. This suggested that inhibition of viral infection, rather than synergy, may occur if the bacterial infection occurred before the viral infection. Viperin (or radical S-adenosyl methionine domain containing 2--RSAD2) and ISG15 (IFN-stimulated gene 15--ubiquitin-like modifier) were most up-regulated. CCS dose and time course for up-regulation of viperin protein levels were determined in treated bovine turbinate (BT) upper respiratory cells and BAT2 lower respiratory cells by Western blotting. Treatment of BAT2 cells with H. somni culture supernatant before BRSV infection dramatically reduced viral replication as determined by qRT PCR, supporting the hypothesis that the bacterial infection may inhibit viral infection. Studies of the role of the two known H. somni cytotoxins showed that viperin protein expression was induced by endotoxin (lipooligosaccharide) but not by IbpA, which mediates alveolar permeability and H. somni invasion. A naturally occurring IbpA negative asymptomatic carrier strain of H. somni (129Pt) does not cause BAT2 cell retraction or permeability of alveolar cell monolayers, so lacks virulence in vitro. To investigate initial steps of pathogenesis, we showed that strain 129Pt attached to BT cells and induced a strong viperin response in vitro. Thus colonization of the bovine upper respiratory tract with an asymptomatic carrier strain lacking virulence may decrease viral infection and the subsequent enhancement of bacterial respiratory infection in vivo.

The Effectiveness of Crataegus orientalis M Bieber. (Hawthorn) Extract Administration in Preventing Alveolar Bone Loss in Rats with Experimental Periodontitis

PubMed Central

Hatipoğlu, Mükerrem; Sağlam, Mehmet; Köseoğlu, Serhat; Köksal, Ekrem; Keleş, Ali; Esen, Hacı Hasan

2015-01-01

The purpose of this animal study was to evaluate the effects of hawthorn (Crataeus orientalis M Bieber.) extract on serum oxidative status and alveolar bone loss in experimental periodontitis. Twenty-seven Wistar rats were assigned to one of the following groups: non- ligated+placebo (saline) (NL, n = 9), ligature only+placebo (saline) (LO, n = 9), and ligature and treated with hawthorn extract in saline (H, n = 9) (100 mg/kg orogastrically, once a day for 11 days). Periodontitis was induced by submerging a 4/0 silk ligature in the sulcus of the mandibular right first molars of rats, and the animals were sacrificed after 11 days. Micro-CT examinations were performed for linear and volumetric parameter assessment of alveolar bone. Periodontal tissues were histopathologically examined to assess the differences among the study groups. Levels of serum total antioxidant status (TAS)/total oxidant status (TOS), and oxidative stress index (OSI) were also analyzed. Alveolar bone loss was significantly reduced by hawthorn administration compared to LO group (p<0.05). The number of inflammatory cells and osteoclasts in the LO group was significantly higher than that of the NL and H groups (p< 0.05). The number of osteoblasts in the LO and H groups was significantly higher than that of the NL group (p<0.05). TOS and OSI levels were significantly reduced in H group compared to LO group (P <0.05) and TAS levels were similar in H and NL group (p< 0.05). Hawthorn extract showed inhibitory effect on periodontal inflammation and alveolar bone loss by regulating TAS, TOS and OSI levels in periodontal disease in rats when administered systemically. PMID:26030160

Rapid elevation of sodium transport through insulin is mediated by AKT in alveolar cells

PubMed Central

Mattes, Charlott; Laube, Mandy; Thome, Ulrich H.

2014-01-01

Abstract Alveolar fluid clearance is driven by vectorial Na+ transport and promotes postnatal lung adaptation. The effect of insulin on alveolar epithelial Na+ transport was studied in isolated alveolar cells from 18–19‐day gestational age rat fetuses. Equivalent short‐circuit currents (ISC) were measured in Ussing chambers and different kinase inhibitors were used to determine the pathway of insulin stimulation. In Western Blot measurements the activation of mediators stimulated by insulin was analyzed. The ISC showed a fast dose‐dependent increase by insulin, which could be attributed to an increased ENaC (epithelial Na+ channel) activity in experiments with permeabilized apical or basolateral membrane. 5‐(N‐Ethyl‐N‐isopropyl)amiloride inhibition of ISC was not affected, however, benzamil‐sensitive ISC was increased in insulin‐stimulated monolayers. The application of LY‐294002 and Akti1/2 both completely blocked the stimulating effect of insulin on ISC. PP242 partly blocked the effect of insulin, whereas Rapamycin evoked no inhibition. Western Blot measurements revealed an increased phosphorylation of AKT after insulin stimulation. SGK1 activity was also increased by insulin as shown by Western Blot of pNDRG1. However, in Ussing chamber measurements, GSK650394, an inhibitor of SGK1 did not prevent the increase in ISC induced by insulin. The application of IGF‐1 mimicked the effect of insulin and increased the ENaC activity. In addition, an increased autophosphorylation of the IGF‐1R/IR was observed after insulin stimulation. We conclude that insulin rapidly increases epithelial Na+ transport by enhancing the activity of endogenous ENaC through activation of PI3K/AKT in alveolar cells. PMID:24760523

The Effectiveness of Crataegus orientalis M Bieber. (Hawthorn) Extract Administration in Preventing Alveolar Bone Loss in Rats with Experimental Periodontitis.

PubMed

Hatipoğlu, Mükerrem; Sağlam, Mehmet; Köseoğlu, Serhat; Köksal, Ekrem; Keleş, Ali; Esen, Hacı Hasan

2015-01-01

The purpose of this animal study was to evaluate the effects of hawthorn (Crataeus orientalis M Bieber.) extract on serum oxidative status and alveolar bone loss in experimental periodontitis. Twenty-seven Wistar rats were assigned to one of the following groups: non- ligated+placebo (saline) (NL, n = 9), ligature only+placebo (saline) (LO, n = 9), and ligature and treated with hawthorn extract in saline (H, n = 9) (100 mg/kg orogastrically, once a day for 11 days). Periodontitis was induced by submerging a 4/0 silk ligature in the sulcus of the mandibular right first molars of rats, and the animals were sacrificed after 11 days. Micro-CT examinations were performed for linear and volumetric parameter assessment of alveolar bone. Periodontal tissues were histopathologically examined to assess the differences among the study groups. Levels of serum total antioxidant status (TAS)/total oxidant status (TOS), and oxidative stress index (OSI) were also analyzed. Alveolar bone loss was significantly reduced by hawthorn administration compared to LO group (p<0.05). The number of inflammatory cells and osteoclasts in the LO group was significantly higher than that of the NL and H groups (p< 0.05). The number of osteoblasts in the LO and H groups was significantly higher than that of the NL group (p<0.05). TOS and OSI levels were significantly reduced in H group compared to LO group (P <0.05) and TAS levels were similar in H and NL group (p< 0.05). Hawthorn extract showed inhibitory effect on periodontal inflammation and alveolar bone loss by regulating TAS, TOS and OSI levels in periodontal disease in rats when administered systemically.

Romo1 expression contributes to oxidative stress-induced death of lung epithelial cells

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

Shin, Jung Ar; Chung, Jin Sil; Cho, Sang-Ho

Highlights: •Romo1 mediates oxidative stress-induced mitochondrial ROS production. •Romo1 induction by oxidative stress plays an important role in oxidative stress-induced apoptosis. •Romo1 overexpression correlates with epithelial cell death in patients with IPF. -- Abstract: Oxidant-mediated death of lung epithelial cells due to cigarette smoking plays an important role in pathogenesis in lung diseases such as idiopathic pulmonary fibrosis (IPF). However, the exact mechanism by which oxidants induce epithelial cell death is not fully understood. Reactive oxygen species (ROS) modulator 1 (Romo1) is localized in the mitochondria and mediates mitochondrial ROS production through complex III of the mitochondrial electron transport chain.more » Here, we show that Romo1 mediates mitochondrial ROS production and apoptosis induced by oxidative stress in lung epithelial cells. Hydrogen peroxide (H{sub 2}O{sub 2}) treatment increased Romo1 expression, and Romo1 knockdown suppressed the cellular ROS levels and cell death triggered by H{sub 2}O{sub 2} treatment. In immunohistochemical staining of lung tissues from patients with IPF, Romo1 was mainly localized in hyperplastic alveolar and bronchial epithelial cells. Romo1 overexpression was detected in 14 of 18 patients with IPF. TUNEL-positive alveolar epithelial cells were also detected in most patients with IPF but not in normal controls. These findings suggest that Romo1 mediates apoptosis induced by oxidative stress in lung epithelial cells.« less

Characteristic features of tacrolimus-induced lung disease in rheumatoid arthritis patients.

PubMed

Sasaki, Takanori; Nakamura, Wataru; Inokuma, Shigeko; Matsubara, Erika

2016-02-01

This paper aims to study the background and clinical characteristics of tacrolimus (TAC)-induced lung disease. A case of a rheumatoid arthritis (RA) patient who developed TAC-induced interstitial lung disease (TAC-ILD) is reported. The Japanese Pharmaceuticals and Medical Devices Agency (PMDA) website was searched for cases of TAC-ILD and its prevalence among all cases of TAC-related adverse events. As for cases of TAC-ILD, its underlying disease, preexisting lung diseases, and fatal outcome were also searched. Literature review of TAC-ILD cases was added. A 65-year-old female RA patient with preexisting bronchiectasis developed near-fatal TAC-ILD. Amelioration of RA, ground-glass opacities in the upper, anterior, and central lung fields, and decrease in peripheral blood lymphocyte count were the major findings in this patient. A search of the PMDA website revealed the following: the prevalence of TAC-ILD was 3 % of all cases of TAC-related adverse events, 56 out of 85 RA cases (66 %), and one out of 15 other cases had a preexisting lung disease; the prevalences of fatal outcome in RA and other cases were 24 and 38 %, respectively. A few cases in the literature had preexisting ILD and developed diffuse alveolar damage. In our case, preexisting bronchiectasis, arthritis remission, newly developed ground-glass opacities (GGOs) in the upper, anterior, and central lung fields, and decrease in peripheral blood lymphocyte count were the major findings. From the search of the PMDA website, about one fourth of the cases with TAC-related lung injury had a fatal outcome, and among RA patients, two thirds had preexisting lung diseases.

Epimorphin expression in interstitial pneumonia

PubMed Central

Terasaki, Yasuhiro; Fukuda, Yuh; Suga, Moritaka; Ikeguchi, Naoki; Takeya, Motohiro

2005-01-01

Epimorphin modulates epithelial morphogenesis in embryonic mouse organs. We previously suggested that epimorphin contributes to repair of bleomycin-induced pulmonary fibrosis in mice via epithelium-mesenchyme interactions. To clarify the role of epimorphin in human lungs, we evaluated epimorphin expression and localization in normal lungs, lungs with nonspecific interstitial pneumonia (NSIP), and lungs with usual interstitial pneumonia (UIP); we also studied the effect of recombinant epimorphin on cultured human alveolar epithelial cells in vitro. Northern and Western blotting analyses revealed that epimorphin expression in NSIP samples were significantly higher than those in control lungs and lungs with UIP. Immunohistochemistry showed strong epimorphin expression in mesenchymal cells of early fibrotic lesions and localization of epimorphin protein on mesenchymal cells and extracellular matrix of early fibrotic lesions in the nonspecific interstitial pneumonia group. Double-labeled fluorescent images revealed expression of matrix metalloproteinase 2 in re-epithelialized cells overlying epimorphin-positive early fibrotic lesions. Immunohistochemistry and metalloproteinase activity assay demonstrated augmented expression of metalloproteinase induced by recombinant epimorphin in human alveolar epithelial cells. These findings suggest that epimorphin contributes to repair of pulmonary fibrosis in nonspecific interstitial pneumonia, perhaps partly by inducing expression of matrix metalloproteinase 2, which is an important proteolytic factor in lung remodeling. PMID:15651999

Platelet-rich plasma, plasma rich in growth factors and simvastatin in the regeneration and repair of alveolar bone.

PubMed

Rivera, César; Monsalve, Francisco; Salas, Juan; Morán, Andrea; Suazo, Iván

2013-12-01

Platelet preparations promote bone regeneration by inducing cell migration, proliferation and differentiation in the area of the injury, which are essential processes for regeneration. In addition, several studies have indicated that simvastatin (SIMV), widely used for the treatment of hypercholesterolemia, stimulates osteogenesis. The objective of this study was to evaluate the effects of treatment with either platelet-rich plasma (PRP) or plasma rich in growth factors (PRGF) in combination with SIMV in the regeneration and repair of alveolar bone. The jaws of Sprague Dawley rats (n=18) were subjected to rotary instrument-induced bone damage (BD). Animals were divided into six groups: BD/H 2 O (n=3), distilled water without the drug and alveolar bone damage; BD/H 2 O/PRP (n=3), BD and PRP; BD/H 2 O/PRGF (n=3), BD and PRGF; BD/SIMV (n=3), BD and water with SIMV; BD/SIMV/PRP (n=3), BD, PRP and SIMV; and BD/SIMV/PRGF (n=3), BD, PRGF and SIMV. Conventional histological analysis (hematoxylin and eosin staining) revealed that the BD/SIMV group showed indicators for mature bone tissue, while the BD/SIMV/PRP and BD/SIMV/PRGF groups showed the coexistence of indicators for mature and immature bone tissue, with no statistical differences between the platelet preparations. Simvastatin did not improve the effect of platelet-rich plasma and plasma rich in growth factors. It was not possible to determine which platelet preparation produced superior effects.

Platelet-rich plasma, plasma rich in growth factors and simvastatin in the regeneration and repair of alveolar bone

PubMed Central

RIVERA, CÉSAR; MONSALVE, FRANCISCO; SALAS, JUAN; MORÁN, ANDREA; SUAZO, IVÁN

2013-01-01

Platelet preparations promote bone regeneration by inducing cell migration, proliferation and differentiation in the area of the injury, which are essential processes for regeneration. In addition, several studies have indicated that simvastatin (SIMV), widely used for the treatment of hypercholesterolemia, stimulates osteogenesis. The objective of this study was to evaluate the effects of treatment with either platelet-rich plasma (PRP) or plasma rich in growth factors (PRGF) in combination with SIMV in the regeneration and repair of alveolar bone. The jaws of Sprague Dawley rats (n=18) were subjected to rotary instrument-induced bone damage (BD). Animals were divided into six groups: BD/H2O (n=3), distilled water without the drug and alveolar bone damage; BD/H2O/PRP (n=3), BD and PRP; BD/H2O/PRGF (n=3), BD and PRGF; BD/SIMV (n=3), BD and water with SIMV; BD/SIMV/PRP (n=3), BD, PRP and SIMV; and BD/SIMV/PRGF (n=3), BD, PRGF and SIMV. Conventional histological analysis (hematoxylin and eosin staining) revealed that the BD/SIMV group showed indicators for mature bone tissue, while the BD/SIMV/PRP and BD/SIMV/PRGF groups showed the coexistence of indicators for mature and immature bone tissue, with no statistical differences between the platelet preparations. Simvastatin did not improve the effect of platelet-rich plasma and plasma rich in growth factors. It was not possible to determine which platelet preparation produced superior effects. PMID:24250728

Dysregulated Functions of Lung Macrophage Populations in COPD.

PubMed

Kapellos, Theodore S; Bassler, Kevin; Aschenbrenner, Anna C; Fujii, Wataru; Schultze, Joachim L

2018-01-01

Chronic obstructive pulmonary disease (COPD) is a diverse respiratory disease characterised by bronchiolitis, small airway obstruction, and emphysema. Innate immune cells play a pivotal role in the disease's progression, and in particular, lung macrophages exploit their prevalence and strategic localisation to orchestrate immune responses. To date, alveolar and interstitial resident macrophages as well as blood monocytes have been described in the lungs of patients with COPD contributing to disease pathology by changes in their functional repertoire. In this review, we summarise recent evidence from human studies and work with animal models of COPD with regard to altered functions of each of these myeloid cell populations. We primarily focus on the dysregulated capacity of alveolar macrophages to secrete proinflammatory mediators and proteases, induce oxidative stress, engulf microbes and apoptotic cells, and express surface and intracellular markers in patients with COPD. In addition, we discuss the differences in the responses between alveolar macrophages and interstitial macrophages/monocytes in the disease and propose how the field should advance to better understand the implications of lung macrophage functions in COPD.

Transcription factor Etv5 is essential for the maintenance of alveolar type II cells.

PubMed

Zhang, Zhen; Newton, Kim; Kummerfeld, Sarah K; Webster, Joshua; Kirkpatrick, Donald S; Phu, Lilian; Eastham-Anderson, Jeffrey; Liu, Jinfeng; Lee, Wyne P; Wu, Jiansheng; Li, Hong; Junttila, Melissa R; Dixit, Vishva M

2017-04-11

Alveolar type II (AT2) cell dysfunction contributes to a number of significant human pathologies including respiratory distress syndrome, lung adenocarcinoma, and debilitating fibrotic diseases, but the critical transcription factors that maintain AT2 cell identity are unknown. Here we show that the E26 transformation-specific (ETS) family transcription factor Etv5 is essential to maintain AT2 cell identity. Deletion of Etv5 from AT2 cells produced gene and protein signatures characteristic of differentiated alveolar type I (AT1) cells. Consistent with a defect in the AT2 stem cell population, Etv5 deficiency markedly reduced recovery following bleomycin-induced lung injury. Lung tumorigenesis driven by mutant KrasG12D was also compromised by Etv5 deficiency. ERK activation downstream of Ras was found to stabilize Etv5 through inactivation of the cullin-RING ubiquitin ligase CRL4 COP1/DET1 that targets Etv5 for proteasomal degradation. These findings identify Etv5 as a critical output of Ras signaling in AT2 cells, contributing to both lung homeostasis and tumor initiation.

Dysregulated Functions of Lung Macrophage Populations in COPD

PubMed Central

Bassler, Kevin; Aschenbrenner, Anna C.

2018-01-01

Chronic obstructive pulmonary disease (COPD) is a diverse respiratory disease characterised by bronchiolitis, small airway obstruction, and emphysema. Innate immune cells play a pivotal role in the disease's progression, and in particular, lung macrophages exploit their prevalence and strategic localisation to orchestrate immune responses. To date, alveolar and interstitial resident macrophages as well as blood monocytes have been described in the lungs of patients with COPD contributing to disease pathology by changes in their functional repertoire. In this review, we summarise recent evidence from human studies and work with animal models of COPD with regard to altered functions of each of these myeloid cell populations. We primarily focus on the dysregulated capacity of alveolar macrophages to secrete proinflammatory mediators and proteases, induce oxidative stress, engulf microbes and apoptotic cells, and express surface and intracellular markers in patients with COPD. In addition, we discuss the differences in the responses between alveolar macrophages and interstitial macrophages/monocytes in the disease and propose how the field should advance to better understand the implications of lung macrophage functions in COPD. PMID:29670919

DIESEL EXHAUST PARTICLES INDUCE ABERRANT ALVEOLAR EPITHELIAL DIRECTED CELL MOVEMENT BY DISRUPTION OF POLARITY MECHANISMS

EPA Science Inventory

Disruption of the respiratory epithelium contributes to the progression of a variety of respiratory diseases that are aggravated by exposure to air pollutants, specifically traffic-based pollutants such as diesel exhaust particles (DEP). Recognizing that lung repair following inj...

The increase of microRNA-21 during lung fibrosis and its contribution to epithelial-mesenchymal transition in pulmonary epithelial cells.

PubMed

Yamada, Mitsuhiro; Kubo, Hiroshi; Ota, Chiharu; Takahashi, Toru; Tando, Yukiko; Suzuki, Takaya; Fujino, Naoya; Makiguchi, Tomonori; Takagi, Kiyoshi; Suzuki, Takashi; Ichinose, Masakazu

2013-09-24

The excess and persistent accumulation of fibroblasts due to aberrant tissue repair results in fibrotic diseases such as idiopathic pulmonary fibrosis. Recent reports have revealed significant changes in microRNAs during idiopathic pulmonary fibrosis and evidence in support of a role for microRNAs in myofibroblast differentiation and the epithelial-mesenchymal transition in the context of fibrosis. It has been reported that microRNA-21 is up-regulated in myofibroblasts during fibrosis and promotes transforming growth factor-beta signaling by inhibiting Smad7. However, expression changes in microRNA-21 and the role of microRNA-21 in epithelial-mesenchymal transition during lung fibrosis have not yet been defined. Lungs from saline- or bleomycin-treated C57BL/6 J mice and lung specimens from patients with idiopathic pulmonary fibrosis were analyzed. Enzymatic digestions were performed to isolate single lung cells. Lung epithelial cells were isolated by flow cytometric cell sorting. The expression of microRNA-21 was analyzed using both quantitative PCR and in situ hybridization. To induce epithelial-mesenchymal transition in culture, isolated mouse lung alveolar type II cells were cultured on fibronectin-coated chamber slides in the presence of transforming growth factor-β, thus generating conditions that enhance epithelial-mesenchymal transition. To investigate the role of microRNA-21 in epithelial-mesenchymal transition, we transfected cells with a microRNA-21 inhibitor. Total RNA was isolated from the freshly isolated and cultured cells. MicroRNA-21, as well as mRNAs of genes that are markers of alveolar epithelial or mesenchymal cell differentiation, were quantified using quantitative PCR. The lung epithelial cells isolated from the bleomycin-induced lung fibrosis model system had decreased expression of epithelial marker genes, whereas the expression of mesenchymal marker genes was increased. MicroRNA-21 was significantly upregulated in isolated lung epithelial cells during bleomycin-induced lung fibrosis and human idiopathic pulmonary fibrosis. MicroRNA-21 was also upregulated in the cultured alveolar epithelial cells under the conditions that enhance epithelial-mesenchymal transition. Exogenous administration of a microRNA-21 inhibitor prevented the increased expression of vimentin and alpha-smooth muscle actin in cultured primary mouse alveolar type II cells under culture conditions that induce epithelial-mesenchymal transition. Our experiments demonstrate that microRNA-21 is increased in lung epithelial cells during lung fibrosis and that it promotes epithelial-mesenchymal transition.

Ventilation-perfusion matching during exercise

NASA Technical Reports Server (NTRS)

Wagner, P. D.

1992-01-01

In normal subjects, exercise widens the alveolar-arterial PO2 difference (P[A-a]O2) despite a more uniform topographic distribution of ventilation-perfusion (VA/Q) ratios. While part of the increase in P(A-a)O2 (especially during heavy exercise) is due to diffusion limitation, a considerable amount is caused by an increase in VA/Q mismatch as detected by the multiple inert gas elimination technique. Why this occurs is unknown, but circumstantial evidence suggests it may be related to interstitial pulmonary edema rather than to factors dependent on ventilation, airway gas mixing, airway muscle tone, or pulmonary vascular tone. In patients with lung disease, the gas exchange consequences of exercise are variable. Thus, arterial PO2 may increase, remain the same, or fall. In general, patients with advanced chronic obstructive pulmonary disease (COPD) or interstitial fibrosis who exercise show a fall in PO2. This is usually not due to worsening VA/Q relationships but mostly to the well-known fall in mixed venous PO2, which itself results from a relatively smaller increase in cardiac output than VO2. However, in interstitial fibrosis (but not COPD), there is good evidence that a part of the fall in PO2 on exercise is caused by alveolar-capillary diffusion limitation of O2 transport; in COPD (but not interstitial fibrosis), a frequent additional contributing factor to the hypoxemia of exercise is an inadequate ventilatory response, such that minute ventilation does not rise as much as does CO2 production or O2 uptake, causing arterial PCO2 to increase and PO2 to fall.

Pulmonary arterial hypertension and cor pulmonale associated with chronic domestic woodsmoke inhalation

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

Sandoval, J.; Salas, J.; Martinez-Guerra, M.L.

1993-01-01

We describe the clinical, radiologic, functional, and pulmonary hemodynamic characteristics of a group of 30 nonsmoking patients with a lung disease that may be related to intense, long-standing indoor wood-smoke exposure. The endoscopic and some of the pathologic findings are also presented. Intense and prolonged wood-smoke inhalation may produce a chronic pulmonary disease that is similar in many aspects to other forms of inorganic dust-exposure interstitial lung disease. It affects mostly country women in their 60s, and severe dyspnea and cough are the outstanding complaints. The chest roentgenograms show a diffuse, bilateral, reticulonodular pattern, combined with normalized or hyperinflated lungs,more » as well as indirect signs of pulmonary arterial hypertension (PAH). On the pulmonary function test the patients show a mixed restrictive-obstructive pattern with severe hypoxemia and variable degrees of hypercapnia. Endoscopic findings are those of acute and chronic bronchitis and intense anthracotic staining of the airways appears to be quite characteristic. Fibrous and inflammatory focal thickening of the alveolar septa as well as diffuse parenchymal anthracotic deposits are the most prominent pathologic findings, although inflammatory changes of the bronchial epithelium are also present. The patients had severe PAH in which, as in other chronic lung diseases, chronic alveolar hypoxia may play the main pathogenetic role. However, PAH in wood-smoke inhalation-associated lung disease (WSIALD) appears to be more severe than in other forms of interstitial lung disease and tobacco-related COPD. The patients we studied are a selected group and they may represent one end of the spectrum of the WSIALD.« less

Stimulation of alveolar macrophages by BCG vaccine enhances the process of lung fibrosis induced by bleomycin.

PubMed

Chyczewska, E; Chyczewski, L; Bańkowski, E; Sułkowski, S; Nikliński, J

1993-01-01

It was found that the BCG vaccine injected subcutaneously to the rats enhances the process of lung fibrosis induced by bleomycin. Pretreatment of rats with this vaccine results in accumulation of activated macrophages in lung interstitium and in the bronchoalveolar spaces. It may be suggested that the activated macrophages release various cytokines which may stimulate the proliferation of fibroblasts and biosynthesis of extracellular matrix components.

Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span

PubMed Central

Morales-Nebreda, Luisa; Cuda, Carla M.; Walter, James M.; Chen, Ching-I; Anekalla, Kishore R.; Joshi, Nikita; Williams, Kinola J.N.; Abdala-Valencia, Hiam; Yacoub, Tyrone J.; Chi, Monica; Gates, Khalilah; Homan, Philip J.; Soberanes, Saul; Dominguez, Salina; Saber, Rana; Hinchcliff, Monique; Marshall, Stacy A.; Bharat, Ankit; Berdnikovs, Sergejs; Bhorade, Sangeeta M.; Balch, William E.; Chandel, Navdeep S.; Jain, Manu; Ridge, Karen M.; Bagheri, Neda; Shilatifard, Ali

2017-01-01

Little is known about the relative importance of monocyte and tissue-resident macrophages in the development of lung fibrosis. We show that specific genetic deletion of monocyte-derived alveolar macrophages after their recruitment to the lung ameliorated lung fibrosis, whereas tissue-resident alveolar macrophages did not contribute to fibrosis. Using transcriptomic profiling of flow-sorted cells, we found that monocyte to alveolar macrophage differentiation unfolds continuously over the course of fibrosis and its resolution. During the fibrotic phase, monocyte-derived alveolar macrophages differ significantly from tissue-resident alveolar macrophages in their expression of profibrotic genes. A population of monocyte-derived alveolar macrophages persisted in the lung for one year after the resolution of fibrosis, where they became increasingly similar to tissue-resident alveolar macrophages. Human homologues of profibrotic genes expressed by mouse monocyte-derived alveolar macrophages during fibrosis were up-regulated in human alveolar macrophages from fibrotic compared with normal lungs. Our findings suggest that selectively targeting alveolar macrophage differentiation within the lung may ameliorate fibrosis without the adverse consequences associated with global monocyte or tissue-resident alveolar macrophage depletion. PMID:28694385

Comparative Toxicity of Biodiesel Exhaust and Petroleum Diesel Exhaust Particulate Matter Using WKY Rat Alveolar Machrophages

EPA Science Inventory

Exposure to fine ambient particulate matter <2.5um (PM2.5) can induce airway inflammation, cardiopulmonary morbidity and mortality. Combustion of petroleum diesel and biodiesel contributes to PM2.5. Possible toxicity caused by inhalation of biodiesel emission particles (BioDEP) h...

Soluble Iron in Alveolar Macrophages Modulates Iron Oxide Particle-Induced Inflammatory Response via Prostaglandin E2 Synthesis

EPA Science Inventory

Ambient particulate matter (PM)-associated metals have been shown to play an important role in cardiopulmonary health outcomes. To study the modulation of inflammation by PM-associated soluble metal, we investigated intracellular solubility of radiolabelled iron oxide (⁵⁹

FE2O3 PARTICLE-INDUCED PROSTAGLANDIN E2 (PGE2) SYNTHESIS IN ALVEOLAR MACROPHAGES (AM) DETERMINES PARTICULATE INFLAMMATORY POTENTIAL

EPA Science Inventory

As shown by epidemiologic studies, acute exposure to ambient particles is associated with exacerbation of pulmonary and cardiovascular diseases. Metals associated with particles are able to mediate lung injury via oxidant-catalyzed reactions. However, the underlying mechanism i...

Polymethoxy flavonoids, nobiletin and tangeretin, prevent lipopolysaccharide-induced inflammatory bone loss in an experimental model for periodontitis.

PubMed

Tominari, Tsukasa; Hirata, Michiko; Matsumoto, Chiho; Inada, Masaki; Miyaura, Chisato

2012-01-01

Nobiletin, a polymethoxy flavonoid (PMF), inhibits systemic bone resorption and maintains bone mass in estrogen-deficient ovariectomized mice. This study examined the anti-inflammatory effects of PMFs, nobiletin, and tangeretin on lipopolysaccharide (LPS)-induced bone resorption. Nobiletin and tangeretin suppressed LPS-induced osteoclast formation and bone resorption and suppressed the receptor activator of NFκB ligand-induced osteoclastogenesis in RAW264.7 macrophages. Nobiletin clearly restored the alveolar bone mass in a mouse experimental model for periodontitis by inhibiting LPS-induced bone resorption. PMFs may therefore provide a new therapeutic approach for periodontal bone loss.

Analysis of the Protective Biochemical and Pathologic Effects of Aminoguanidine on an Experimental Aspiration Pneumonitis Model Induced by Bile Acids

PubMed Central

Karli, Rifat; Alacam, Hasan; Duran, Latif; Alici, Omer; Kati, Celal; Karli, Arzu; Guzel, Ahmet

2012-01-01

Background Gastroesophageal reflux (GER) is a common clinical pathology detected in childhood. Bile acids (BAs) are present in reflux and cause various pathologies in the esophagus, the larynx, and the lungs. Objective We aimed to show if aminoguanidine (AG) contributes to the biochemical and histopathologic treatment of experimental aspiration pneumonitis induced by BAs. Methods Twenty-eight female Sprague Dawley rats were used. There were 4 groups in the study: (1) group aspirated with 0.9% saline (n = 7), (2) group aspirated with 0.9% saline and treated with AG (n = 7), (3) group aspirated with a solution of 10 mg/kg taurocholic acid and 5 mg/kg taurochenodeoxycholate (n = 7), and (4) group aspirated with BA and treated with AG (n = 7). The saline and BA solutions were administered as 1 mL/kg intratracheally. The AG was administered intraperitoneally twice a day at a 150 mg/kg dose for 7 days. The different histopathologic and biochemical parameters were analyzed. Results Clara cell protein 16 and malondialdehyde levels were found to be significantly higher in the BA group than in the group where saline was administered; however, they were significantly lower in the BA + AG group than in the BA group. The total superoxide dismutase activity decreased significantly in the BA group compared with the group where saline was administered. A significant increase in superoxide dismutase activity was observed in the BA + AG group when compared with the group where only BA was administered. When the group where BA was administered solely was compared with the group where saline was administered, peribronchial inflammatory cell infiltration, alveolar septal infiltration, alveolar histiocytes, interstitial fibrosis, and granuloma were significantly higher in the BA group than in the saline group. When the BA + AG group was compared with the BA group, peribronchial inflammatory cell infiltration, alveolar septal infiltration, alveolar histiocytes, interstitial fibrosis, and granuloma were found to be significantly lower. Conclusions Oxidant stress increases and antioxidant capacity decreases in pneumonitis induced by BAs. AG administration as an antioxidant helps in recovery, both biochemically and histopathologically. Consequently, AG seems to be an alternative that should be considered in a conservative approach to treating aspiration pneumonitis. PMID:24653522

Elastase-Induced Parenchymal Disruption and Airway Hyper Responsiveness in Mouse Precision Cut Lung Slices: Toward an Ex vivo COPD Model.

PubMed

Van Dijk, Eline M; Culha, Sule; Menzen, Mark H; Bidan, Cécile M; Gosens, Reinoud

2016-01-01

Background: COPD is a progressive lung disease characterized by emphysema and enhanced bronchoconstriction. Current treatments focused on bronchodilation can delay disease progression to some extent, but recovery or normalization of loss of lung function is impossible. Therefore, novel therapeutic targets are needed. The importance of the parenchyma in airway narrowing is increasingly recognized. In COPD, the parenchyma and extracellular matrix are altered, possibly affecting airway mechanics and enhancing bronchoconstriction. Our aim was to set up a comprehensive ex vivo Precision Cut Lung Slice (PCLS) model with a pathophysiology resembling that of COPD and integrate multiple readouts in order to study the relationship between parenchyma, airway functionality, and lung repair processes. Methods: Lungs of C57Bl/6J mice were sliced and treated ex vivo with elastase (2.5 μg/ml) or H 2 O 2 (200 μM) for 16 h. Following treatment, parenchymal structure, airway narrowing, and gene expression levels of alveolar Type I and II cell repair were assessed. Results: Following elastase, but not H 2 O 2 treatment, slices showed a significant increase in mean linear intercept (Lmi), reflective of emphysema. Only elastase-treated slices showed disorganization of elastin and collagen fibers. In addition, elastase treatment lowered both alveolar Type I and II marker expression, whereas H 2 O 2 stimulation lowered alveolar Type I marker expression only. Furthermore, elastase-treated slices showed enhanced methacholine-induced airway narrowing as reflected by increased pEC50 (5.87 at basal vs. 6.50 after elastase treatment) and Emax values (47.96 vs. 67.30%), and impaired chloroquine-induced airway opening. The increase in pEC50 correlated with an increase in mean Lmi. Conclusion: Using this model, we show that structural disruption of elastin fibers leads to impaired alveolar repair, disruption of the parenchymal compartment, and altered airway biomechanics, enhancing airway contraction. This finding may have implications for COPD, as the amount of elastin fiber and parenchymal tissue disruption is associated with disease severity. Therefore, we suggest that PCLS can be used to model certain aspects of COPD pathophysiology and that the parenchymal tissue damage observed in COPD contributes to lung function decline by disrupting airway biomechanics. Targeting the parenchymal compartment may therefore be a promising therapeutic target in the treatment of COPD.

Blunt Chest Trauma in Mice after Cigarette Smoke-Exposure: Effects of Mechanical Ventilation with 100% O2.

PubMed

Wagner, Katja; Gröger, Michael; McCook, Oscar; Scheuerle, Angelika; Asfar, Pierre; Stahl, Bettina; Huber-Lang, Markus; Ignatius, Anita; Jung, Birgit; Duechs, Matthias; Möller, Peter; Georgieff, Michael; Calzia, Enrico; Radermacher, Peter; Wagner, Florian

2015-01-01

Cigarette smoking (CS) aggravates post-traumatic acute lung injury and increases ventilator-induced lung injury due to more severe tissue inflammation and apoptosis. Hyper-inflammation after chest trauma is due to the physical damage, the drop in alveolar PO2, and the consecutive hypoxemia and tissue hypoxia. Therefore, we tested the hypotheses that 1) CS exposure prior to blunt chest trauma causes more severe post-traumatic inflammation and thereby aggravates lung injury, and that 2) hyperoxia may attenuate this effect. Immediately after blast wave-induced blunt chest trauma, mice (n=32) with or without 3-4 weeks of CS exposure underwent 4 hours of pressure-controlled, thoraco-pulmonary compliance-titrated, lung-protective mechanical ventilation with air or 100% O2. Hemodynamics, lung mechanics, gas exchange, and acid-base status were measured together with blood and tissue cytokine and chemokine concentrations, heme oxygenase-1 (HO-1), activated caspase-3, and hypoxia-inducible factor 1-α (HIF-1α) expression, nuclear factor-κB (NF-κB) activation, nitrotyrosine formation, purinergic receptor 2X4 (P2XR4) and 2X7 (P2XR7) expression, and histological scoring. CS exposure prior to chest trauma lead to higher pulmonary compliance and lower PaO2 and Horovitz-index, associated with increased tissue IL-18 and blood MCP-1 concentrations, a 2-4-fold higher inflammatory cell infiltration, and more pronounced alveolar membrane thickening. This effect coincided with increased activated caspase-3, nitrotyrosine, P2XR4, and P2XR7 expression, NF-κB activation, and reduced HIF-1α expression. Hyperoxia did not further affect lung mechanics, gas exchange, pulmonary and systemic cytokine and chemokine concentrations, or histological scoring, except for some patchy alveolar edema in CS exposed mice. However, hyperoxia attenuated tissue HIF-1α, nitrotyrosine, P2XR7, and P2XR4 expression, while it increased HO-1 formation in CS exposed mice. Overall, CS exposure aggravated post-traumatic inflammation, nitrosative stress and thereby organ dysfunction and injury; short-term, lung-protective, hyperoxic mechanical ventilation have no major beneficial effect despite attenuation of nitrosative stress, possibly due to compensation of by regional alveolar hypoxia and/or consecutive hypoxemia, resulting in down-regulation of HIF-1α expression.

Non-lobar atelectasis generates inflammation and structural alveolar injury in the surrounding healthy tissue during mechanical ventilation.

PubMed

Retamal, Jaime; Bergamini, Bruno Curty; Carvalho, Alysson R; Bozza, Fernando A; Borzone, Gisella; Borges, João Batista; Larsson, Anders; Hedenstierna, Göran; Bugedo, Guillermo; Bruhn, Alejandro

2014-09-09

When alveoli collapse the traction forces exerted on their walls by adjacent expanded units may increase and concentrate. These forces may promote its re-expansion at the expense of potentially injurious stresses at the interface between the collapsed and the expanded units. We developed an experimental model to test the hypothesis that a local non-lobar atelectasis can act as a stress concentrator, contributing to inflammation and structural alveolar injury in the surrounding healthy lung tissue during mechanical ventilation. A total of 35 rats were anesthetized, paralyzed and mechanically ventilated. Atelectasis was induced by bronchial blocking: after five minutes of stabilization and pre-oxygenation with FIO2 = 1.0, a silicon cylinder blocker was wedged in the terminal bronchial tree. Afterwards, the animals were randomized between two groups: 1) Tidal volume (VT) = 10 ml/kg and positive end-expiratory pressure (PEEP) = 3 cmH2O (VT10/PEEP3); and 2) VT = 20 ml/kg and PEEP = 0 cmH2O (VT20/zero end-expiratory pressure (ZEEP)). The animals were then ventilated during 180 minutes. Three series of experiments were performed: histological (n = 12); tissue cytokines (n = 12); and micro-computed tomography (microCT; n = 2). An additional six, non-ventilated, healthy animals were used as controls. Atelectasis was successfully induced in the basal region of the lung of 26 out of 29 animals. The microCT of two animals revealed that the volume of the atelectasis was 0.12 and 0.21 cm3. There were more alveolar disruption and neutrophilic infiltration in the peri-atelectasis region than the corresponding contralateral lung (control) in both groups. Edema was higher in the peri-atelectasis region than the corresponding contralateral lung (control) in the VT20/ZEEP than VT10/PEEP3 group. The volume-to-surface ratio was higher in the peri-atelectasis region than the corresponding contralateral lung (control) in both groups. We did not find statistical difference in tissue interleukin-1β and cytokine-induced neutrophil chemoattractant-1 between regions. The present findings suggest that a local non-lobar atelectasis acts as a stress concentrator, generating structural alveolar injury and inflammation in the surrounding lung tissue.

Positive End-Expiratory Pressure and Variable Ventilation in Lung-Healthy Rats under General Anesthesia

PubMed Central

Camilo, Luciana M.; Ávila, Mariana B.; Cruz, Luis Felipe S.; Ribeiro, Gabriel C. M.; Spieth, Peter M.; Reske, Andreas A.; Amato, Marcelo; Giannella-Neto, Antonio; Zin, Walter A.; Carvalho, Alysson R.

2014-01-01

Objectives Variable ventilation (VV) seems to improve respiratory function in acute lung injury and may be combined with positive end-expiratory pressure (PEEP) in order to protect the lungs even in healthy subjects. We hypothesized that VV in combination with moderate levels of PEEP reduce the deterioration of pulmonary function related to general anesthesia. Hence, we aimed at evaluating the alveolar stability and lung protection of the combination of VV at different PEEP levels. Design Randomized experimental study. Setting Animal research facility. Subjects Forty-nine male Wistar rats (200–270 g). Interventions Animals were ventilated during 2 hours with protective low tidal volume (VT) in volume control ventilation (VCV) or VV and PEEP adjusted at the level of minimum respiratory system elastance (Ers), obtained during a decremental PEEP trial subsequent to a recruitment maneuver, and 2 cmH2O above or below of this level. Measurements and Main Results Ers, gas exchange and hemodynamic variables were measured. Cytokines were determined in lung homogenate and plasma samples and left lung was used for histologic analysis and diffuse alveolar damage scoring. A progressive time-dependent increase in Ers was observed independent on ventilatory mode or PEEP level. Despite of that, the rate of increase of Ers and lung tissue IL-1 beta concentration were significantly lower in VV than in VCV at the level of the PEEP of minimum Ers. A significant increase in lung tissue cytokines (IL-6, IL-1 beta, CINC-1 and TNF-alpha) as well as a ventral to dorsal and cranial to caudal reduction in aeration was observed in all ventilated rats with no significant differences among groups. Conclusions VV combined with PEEP adjusted at the level of the PEEP of minimal Ers seemed to better prevent anesthesia-induced atelectasis and might improve lung protection throughout general anesthesia. PMID:25383882

Histopathology of ventilator-associated pneumonia (VAP) and its clinical implications.

PubMed

Torres, A; Fábregas, N; Arce, Y; López-Boado, M A

1999-01-01

Ventilator-associated pneumonia (VAP) is a diffuse polymicrobial and dynamic process, with heterogeneous distribution of lesions, showing different degrees of histological evolution predominating in the dependent lung zones, in which microbiology and histology can be dissociated. This might explain why blind endobronchial techniques to collect respiratory secretions have similar accuracy compared to visually guided samples, explaining the difficulties in validating any methods for its diagnosis. In the clinical setting the association of acute lung injury (ALI) and pneumonia is controversial. However, it is rare to detect diffuse alveolar damage (DAD) in absence of histological signs of pneumonia, probably evidencing that ALI favors the development of pneumonia. Histopathologically, it is difficult to distinguish initial and resolution phases of DAD from pneumonia and vice versa. On the other hand, there is a clear relationship between antimicrobial treatment and the decreased lung bacterial burden which strengthens the importance of distal airway sampling before starting antibiotic therapy.

High times, low sats: diffuse pulmonary infiltrates associated with chronic synthetic cannabinoid use.

PubMed

Alhadi, Sameir; Tiwari, Anupama; Vohra, Rais; Gerona, Roy; Acharya, Janak; Bilello, Kathryn

2013-06-01

In recent years, cases of severe adverse effects from recreational use of synthetic cannabinoids (SC) have established that these agents represent a novel toxicologic hazard. A 21-year-old male presenting as a vehicular trauma victim was noted with diffuse pulmonary infiltrates related to chronic inhalation of multiple synthetic cannabinoid-containing products. Chest imaging revealed bilateral, subacute lung infiltrates; histopathological analysis of bronchial and alveolar tissues revealed an inflammatory process. An extensive workup failed to identify infectious, malignant, autoimmune, or hematologic causes of the syndrome, and toxicological analysis of the blood and body fluids confirmed the presence of multiple synthetic cannabinoids and metabolites. The patient recovered after an 8-day ICU course, wherein he received antibiotics, steroids, and mechanical ventilation. This case contributes to the currently evolving knowledge about SC agents, adding a rarely described pulmonary complication to the growing list of adverse effects associated with these products.

Intratracheal transplantation of human umbilical cord blood-derived mesenchymal stem cells dose-dependently attenuates hyperoxia-induced lung injury in neonatal rats.

PubMed

Chang, Yun Sil; Choi, Soo Jin; Sung, Dong Kyung; Kim, Soo Yoon; Oh, Wonil; Yang, Yoon Sun; Park, Won Soon

2011-01-01

Intratracheal transplantation of human umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) attenuates the hyperoxia-induced neonatal lung injury. The aim of this preclinical translation study was to optimize the dose of human UCB-derived MSCs in attenuating hyperoxia-induced lung injury in newborn rats. Newborn Sprague-Dawley rats were randomly exposed to hyperoxia (95% oxygen) or normoxia after birth for 14 days. Three different doses of human UCB-derived MSCs, 5 × 10(3) (HT1), 5 × 10(4) (HT2), and 5 × 10(5) (HT3), were delivered intratracheally at postnatal day (P) 5. At P14, lungs were harvested for analyses including morphometry for alveolarization, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) staining, myeoloperoxidase activity, mRNA level of tumor necross factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, and transforming growth factor-β (TGF-β), human glyceradehyde-3-phosphate dehydrogenase (GAPDH), and p47(phox), and collagen levels. Increases in TUNEL-positive cells were attenuated in all transplantation groups. However, hyperoxia-induced lung injuries, such as reduced alveolarization, as evidenced by increased mean linear intercept and mean alveolar volume, and increased collagen levels were significantly attenuated in both HT2 and HT3, but not in HT1, with better attenuation in HT3 than in HT2. Dose-dependent human GAPDH expression, indicative of the presence of human RNA in lung tissue, was observed only in the transplantation groups, with higher expression in HT3 than in HT2, and higher expression in HT2 than in HT1. Hyperoxia-induced inflammatory responses such as increased myeloperoxidase acitivity, mRNA levels of TNF-α, IL-1β, IL-6, and TGF-β of the lung tissue, and upregulation of both cytosolic and membrane p47(phox), indicative of oxidative stress, were significantly attenuated in both HT2 and HT3 but not in HT1. These results demonstrate that intratracheal transplantation of human UCB-derived MSCs with appropriate doses may attenuate hyperoxia-induced lung injury through active involvement of these cells in modulating host inflammatory responses and oxidative stress in neonatal rats.

A case report of Gorlin–Goltz syndrome as a rare hereditary disorder

PubMed Central

Sirous, Mehri; Tayari, Nazila

2011-01-01

Gorlin–Goltz syndrome is an autosomal dominant and a rare hereditary disease. Diagnosis of this syndrome is based on major and minor criteria. We report a Gorlin–Goltz syndrome in a 25-year-old male who was presented with progressive pain of maxilla and mandible over 5 years. The pain was diffuse and compatible with expansile cyst in alveolar ridges on panoramic radiography. In physical examination, he had coarse face and prognathism. Computer tomography of face revealed two expansile maxillary and one mandibular cyst. Calcification of entire length in falx and tentorium were detected in bone window. PMID:22091315

A case report of Gorlin-Goltz syndrome as a rare hereditary disorder.

PubMed

Sirous, Mehri; Tayari, Nazila

2011-06-01

Gorlin-Goltz syndrome is an autosomal dominant and a rare hereditary disease. Diagnosis of this syndrome is based on major and minor criteria. We report a Gorlin-Goltz syndrome in a 25-year-old male who was presented with progressive pain of maxilla and mandible over 5 years. The pain was diffuse and compatible with expansile cyst in alveolar ridges on panoramic radiography. In physical examination, he had coarse face and prognathism. Computer tomography of face revealed two expansile maxillary and one mandibular cyst. Calcification of entire length in falx and tentorium were detected in bone window.

Volumetric Optical Frequency Domain Imaging of Pulmonary Pathology With Precise Correlation to Histopathology

PubMed Central

Hariri, Lida P.; Applegate, Matthew B.; Mino-Kenudson, Mari; Mark, Eugene J.; Medoff, Benjamin D.; Luster, Andrew D.; Bouma, Brett E.; Tearney, Guillermo J.

2013-01-01

Background: Lung cancer is the leading cause of cancer-related mortality. Radiology and bronchoscopy techniques do not have the necessary resolution to evaluate lung lesions on the microscopic scale, which is critical for diagnosis. Bronchial biopsy specimens can be limited by sampling error and small size. Optical frequency domain imaging (OFDI) provides volumetric views of tissue microstructure at near-histologic resolution and may be useful for evaluating pulmonary lesions to increase diagnostic accuracy. Bronchoscopic OFDI has been evaluated in vivo, but a lack of correlated histopathology has limited the ability to develop accurate image interpretation criteria. Methods: We performed OFDI through two approaches (airway-centered and parenchymal imaging) in 22 ex vivo lung specimens, using tissue dye to precisely correlate imaging and histology. Results: OFDI of normal airway allowed visualization of epithelium, lamina propria, cartilage, and alveolar attachments. Carcinomas exhibited architectural disarray, loss of normal airway and alveolar structure, and rapid light attenuation. Squamous cell carcinomas showed nested architecture. Atypical glandular formation was appreciated in adenocarcinomas, and uniform trabecular gland formation was seen in salivary gland carcinomas. Mucinous adenocarcinomas showed alveolar wall thickening with intraalveolar mucin. Interstitial fibrosis was visualized as signal-dense tissue, with an interstitial distribution in mild interstitial fibrotic disease and a diffuse subpleural pattern with cystic space formation in usual interstitial pneumonitis. Conclusions: To our knowledge, this study is the first demonstration of volumetric OFDI with precise correlation to histopathology in lung pathology. We anticipate that OFDI may play a role in assessing airway and parenchymal pathology, providing fresh insights into the volumetric features of pulmonary disease. PMID:22459781

Reduction in membrane component of diffusing capacity is associated with the extent of acute pulmonary embolism.

PubMed

Piirilä, Päivi; Laiho, Mia; Mustonen, Pirjo; Graner, Marit; Piilonen, Anneli; Raade, Merja; Sarna, Seppo; Harjola, Veli-Pekka; Sovijärvi, Anssi

2011-05-01

Acute pulmonary embolism (PE) often decreases pulmonary diffusing capacity for carbon monoxide (DL,CO), but data on the mechanisms involved are inconsistent. We wanted to investigate whether reduction in diffusing capacity of alveolo-capillary membrane (DM) and pulmonary capillary blood volume (Vc) is associated with the extent of PE or the presence and severity of right ventricular dysfunction (RVD) induced by PE and how the possible changes are corrected after 7-month follow-up. Forty-seven patients with acute non-massive PE in spiral computed tomography (CT) were included. The extent of PE was assessed by scoring mass of embolism. DL,CO, Vc, DM and alveolar volume (VA) were measured by using a single breath method with carbon monoxide and oxygen both at the acute phase and 7 months later. RVD was evaluated with transthoracic echocardiography and electrocardiogram. Fifteen healthy subjects were included as controls. DL,CO, DL, CO/VA, DM, vital capacity (VC) and VA were significantly lower in the patients with acute PE than in healthy controls (P < 0.001). DM/Vc relation was significantly lower in patients with RVD than in healthy controls (P = 0.004). DM correlated inversely with central mass of embolism (r = -0.312; P = 0.047) whereas Vc did not. DM, DL,CO, VC and VA improved significantly within 7 months. In all patients (P = 0.001, P = 0.001) and persistent RVD (P = 0.020, P = 0.012), DM and DL,CO remained significantly lower than in healthy controls in the follow-up. DM was inversely related to central mass of embolism. Reduction in DM mainly explains the sustained decrease in DL,CO in PE after 7 months despite modern treatment of PE. © 2010 The Authors. Clinical Physiology and Functional Imaging © 2010 Scandinavian Society of Clinical Physiology and Nuclear Medicine.

Kras, Egfr, and Tp53 Mutations in B6C3F1/N Mouse and F344/NTac Rat Alveolar/Bronchiolar Carcinomas Resulting from Chronic Inhalation Exposure to Cobalt Metal

PubMed Central

Hong, Hue-Hua L.; Hoenerhoff, Mark J.; Ton, Thai-Vu; Herbert, Ronald A.; Kissling, Grace E.; Hooth, Michelle J.; Behl, Mamta; Witt, Kristine L.; Smith-Roe, Stephanie L.; Sills, Robert C.; Pandiri, Arun R.

2015-01-01

Rodent lung tumors are morphologically similar to a subtype of human lung adenocarcinomas. The objective of this study was to evaluate Kras, Egfr and Tp53 mutations, which are relevant to human lung cancer, in cobalt metal dust (CMD) induced alveolar/bronchiolar tumors of B6C3F1/N mice and F344/NTac rats. Kras mutations were detected in 67% (mice) and 31% (rats) of CMD-induced lung tumors, and were predominantly exon 1 codon 12 G to T transversions (80% in mice and 57% in rats). Egfr mutations were detected in 17% (both mice and rats) of CMD-induced lung tumors, and were predominantly in exon 20 with 50% G to A transitions (mice and rats). Tp53 mutations were detected in 19% (mice) and 23% (rats) of CMD-induced lung tumors and were predominantly in exon 5 (mice, 69% transversions) and exon 6 (rats, all transitions). No mutations were observed for these genes in spontaneous lung tumors or normal lungs from untreated controls. Ames assays indicated that CMD is mutagenic in the absence but not in the presence of S9 mix. Thus, the mutation data (G to T transversions) and Ames assay results suggest that oxidative damage to DNA may be a contributing factor in CMD-induced pulmonary carcinogenesis in rodents. PMID:26059825

MTOR Suppresses Environmental Particle-Induced Inflammatory Response in Macrophages.

PubMed

Li, Zhouyang; Wu, Yinfang; Chen, Hai-Pin; Zhu, Chen; Dong, Lingling; Wang, Yong; Liu, Huiwen; Xu, Xuchen; Zhou, Jiesen; Wu, Yanping; Li, Wen; Ying, Songmin; Shen, Huahao; Chen, Zhi-Hua

2018-04-15

Increasing toxicological and epidemiological studies have demonstrated that ambient particulate matter (PM) could cause adverse health effects including inflammation in the lung. Alveolar macrophages represent a major type of innate immune responses to foreign substances. However, the detailed mechanisms of inflammatory responses induced by PM exposure in macrophages are still unclear. We observed that coarse PM treatment rapidly activated mechanistic target of rapamycin (MTOR) in mouse alveolar macrophages in vivo, and in cultured mouse bone marrow-derived macrophages, mouse peritoneal macrophages, and RAW264.7 cells. Pharmacological inhibition or genetic knockdown of MTOR in bone marrow-derived macrophages leads to an amplified cytokine production upon PM exposure, and mice with specific knockdown of MTOR or ras homolog enriched in brain in myeloid cells exhibit significantly aggregated airway inflammation. Mechanistically, PM activated MTOR through modulation of ERK, AKT serine/threonine kinase 1, and tuberous sclerosis complex signals, whereas MTOR deficiency further enhanced the PM-induced necroptosis and activation of subsequent NF κ light-chain-enhancer of activated B cells (NFKB) signaling. Inhibition of necroptosis or NFKB pathways significantly ameliorated PM-induced inflammatory response in MTOR-deficient macrophages. The present study thus demonstrates that MTOR serves as an early adaptive signal that suppresses the PM-induced necroptosis, NFKB activation, and inflammatory response in lung macrophages, and suggests that activation of MTOR or inhibition of necroptosis in macrophages may represent novel therapeutic strategies for PM-related airway disorders. Copyright © 2018 by The American Association of Immunologists, Inc.

Role of Complement Activation in a Model of Adult Respiratory Distress Syndrome

PubMed Central

Hosea, Stephen; Brown, Eric; Hammer, Carl; Frank, Michael

1980-01-01

The adult respiratory distress syndrome is characterized by arterial hypoxemia as a result of increased alveolar capillary permeability to serum proteins in the setting of normal capillary hydrostatic pressures. Because bacterial sepsis is prominent among the various diverse conditions associated with altered alveolar capillary permeability, we studied the effect of bacteremia with attendant complement activation on the sequestration of microorganisms and the leakage of albumin in the lungs of guinea pigs. Pneumococci were injected intravenously into guinea pigs and their localization was studied. Unlike normal guinea pigs, complement-depleted guinea pigs did not localize injected bacteria to the lungs. Preopsonization of organisms did not correct this defect in pulmonary localization of bacteria in complement-depleted animals, suggesting that a fluid-phase component of complement activation was required. Genetically C5-deficient mice showed no pulmonary localization of bacteria. C5-sufficient mice demonstrated the usual pulmonary localization, thus further suggesting that the activation of C5 might be important in this localization. The infusion of activated C5 increased alveolar capillary permeability to serum proteins as assayed by the amount of radioactive albumin sequestered in the lung. Neutropenic animals did not develop altered capillary permeability after challenge with activated C5. Thus, complement activation through C5, in the presence of neutrophils, induces alterations in pulmonary alveolar capillary permeability and causes localization of bacteria to the pulmonary parenchyma. Complement activation in other disease states could potentially result in similar clinical manifestations. PMID:7400321

Perivascular fluid cuffs decrease lung compliance by increasing tissue resistance.

PubMed

Lowe, Kevin; Alvarez, Diego F; King, Judy A; Stevens, Troy

2010-06-01

Lung inflammation causes perivascular fluid cuffs to form around extra-alveolar blood vessels; however, the physiologic consequences of such cuffs remain poorly understood. Herein, we tested the hypothesis that perivascular fluid cuffs, without concomitant alveolar edema, are sufficient to decrease lung compliance. Prospective, randomized, controlled study. Research laboratory. One hundred twenty male CD40 rats. To test this hypothesis, the plant alkaloid thapsigargin was used to activate store-operated calcium entry and increase cytosolic calcium in endothelium. Thapsigargin was infused into a central venous catheter of intact, sedated, and mechanically ventilated rats. Static and dynamic lung mechanics and hemodynamics were measured continuously. Thapsigargin produced perivascular fluid cuffs along extra-alveolar vessels but did not cause alveolar flooding or blood gas abnormalities. Lung compliance dose-dependently decreased after thapsigargin infusion, attributable to an increase in tissue resistance that was attributed to increased tissue damping and tissue elastance. Airway resistance was not changed. Neither central venous pressure nor left ventricular end diastolic pressure was altered by thapsigargin. Heart rate did not change, although thapsigargin decreased left ventricular systolic function sufficient to reduce cardiac output by 50%. Infusion of the type 4 phosphodiesterase inhibitor, rolipram, prevented thapsigargin from inducing perivascular cuffs and decreasing lung compliance. Rolipram also normalized pressure over time and corrected the deficit in cardiac output. Our findings resolve for the first time that perivascular cuff formation negatively impacts mechanical coupling between the bronchovascular bundle and the lung parenchyma, decreasing lung compliance without impacting central venous pressure.

TALEN-mediated functional correction of human iPSC-derived macrophages in context of hereditary pulmonary alveolar proteinosis.

PubMed

Kuhn, Alexandra; Ackermann, Mania; Mussolino, Claudio; Cathomen, Toni; Lachmann, Nico; Moritz, Thomas

2017-11-09

Hereditary pulmonary alveolar proteinosis (herPAP) constitutes a rare, life threatening lung disease characterized by the inability of alveolar macrophages to clear the alveolar airspaces from surfactant phospholipids. On a molecular level, the disorder is defined by a defect in the CSF2RA gene coding for the GM-CSF receptor alpha-chain (CD116). As therapeutic options are limited, we currently pursue a cell and gene therapy approach aiming for the intrapulmonary transplantation of gene-corrected macrophages derived from herPAP-specific induced pluripotent stem cells (herPAP-iPSC) employing transcriptional activator-like effector nucleases (TALENs). Targeted insertion of a codon-optimized CSF2RA-cDNA driven by the hybrid cytomegalovirus (CMV) early enhancer/chicken beta actin (CAG) promoter into the AAVS1 locus resulted in robust expression of the CSF2RA gene in gene-edited herPAP-iPSCs as well as thereof derived macrophages. These macrophages displayed typical morphology, surface phenotype, phagocytic and secretory activity, as well as functional CSF2RA expression verified by STAT5 phosphorylation and GM-CSF uptake studies. Thus, our study provides a proof-of-concept, that TALEN-mediated integration of the CSF2RA gene into the AAVS1 safe harbor locus in patient-specific iPSCs represents an efficient strategy to generate functionally corrected monocytes/macrophages, which in the future may serve as a source for an autologous cell-based gene therapy for the treatment of herPAP.

Absence of lung fibrosis after a single pulmonary delivery of lipid nanocapsules in rats.

PubMed

Hureaux, José; Lacoeuille, Franck; Lagarce, Frédéric; Rousselet, Marie-Christine; Contini, Aurélien; Saulnier, Patrick; Benoit, Jean-Pierre; Urban, Thierry

2017-01-01

Lipid nanocapsules (LNCs) are potential drug carriers for pulmonary delivery since they can be nebulized without any structural or functional changes, and the aerosols produced are highly compatible with pulmonary drug delivery in human beings. The alveolar surface tension, in vitro cytotoxicity, biodistribution and pulmonary toxicity in rats of a single endotracheal spray of LNCs or paclitaxel-loaded LNCs were studied. In vitro cytotoxicity of LNCs after a spray remained unchanged. Biodistribution study showed a homogeneous repartition in the lungs in rats with an improvement in lung retention of the radiolabeled tracer loaded in LNCs compared to the absence of LNCs with a lung half-time of 8.8±0.7 hours. Bronchoalveolar fluid analysis revealed transient 7-day alveolar inflammation, reaching a maximum between days 2 and 4, characterized by a peak of granulocytes at day 1 followed by a peak of lymphocytes at day 3. Alveolar protein levels were increased at days 3 and 7. Acute inflammation was increased with paclitaxel-loaded LNCs in comparison with blank LNCs but dropped out at day 7. No histological pulmonary lesion was observed at day 60. LNCs lowered surface tension to a greater degree than Curosurf ® in a physicochemical model of the pulmonary alveolus. A single pulmonary delivery of LNCs induces a short-term alveolar inflammation with no residual lesions in rats at day 60. These data permit to start the study of LNCs in surfactant replacement therapy.

Alveolar ridge reduction after tooth extraction in adolescents: an animal study

PubMed Central

Sun, Zongyang; Herring, Susan W.; Tee, Boon Ching; Gales, Jordan

2013-01-01

Objective The mechanism for tooth extraction induced residual alveolar ridge reduction (RRR) during adolescence is poorly understood. This study investigated the alveolar bone morphology, growth, resorption and functional loading at normal and extraction sites using an adolescent pig model. Design Sixteen 3-month-old pigs were divided into two groups – immediate post-extraction (IE) and 6-week post-extraction (SE). The IE group received an extraction of one deciduous mandibular molar, immediately followed by a final experiment to record masseter muscle EMGs and strains from the buccal surface of the extraction and contralateral non-extraction sites during function (mastication). The SE group was given the same tooth extraction, then kept for 6 weeks before the same final functional recording as the IE group. Both groups also received baseline (pre-extraction) EMGs and fluorescent vital stains 10 and 3 days before the final functional recording. Immediately after the final functional recording, animals were euthanized and alveolar bone specimens from extraction and contralateral non-extraction sites were collected and used to analyze alveolar bone morphology, apposition and resorption based on fluorescent and hematoxylin and eosin stained histological sections. Results At control sites (IE-extraction, IE-non-extraction and SE-non-extraction), the alveolar ridges grew gingivally and buccally. Bone formation characterized the buccal surface and lingual bundle bone, whereas resorption characterized the lingual surface and buccal bundle bone. The SE-extraction sites showed three major alterations: convergence of the buccal and lingual gingival crests, loss of apposition on the lingual bundle bone, and decelerated growth at the entire buccal surface. These alterations likely resulted from redirected crestal growth as part of the socket healing process, loss of tongue pressure to the lingual side of the teeth which normally provides mechanical stimulation for dental arch expansion, and masticatory underloading during the initial post-extraction period, respectively. Conclusions These data indicate that the initial phase of RRR in adolescents is a product of modified growth, not resorption, possibly because of decreased mechanical stimulation at the extraction site. PMID:23380583

Experiment K-7-28: Lung Morphology Study

NASA Technical Reports Server (NTRS)

West, J. B.; Elliott, A. R.; Mathieu-Costello, O.; Kaplansky, A. S.

1994-01-01

There are no previous studies investigating the effect of microgravity exposure during spaceflight on lung tissue. We examined the ultrastructure of the left lungs of 5 Czechoslovakian Wistar rats flown on the 13 day, 19+ hr. Cosmos 2044 mission, and compared them to 5 vivarium and 5 synchronous controls at 1-g conditions, and 5 rats exposed to 14 days of tail-suspension. Within 10 minutes of sacrifice by decapitation, the lungs were removed and immersed in 3% glutaraldehyde in 0.1M phosphate buffer (total osmolarity of the fixative: 560 mOsm; pH = 7.4). The tissue stored at 5 C was transported to our laboratory where it was processed for light and electron microscopy. No significant perivascular cuffing caused by interstitial edema was present in the tissue samples. Some of the flight, tail-suspended, and synchronous control rats showed alveolar edema, while vivarium controls did not. The pulmonary capillaries appeared to be more congested in the flight animals than in the other groups. This could be related to the increased hematocrit due to the microgravity exposure. In all 5 flight, 4 tail-suspended, and 3 synchronous rats, red blood cells (RBC) were present in the alveolar spaces. The RBC were either suspended free in the alveoli or observed lining the alveolar wall. The frequency of RBC lining the alveolar walls appeared greater in the dorsal (gravity non-dependent) than in ventral (gravity dependent) regions of the lung in these three animal groups. In 3 of the vivarium controls, a few RBC were found in the alveolar spaces. Intra-capillary fluid-filled vesicles were observed in the flight, tail-suspended and synchronous animals, but not in the vivarium controls. The formation of intra-capillary fluid-filled vesicles has been previously associated with pulmonary hypertension induced by high altitude exposure and mitral stenosis. In conclusion, pulmonary hemorrhage and alveolar edema of unknown origin occurred to a greater extent in the flight, tail-suspended, and synchronous control animals, and in the dorsal regions of the lung when compared to the vivarium controls. The etiology of these changes, which are possibly due to an increase in pulmonary vascular pressure, requires further investigation.

LPS-induced expression of CD14 in the TRIF pathway is epigenetically regulated by sulforaphane in porcine pulmonary alveolar macrophages.

PubMed

Yang, Qin; Pröll, Maren J; Salilew-Wondim, Dessie; Zhang, Rui; Tesfaye, Dawit; Fan, Huitao; Cinar, Mehmet U; Große-Brinkhaus, Christine; Tholen, Ernst; Islam, Mohammad A; Hölker, Michael; Schellander, Karl; Uddin, Muhammad J; Neuhoff, Christiane

2016-11-01

Pulmonary alveolar macrophages (AMs) are important in defense against bacterial lung inflammation. Cluster of differentiation 14 (CD14) is involved in recognizing bacterial lipopolysaccharide (LPS) through MyD88-dependent and TRIF pathways of innate immunity. Sulforaphane (SFN) shows anti-inflammatory activity and suppresses DNA methylation. To identify CD14 epigenetic changes by SFN in the LPS-induced TRIF pathway, an AMs model was investigated in vitro. CD14 gene expression was induced by 5 µg/ml LPS at the time point of 12 h and suppressed by 5 µM SFN. After 12 h of LPS stimulation, gene expression was significantly up-regulated, including TRIF, TRAF6, NF-κB, TRAF3, IRF7, TNF-α, IL-1β, IL-6, and IFN-β. LPS-induced TRAM, TRIF, RIPK1, TRAF3, TNF-α, IL-1β and IFN-β were suppressed by 5 µM SFN. Similarly, DNMT3a expression was increased by LPS but significantly down-regulated by 5 µM SFN. It showed positive correlation of CD14 gene body methylation with in LPS-stimulated AMs, and this methylation status was inhibited by SFN. This study suggests that SFN suppresses CD14 activation in bacterial inflammation through epigenetic regulation of CD14 gene body methylation associated with DNMT3a. The results provide insights into SFN-mediated epigenetic down-regulation of CD14 in LPS-induced TRIF pathway inflammation and may lead to new methods for controlling LPS-induced inflammation in pigs.

Pharmacokinetics and metabolism of all-trans- and 13-cis-retinoic acid in pulmonary emphysema patients.

PubMed

Muindi, Josephia R; Roth, Michael D; Wise, Robert A; Connett, John E; O'Connor, George T; Ramsdell, Joe W; Schluger, Neil W; Romkes, Marjorie; Branch, Robert A; Sciurba, Frank C

2008-01-01

Retinoids promote lung alveolarization in animal models and were administered to patients as part of the Feasibility of Retinoid Therapy for Emphysema (FORTE) study. This FORTE substudy investigated the pharmacokinetic profiles of 2 retinoic acid isomers-all-trans-retinoic acid (ATRA) and 13-cis-retinoic acid (13-cRA)-in subjects with emphysema, evaluated strategies to overcome self-induced ATRA catabolism, and identified pharmacodynamic relationships. Comprehensive and limited pharmacokinetics were obtained at multiple visits in emphysema subjects treated with placebo (n = 30), intermittent dosing (4 days/week) with low-dose ATRA (1 mg/kg/day, n = 21), or high-dose ATRA (2 mg/kg/day, n = 25) or daily administration of 13-cRA (1 mg/kg/day, n = 40). High-dose ATRA produced the highest peak plasma ATRA Cmax. However, at follow-up, plasma ATRA C(max) was significantly decreased from baseline in subjects whose day 1 levels exceeded 100 ng/mL (P < .0001). In contrast, administration of 13-cRA produced lower plasma ATRA C(max) (<100 ng/mL), but the levels were significantly higher at follow-up than those on day 1 (P < .001). Plasma ATRA levels as determined on day 1 correlated with changes in pulmonary diffusing capacity at 6 months, consistent with concentration-dependent biologic effects (r2 = -0.25). The authors conclude that intermittent therapy with high-dose ATRA produced the greatest ATRA exposure, but alternative approaches for limiting self-induced ATRA catabolism should be sought.

Non-Invasive Detection of Lung Inflammation by Near-Infrared Fluorescence Imaging Using Bimodal Liposomes.

PubMed

Desu, Hari R; Wood, George C; Thoma, Laura A

2016-01-01

Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome results in respiratory obstruction and severe lung inflammation. Critical characteristics of ALI are alveolar edema, infiltration of leukocytes (neutrophils and monocytes), release of pro-inflammatory cytokines and chemokines into broncho-alveolar lavage fluid, and activation of integrin receptors. The purpose of the study was to demonstrate non-invasive detection of lung inflammation using integrin receptor targeted fluorescence liposomes. An inflammation similar to that observed in ALI was elicited in rodents by intra-tracheal instillation of interleukin-1beta (IL-1beta). Cyclic arginine glycine-(D)-aspartic acid-peptide (cRGD-peptide) grafted fluorescence liposomes were administered to ALI induced male Sprague-Dawley rats for targeting lung integrin receptors. Near-infrared fluorescence imaging (NIRFI) was applied for visualization and quantitation of lung inflammation. NIRFI signals were correlated with inflammatory cellular and biochemical markers of lungs. A positive correlation was observed between NIRF signals and lung inflammation markers. Compared to control group, an intense NIRF signal was observed in ALI induced rats in the window 6-24 h post-IL-1beta instillation. Interaction of integrin receptors with targeted liposomes was assumed to contribute to intense NIRF signal. RT-PCR studies showed an elevated lung expression of alphavbeta5 integrin receptors, 12 h post-IL-1beta instillation. In vitro studies demonstrated integrin receptor specificity of targeted liposomes. These targeted liposomes showed binding to alphavbeta5 integrin receptors expressed on alveolar cells. Non-invasive detection of lung inflammation was demonstrated using a combination of integrin receptor targeting and NIRFI.

Jamming dynamics of stretch-induced surfactant release by alveolar type II cells

PubMed Central

Majumdar, Arnab; Arold, Stephen P.; Bartolák-Suki, Erzsébet; Parameswaran, Harikrishnan

2012-01-01

Secretion of pulmonary surfactant by alveolar epithelial type II cells is vital for the reduction of interfacial surface tension, thus preventing lung collapse. To study secretion dynamics, rat alveolar epithelial type II cells were cultured on elastic membranes and cyclically stretched. The amounts of phosphatidylcholine, the primary lipid component of surfactant, inside and outside the cells, were measured using radiolabeled choline. During and immediately after stretch, cells secreted less surfactant than unstretched cells; however, stretched cells secreted significantly more surfactant than unstretched cells after an extended lag period. We developed a model based on the hypothesis that stretching leads to jamming of surfactant traffic escaping the cell, similar to vehicular traffic jams. In the model, stretch increases surfactant transport from the interior to the exterior of the cell. This transport is mediated by a surface layer with a finite capacity due to the limited number of fusion pores through which secretion occurs. When the amount of surfactant in the surface layer approaches this capacity, interference among lamellar bodies carrying surfactant reduces the rate of secretion, effectively creating a jam. When the stretch stops, the jam takes an extended time to clear, and subsequently the amount of secreted surfactant increases. We solved the model analytically and show that its dynamics are consistent with experimental observations, implying that surfactant secretion is a fundamentally nonlinear process with memory representing collective behavior at the level of single cells. Our results thus highlight the importance of a jamming dynamics in stretch-induced cellular secretory processes. PMID:22033531

Ventilation-induced release of phosphatidylcholine from neonatal-rat lungs in vitro.

PubMed Central

Nijjar, M S

1984-01-01

Factors regulating the release of phosphatidylcholine (PC) from neonatal-rat lungs were investigated. The results show that the release of prelabelled PC from the newborn-rat lung was augmented by air ventilation at the onset of breathing. This response was mimicked in lungs of pups delivered 1 day before term and allowed to breathe for different time intervals. Anoxia further augmented the ventilation-enhanced PC release from the newborn-rat lungs. The ventilation-induced release of PC was not abolished by the prior treatment of pups in utero or mothers in vivo with phenoxybenzamine, propranolol or atropine, suggesting the lack of receptor stimulation in the ventilation-enhanced PC release at birth. The results also show that ventilation stimulated [methyl-14C]choline incorporation into lung PC, presumably to replenish the depleted surfactant stores. The ratio of adenylate cyclase/cyclic AMP phosphodiesterase activities, which reflects cyclic AMP levels in the developing rat lungs, did not change during the 120 min of air ventilation when the release of PC was much enhanced, implying that cyclic AMP may not be involved. This confirms our conclusion that stimulation of beta-adrenergic receptor was not involved in the air-ventilation-enhanced release of PC. Since the cell number or size did not change during 120 min of ventilation when the alveolar-cell surface was maximally distended, it is suggested that distension of alveolar wall by air ventilation at the onset of breathing may bring the lamellar bodies containing surfactant close to the luminal surface of alveolar type II cells, thereby enhancing their fusion and extrusion by exocytosis. PMID:6477485

Mangiferin ameliorates Porphyromonas gingivalis-induced experimental periodontitis by inhibiting phosphorylation of nuclear factor-κB and Janus kinase 1-signal transducer and activator of transcription signaling pathways.

PubMed

Li, H; Wang, Q; Ding, Y; Bao, C; Li, W

2017-02-01

Mangiferin is a natural polyphenol compound with anti-inflammatory properties. However, there have been few reports on the effect of mangiferin on periodontitis. Here, we investigated the anti-inflammatory effects of this compound on experimental periodontitis and the underlying mechanisms. Mice were inoculated with Porphyromonas gingivalis to induce periodontitis, and treated with mangiferin orally (50 mg/kg bodyweight, once a day) for 8 wk. Then, the alveolar bone loss was examined using a scanning electronic microscope. Expression of tumor necrosis factor-α (TNF-α) and the phosphorylation levels of nuclear factor-κB (NF-κB) and Janus kinase 1-signal transducer and activator of adhesion (JAK1-STAT) pathways in the gingival epithelium were detected using western blot analysis and immunohistochemical staining. The results showed that mice with periodontitis exhibited greater alveolar bone loss, stronger expression of TNF-α and higher phosphorylation levels of NF-κB and JAK1-STAT1/3 pathways in gingival epithelia, compared with control mice with no periodontitis. Moreover, treatment with mangiferin could significantly inhibit alveolar bone loss, TNF-α production and phosphorylation of NF-κB and JAK1-STAT1/3 pathways in gingival epithelia. Mangiferin has anti-inflammatory effects on periodontitis, which is associated with its ability to down-regulate the phosphorylation of NF-κB and JAK1-STAT1/3 pathways in gingival epithelia. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Is there a relation between local bone quality as assessed on panoramic radiographs and alveolar bone level?

PubMed

Nackaerts, Olivia; Gijbels, Frieda; Sanna, Anna-Maria; Jacobs, Reinhilde

2008-03-01

The aim was to explore the relation between radiographic bone quality on panoramic radiographs and relative alveolar bone level. Digital panoramic radiographs of 94 female patients were analysed (mean age, 44.5; range, 35-74). Radiographic density of the alveolar bone in the premolar region was determined using Agfa Musica software. Alveolar bone level and bone quality index (BQI) were also assessed. Relationships between bone density and BQI on one hand and the relative loss of alveolar bone level on the other were assessed. Mandibular bone density and loss of alveolar bone level were weakly but significantly negatively correlated for the lower premolar area (r = -.27). The BQI did not show a statistically significant relation to alveolar bone level. Radiographic mandibular bone density on panoramic radiographs shows a weak but significant relation to alveolar bone level, with more periodontal breakdown for less dense alveolar bone.

Listener Perception of Respiratory-Induced Voice Tremor

ERIC Educational Resources Information Center

Farinella, Kimberly A.; Hixon, Thomas J.; Hoit, Jeannette D.; Story, Brad H.; Jones, Patricia A.

2006-01-01

Purpose: The purpose of this study was to determine the relation of respiratory oscillation to the perception of voice tremor. Method: Forced oscillation of the respiratory system was used to simulate variations in alveolar pressure such as are characteristic of voice tremor of respiratory origin. Five healthy men served as speakers, and 6…

ADHESION AND POLLUTION PARTICLE-INDUCED OXIDANT GENERATION IS NEITHER NECESSARY NOR SUFFICIENT FOR CYTOKINE INDUCTION IN HUMAN ALVEOLAR MACROPHAGES

EPA Science Inventory

Adhesion of human monocytes (MOs) results in the rapid transcriptional activation of cytokine genes that are dependent on nuclear factor (NF)-kappaB. Several pathways leading to activation of NF-kappaB have been described, including those involving reactive oxygen intermediates (...

SEASONAL VARIATIONS IN AIR POLLUTION PARTICLE-INDUCED INFLAMMATORY MEDIATOR RELEASE AND OXIDATIVE STRESS

EPA Science Inventory

Normal human bronchial epithelial (NHBE) cells and alveolar macrophages (AMs) were exposed to equal mass of coarse [PM with aerodynamic diameter of 2.510 �m (PM2.510)], fine (PM2.5), and ultrafine (PM < 0.1) ambient PM from Chapel Hill, North Carolina, during October 2001 (f...

COMPARISON OF METAL-INDUCED ALVEOLAR EPITHELIAL INJURY AND CHEMOKINE PRODUCTION DURING PRE,-SIMULTANEOUS, OR CONTINUED EXPOSURE TO TNFA, IL-1B, AND IFNY

EPA Science Inventory

Epidemiological studies have linked air pollution exposure to adverse respiratory health effects, especially in individuals with inflammatory airways disease. Symptomatic asthmatics appear to be at greatest risk. We previously demonstrated that exposure of rats to particulate...

Susceptibility of inflamed ariway and alveolar epithelial cells to injury induced by diesel exhaust particles of varying organic carbon content

EPA Science Inventory

Exposure to traffic-related ambient air pollution, such as diesel exhaust particles (DEP), is associated with adverse health outcomes, especially in individuals with preexisting inflammatory respiratory diseases. Using an analogous in vitro system to model both the healthy and a...

Expression of cathelicidin LL-37 during Mycobacterium tuberculosis infection in human alveolar macrophages, monocytes, neutrophils, and epithelial cells.

PubMed

Rivas-Santiago, Bruno; Hernandez-Pando, Rogelio; Carranza, Claudia; Juarez, Esmeralda; Contreras, Juan Leon; Aguilar-Leon, Diana; Torres, Martha; Sada, Eduardo

2008-03-01

The innate immune response in human tuberculosis is not completely understood. To improve our knowledge regarding the role of cathelicidin hCAP-18/LL37 in the innate immune response to tuberculosis infection, we used immunohistochemistry, immunoelectron microscopy, and gene expression to study the induction and production of the antimicrobial peptide in A549 epithelial cells, alveolar macrophages (AM), neutrophils, and monocyte-derived macrophages (MDM) after infection with Mycobacterium tuberculosis. We demonstrated that mycobacterial infection induced the expression and production of LL-37 in all cells studied, with AM being the most efficient. We did not detect peptide expression in tuberculous granulomas, suggesting that LL-37 participates only during early infection. Through the study of Toll-like receptors (TLR) in MDM, we showed that LL-37 can be induced by stimulation through TLR-2, TLR-4, and TLR-9. This last TLR was strongly stimulated by M. tuberculosis DNA. We concluded that LL-37 may have an important role in the innate immune response against M. tuberculosis.

Expression of Cathelicidin LL-37 during Mycobacterium tuberculosis Infection in Human Alveolar Macrophages, Monocytes, Neutrophils, and Epithelial Cells▿

PubMed Central

Rivas-Santiago, Bruno; Hernandez-Pando, Rogelio; Carranza, Claudia; Juarez, Esmeralda; Contreras, Juan Leon; Aguilar-Leon, Diana; Torres, Martha; Sada, Eduardo

2008-01-01

The innate immune response in human tuberculosis is not completely understood. To improve our knowledge regarding the role of cathelicidin hCAP-18/LL37 in the innate immune response to tuberculosis infection, we used immunohistochemistry, immunoelectron microscopy, and gene expression to study the induction and production of the antimicrobial peptide in A549 epithelial cells, alveolar macrophages (AM), neutrophils, and monocyte-derived macrophages (MDM) after infection with Mycobacterium tuberculosis. We demonstrated that mycobacterial infection induced the expression and production of LL-37 in all cells studied, with AM being the most efficient. We did not detect peptide expression in tuberculous granulomas, suggesting that LL-37 participates only during early infection. Through the study of Toll-like receptors (TLR) in MDM, we showed that LL-37 can be induced by stimulation through TLR-2, TLR-4, and TLR-9. This last TLR was strongly stimulated by M. tuberculosis DNA. We concluded that LL-37 may have an important role in the innate immune response against M. tuberculosis. PMID:18160480

Effects of intraperitoneal and intranasal application of Lentinan on cellular response in rats.

PubMed

Markova, Nadya; Kussovski, Vesselin; Radoucheva, Tatyana; Dilova, Krasimira; Georgieva, Neli

2002-11-01

Lentinan (Ajinomoto, Japan) was administrated intraperitoneally (i.p.) and intranasally (i.n.) at different doses (1, 5 and 10 mg/kg) to rats. Effectiveness of Lentinan treatment was evaluated by comparative testing of cell activation (establishing the number, glycolytic and acid phosphatase activity, H2O2 production and killing ability against Salmonella enteritidis and Staphylococcus aureus) at two different compartments--peritoneal and broncho-alveolar cavities. The results indicated that Lentinan induced high-grade activation of peritoneal cells (PCs) and especially of broncho-alveolar cells (BACs) with markedly enhanced effector function (killing ability against S. aureus). Generally, Lentinan, known usually with its parenteral routes of application, can be successful to stimulate the host cell response in the respiratory tract by intranasal route of administration.

Diffuse alveolar hemorrhage: retrospective review of clinical outcome in allogeneic transplant recipients treated with aminocaproic acid.

PubMed

Wanko, Sam O; Broadwater, Gloria; Folz, Rodney J; Chao, Nelson J

2006-09-01

Diffuse alveolar hemorrhage (DAH) after allogeneic hematopoietic stem cell transplantation (HSCT) is often fatal. Standard therapy with high-dose corticosteroid is not always effective. There is paucity of data in the literature about other potentially useful agents, such as aminocaproic acid (Amicar) in the post-transplantation setting. We retrospectively reviewed our data on 115 consecutive patients who underwent HSCT and had pulmonary complications, with the aim of determining the overall clinical outcome in recipients of allogeneic transplants and in the subgroup of these patients who were treated with concomitant Solu-Medrol and aminocaproic acid. Aminocaproic acid was added at the discretion of the attending physician. We identified 14 allogeneic transplant recipients (median age, 41 years) with 15 episodes of DAH who were treated with Solu-Medrol (250 mg to 1 g intravenously per day). Of these, 8 patients also received concomitant aminocaproic acid at 1000 mg intravenously every 6 hours. Failure to improve was the most common reason for adding aminocaproic acid. The incidence of DAH was 12.2% (10.3% in myeloablative versus 1.9% in nonmyeloablative recipients). The overall 100-day DAH mortality and median transplantation survival were 60% and 99 days, respectively. Among the subset of patients treated with the combination of Solu-Medrol and aminocaproic acid, we observed a 100-day DAH mortality and median transplantation survival of 44% and 167 days, respectively, compared with 83% and 96.5 days in those treated with Solu-Medrol alone. The median time to DAH was 40.5 days, and the median time to death was 53 days in the combined treatment group compared with 29.5 days in those treated with steroid alone. There were no significant differences in coagulation parameters between subsets. Infections (yeast, respiratory syncytial virus, herpes simplex virus, and parainfluenza) were isolated and treated from 6 diagnostic bronchial alveolar lavage samples and were more common in the subgroup treated with Solu-Medrol only. Respiratory failure was the documented cause of death in 89% of patients. There were no clinically significant side effects from aminocaproic acid. Although these historically lower DAH outcomes are intriguing, prospective studies are needed to confirm the role of aminocaproic acid in DAH occurring in the allogeneic transplantation setting.

Morphological study of tooth development in podoplanin-deficient mice.

PubMed

Takara, Kenyo; Maruo, Naoki; Oka, Kyoko; Kaji, Chiaki; Hatakeyama, Yuji; Sawa, Naruhiko; Kato, Yukinari; Yamashita, Junro; Kojima, Hiroshi; Sawa, Yoshihiko

2017-01-01

Podoplanin is a mucin-type highly O-glycosylated glycoprotein identified in several somatyic cells: podocytes, alveolar epithelial cells, lymphatic endothelial cells, lymph node stromal fibroblastic reticular cells, osteocytes, odontoblasts, mesothelial cells, glia cells, and others. It has been reported that podoplanin-RhoA interaction induces cytoskeleton relaxation and cell process stretching in fibroblastic cells and osteocytes, and that podoplanin plays a critical role in type I alveolar cell differentiation. It appears that podoplanin plays a number of different roles in contributing to cell functioning and growth by signaling. However, little is known about the functions of podoplanin in the somatic cells of the adult organism because an absence of podoplanin is lethal at birth by the respiratory failure. In this report, we investigated the tooth germ development in podoplanin-knockout mice, and the dentin formation in podoplanin-conditional knockout mice having neural crest-derived cells with deficiency in podoplanin by the Wnt1 promoter and enhancer-driven Cre recombinase: Wnt1-Cre;PdpnΔ/Δmice. In the Wnt1-Cre;PdpnΔ/Δmice, the tooth and alveolar bone showed no morphological abnormalities and grow normally, indicating that podoplanin is not critical in the development of the tooth and bone.

Effects of repeated cycles of starvation and refeeding on lungs of growing rats.

PubMed

Sahebjami, H; Domino, M

1992-12-01

Adult male rats were subjected to four cycles of mild starvation (2 wk) and refeeding (1 wk) and were compared with a fed group. Starvation was induced by giving rats one-third of their measured daily food consumption. During each starvation cycle, rats lost approximately 20% of their body weight. Despite catch-up growth and overall weight gain, starved rats had lower final body weight than fed rats. Lung dry weight and lung volumes were also reduced in the starved group. The mechanical properties of air- and saline-filled lungs did not change significantly with repeated cycles of starvation. Mean linear intercept was similar in the two groups, but alveolar surface area was reduced in the starved rats. Total content of crude connective tissue and concentration per lung dry weight of hydroxyproline and crude connective tissue were reduced in starved rats. We conclude that lung growth is retarded in growing rats subjected to repeated cycles of mild starvation and refeeding, as manifested by smaller lung volume and reduced alveolar surface area. Because alveolar size is unchanged, a reduced number of alveoli is most likely responsible for decreased lung volumes.

CUX1/Wnt signaling regulates Epithelial Mesenchymal Transition in EBV infected epithelial cells

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

Malizia, Andrea P.; Lacey, Noreen; Walls, Dermot

Idiopathic pulmonary fibrosis (IPF) is a refractory and lethal interstitial lung disease characterized by alveolar epithelial cells apoptosis, fibroblast proliferation and extra-cellular matrix protein deposition. EBV, localised to alveolar epithelial cells of pulmonary fibrosis patients is associated with a poor prognosis. A strategy based on microarray-differential gene expression analysis to identify molecular drivers of EBV-associated lung fibrosis was utilized. Alveolar epithelial cells were infected with EBV to identify genes whose expression was altered following TGF{beta}1-mediated lytic phase. EBV lytic reactivation by TGF{beta}1 drives a selective alteration in CUX1 variant (a) (NCBI accession number NM{sub 1}81552) expression, inducing activation of non-canonicalmore » Wnt pathway mediators, implicating it in Epithelial Mesenchymal Transition (EMT), the molecular event underpinning scar production in tissue fibrosis. The role of EBV in EMT can be attenuated by antiviral strategies and inhibition of Wnt signaling by using All-Trans Retinoic Acids (ATRA). Activation of non-canonical Wnt signaling pathway by EBV in epithelial cells suggests a novel mechanism of EMT via CUX1 signaling. These data present a framework for further description of the link between infectious agents and fibrosis, a significant disease burden.« less

Alveolar macrophages have a dual role in a rat model for trimellitic anhydride-induced occupational asthma

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

Valstar, Dingena L.; Schijf, Marcel A.; Nijkamp, Frans P.

2006-02-15

Occupational exposure to low molecular weight chemicals, like trimellitic anhydride (TMA), can result in occupational asthma. Alveolar macrophages (AMs) are among the first cells to encounter inhaled compounds. These cells can produce many different mediators that have a putative role in asthma. In this study, we examined the role of AMs in lung function and airway inflammation of rats exposed to TMA. Female Brown Norway rats were sensitized by dermal application of TMA or received vehicle alone on days 0 and 7. One day before challenge, rats received intratracheally either empty or clodronate-containing liposomes to deplete the lungs of AMs.more » On day 21, all rats were challenged by inhalation of TMA in air. Lung function parameters were measured before, during, within 1 h after, and 24 h after challenge. IgE levels and parameters of inflammation and tissue damage were assessed 24 h after challenge. Sensitization with TMA led to decreased lung function parameters during and within 1 h after challenge as compared to non-sensitized rats. AM depletion alleviated the TMA-induced drop in lung function parameters and induced a faster recovery compared to sham-depleted TMA-sensitized rats. It also decreased the levels of serum IgE 24 h after challenge, but did not affect the sensitization-dependent increase in lung lavage fluid IL-6 and tissue TNF-{alpha} levels. In contrast, AM depletion augmented the TMA-induced tissue damage and inflammation 24 h after challenge. AMs seem to have a dual role in this model for TMA-induced occupational asthma since they potentiate the immediate TMA-induced decrease in lung function but tended to dampen the TMA-induced inflammatory reaction 24 h later.« less

Survival predictor in patients with acute respiratory distress syndrome and diffuse alveolar damage undergoing open lung biopsy

PubMed Central

Chang, Chih-Hao; Hung, Chen-Yiu; Chiu, Li-Chung; Huang, Chung-Chi; Hu, Han-Chung

2017-01-01

Background Diffuse alveolar damage (DAD) is a typical pathological finding of open lung biopsies in patients with acute respiratory distress syndrome (ARDS). Patients with ARDS and DAD have been reported to have a poorer prognosis than those without DAD. The aim of this study was to investigate the survival predictors in patients with ARDS and DAD. Methods We retrospectively reviewed all ARDS patients who underwent an open lung biopsy which showed evidence of DAD from January 2006 to June 2015 at Chang Gung Memorial Hospital. Clinical data including baseline characteristics, medication, and survival outcomes were analyzed. Results A total of 64 ARDS patients with DAD were eligible for analysis and divided into known etiology (n = 17, 26.6%) and unknown etiology groups (n = 47, 73.4%). There was no significant difference in hospital mortality rate between the two groups (71.9% vs. 70.6%, p = 0.890). Univariate logistic regression analysis revealed that sequential organ failure assessment (SOFA) score at the time of a diagnosis of ARDS, and SOFA score, PaO2/FiO2 ratio, and positive end expiratory pressure level when the biopsy was performed were associated with hospital mortality. Multivariate analysis showed that the SOFA score on the day of the biopsy was an independent predictor of hospital mortality (odds ratio 1.413, 95% confidence interval 1.127–1.772; p = 0.03). There were no significant differences in the use, dose, duration and timing from ARDS to glucocorticoid therapy between the survivors and nonsurvivors. Conclusion For selected ARDS patients who underwent an open lung biopsy with pathological DAD, SOFA score was an independent predictor of hospital mortality. PMID:28678876

CXCR3 ligands are associated with the continuum of diffuse alveolar damage to chronic lung allograft dysfunction.

PubMed

Shino, Michael Y; Weigt, S Samuel; Li, Ning; Palchevskiy, Vyacheslav; Derhovanessian, Ariss; Saggar, Rajan; Sayah, David M; Gregson, Aric L; Fishbein, Michael C; Ardehali, Abbas; Ross, David J; Lynch, Joseph P; Elashoff, Robert M; Belperio, John A

2013-11-01

After lung transplantation, insults to the allograft generally result in one of four histopathologic patterns of injury: (1) acute rejection, (2) lymphocytic bronchiolitis, (3) organizing pneumonia, and (4) diffuse alveolar damage (DAD). We hypothesized that DAD, the most severe form of acute lung injury, would lead to the highest risk of chronic lung allograft dysfunction (CLAD) and that a type I immune response would mediate this process. Determine whether DAD is associated with CLAD and explore the potential role of CXCR3/ligand biology. Transbronchial biopsies from all lung transplant recipients were reviewed. The association between the four injury patterns and subsequent outcomes were evaluated using proportional hazards models with time-dependent covariates. Bronchoalveolar lavage (BAL) concentrations of the CXCR3 ligands (CXCL9/MIG, CXCL10/IP10, and CXCL11/ITAC) were compared between allograft injury patterns and "healthy" biopsies using linear mixed-effects models. The effect of these chemokine alterations on CLAD risk was assessed using Cox models with serial BAL measurements as time-dependent covariates. There were 1,585 biopsies from 441 recipients with 62 episodes of DAD. An episode of DAD was associated with increased risk of CLAD (hazard ratio, 3.0; 95% confidence interval, 1.9-4.7) and death (hazard ratio, 2.3; 95% confidence interval, 1.7-3.0). There were marked elevations in BAL CXCR3 ligand concentrations during DAD. Furthermore, prolonged elevation of these chemokines in serial BAL fluid measurements predicted the development of CLAD. DAD is associated with marked increases in the risk of CLAD and death after lung transplantation. This association may be mediated in part by an aberrant type I immune response involving CXCR3/ligands.

Hyperpolarized 129Xe MRI: A Viable Functional Lung Imaging Modality?

PubMed Central

Patz, Samuel; Hersman, F. William; Muradian, Iga; Hrovat, Mirko I.; Ruset, Iulian C.; Ketel, Stephen; Jacobson, Francine; Topulos, George P.; Hatabu, Hiroto; Butler, James P.

2008-01-01

The majority of researchers investigating hyperpolarized gas MRI as a candidate functional lung imaging modality have used 3He as their imaging agent of choice rather than 129Xe. This preference has been predominantly due to, 3He providing stronger signals due to higher levels of polarization and higher gyromagnetic ratio, as well as its being easily available to more researchers due to availability of polarizers (USA) or ease of gas transport (Europe). Most researchers agree, however, that hyperpolarized 129Xe will ultimately emerge as the imaging agent of choice due to its unlimited supply in nature and its falling cost. Our recent polarizer technology delivers vast improvements in hyperpolarized 129Xe output. Using this polarizer, we have demonstrated the unique property of xenon to measure alveolar surface area noninvasively. In this article, we describe our human protocols and their safety, and our results for the measurement of the partial pressure of pulmonary oxygen (pO2) by observation of 129Xe signal decay. We note that the measurement of pO2 by observation of 129Xe signal decay is more complex than that for 3He because of an additional signal loss mechanism due to interphase diffusion of 129Xe from alveolar gas spaces to septal tissue. This results in measurements of an equivalent pO2 that accounts for both traditional T1 decay from pO2 and that from interphase diffusion. We also provide an update on new technological advancements that form the foundation for an improved compact design polarizer as well as improvements that provide another order-of-magnitude scale-up in xenon polarizer output. PMID:17890035

[Interpretation and use of routine pulmonary function tests: Spirometry, static lung volumes, lung diffusion, arterial blood gas, methacholine challenge test and 6-minute walk test].

PubMed

Bokov, P; Delclaux, C

2016-02-01

Resting pulmonary function tests (PFT) include the assessment of ventilatory capacity: spirometry (forced expiratory flows and mobilisable volumes) and static volume assessment, notably using body plethysmography. Spirometry allows the potential definition of obstructive defect, while static volume assessment allows the potential definition of restrictive defect (decrease in total lung capacity) and thoracic hyperinflation (increase in static volumes). It must be kept in mind that this evaluation is incomplete and that an assessment of ventilatory demand is often warranted, especially when facing dyspnoea: evaluation of arterial blood gas (searching for respiratory insufficiency) and measurement of the transfer coefficient of the lung, allowing with the measurement of alveolar volume to calculate the diffusing capacity of the lung for CO (DLCO: assessment of alveolar-capillary wall and capillary blood volume). All these pulmonary function tests have been the subject of an Americano-European Task force (standardisation of lung function testing) published in 2005, and translated in French in 2007. Interpretative strategies for lung function tests have been recommended, which define abnormal lung function tests using the 5th and 95th percentiles of predicted values (lower and upper limits of normal values). Thus, these recommendations need to be implemented in all pulmonary function test units. A methacholine challenge test will only be performed in the presence of an intermediate pre-test probability for asthma (diagnostic uncertainty), which is an infrequent setting. The most convenient exertional test is the 6-minute walk test that allows the assessment of walking performance, the search for arterial desaturation and the quantification of dyspnoea complaint. Copyright © 2015 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.

Irreversible Electroporation in a Swine Lung Model

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

Dupuy, Damian E., E-mail: ddupuy@lifespan.org; Aswad, Bassam, E-mail: baswad@lifespan.org; Ng, Thomas, E-mail: tng@usasurg.org

2011-04-15

Purpose: This study was designed to evaluate the safety and tissue effects of IRE in a swine lung model. Methods: This study was approved by the institutional animal care committee. Nine anesthetized domestic swine underwent 15 percutaneous irreversible electroporation (IRE) lesion creations (6 with bipolar and 3 with 3-4 monopolar electrodes) under fluoroscopic guidance and with pancuronium neuromuscular blockade and EKG gating. IRE electrodes were placed into the central and middle third of the right mid and lower lobes in all animals. Postprocedure PA and lateral chest radiographs were obtained to evaluate for pneumothorax. Three animals were sacrificed at 2more » weeks and six at 4 weeks. Animals underwent high-resolution CT scanning and PA and lateral radiographs 1 h before sacrifice. The treated lungs were removed en bloc, perfused with formalin, and sectioned. Gross pathologic and microscopic changes after standard hematoxylin and eosin staining were analyzed within the areas of IRE lesion creation. Results: No significant adverse events were identified. CT showed focal areas of spiculated high density ranging in greatest diameter from 1.1-2.2 cm. On gross inspection of the sectioned lung, focal areas of tan discoloration and increased density were palpated in the areas of IRE. Histological analysis revealed focal areas of diffuse alveolar damage with fibrosis and inflammatory infiltration that respected the boundaries of the interlobular septae. No pathological difference could be discerned between the 2- and 4-week time points. The bronchioles and blood vessels within the areas of IRE were intact and did not show signs of tissue injury. Conclusion: IRE creates focal areas of diffuse alveolar damage without creating damage to the bronchioles or blood vessels. Short-term safety in a swine model appears to be satisfactory.« less

Age-Related Adaptation of Bone-PDL-Tooth Complex: Rattus-Norvegicus as a Model System

PubMed Central

Leong, Narita L.; Hurng, Jonathan M.; Djomehri, Sabra I.; Gansky, Stuart A.; Ryder, Mark I.; Ho, Sunita P.

2012-01-01

Functional loads on an organ induce tissue adaptations by converting mechanical energy into chemical energy at a cell-level. The transducing capacity of cells alters physico-chemical properties of tissues, developing a positive feedback commonly recognized as the form-function relationship. In this study, organ and tissue adaptations were mapped in the bone-tooth complex by identifying and correlating biomolecular expressions to physico-chemical properties in rats from 1.5 to 15 months. However, future research using hard and soft chow over relevant age groups would decouple the function related effects from aging affects. Progressive curvature in the distal root with increased root resorption was observed using micro X-ray computed tomography. Resorption was correlated to the increased activity of multinucleated osteoclasts on the distal side of the molars until 6 months using tartrate resistant acid phosphatase (TRAP). Interestingly, mononucleated TRAP positive cells within PDL vasculature were observed in older rats. Higher levels of glycosaminoglycans were identified at PDL-bone and PDL-cementum entheses using alcian blue stain. Decreasing biochemical gradients from coronal to apical zones, specifically biomolecules that can induce osteogenic (biglycan) and fibrogenic (fibromodulin, decorin) phenotypes, and PDL-specific negative regulator of mineralization (asporin) were observed using immunohistochemistry. Heterogeneous distribution of Ca and P in alveolar bone, and relatively lower contents at the entheses, were observed using energy dispersive X-ray analysis. No correlation between age and microhardness of alveolar bone (0.7±0.1 to 0.9±0.2 GPa) and cementum (0.6±0.1 to 0.8±0.3 GPa) was observed using a microindenter. However, hardness of cementum and alveolar bone at any given age were significantly different (P<0.05). These observations should be taken into account as baseline parameters, during development (1.5 to 4 months), growth (4 to 10 months), followed by a senescent phase (10 to 15 months), from which deviations due to experimentally induced perturbations can be effectively investigated. PMID:22558292

Low Levels of IGF-1 Contribute to Alveolar Macrophage Dysfunction in Cystic Fibrosis1

PubMed Central

Bessich, Jamie L.; Nymon, Amanda B.; Moulton, Lisa A; Dorman, Dana; Ashare, Alix

2013-01-01

Alveolar macrophages are major contributors to lung innate immunity. Although alveolar macrophages from CFTR−/− mice have impaired function, no study has investigated primary alveolar macrophages in adults with cystic fibrosis (CF). CF patients have low levels of insulin-like growth factor 1 (IGF-1), and our prior studies demonstrate a relationship between IGF-1 and macrophage function. We hypothesize that reduced IGF-1 in CF leads to impaired alveolar macrophage function and chronic infections. Serum and bronchoalveolar lavage (BAL) samples were obtained from 8 CF subjects and 8 healthy subjects. Macrophages were isolated from BAL fluid. We measured the ability of alveolar macrophages to kill Pseudomonas aeruginosa. Subsequently, macrophages were incubated with IGF-1 prior to inoculation with bacteria to determine the effect of IGF-1 on bacterial killing. We found a significant decrease in bacterial killing by CF alveolar macrophages compared to controls. CF subjects had lower serum and BAL IGF-1 levels compared to healthy controls. Exposure to IGF-1 enhanced alveolar macrophage macrophages in both groups. Finally, exposing healthy alveolar macrophages to CF BAL fluid decreased bacterial killing, and this was reversed by the addition of IGF-1, while IGF-1 blockade worsened bacterial killing. Our studies demonstrate that alveolar macrophage function is impaired in patients with CF. Reductions in IGF-1 levels in CF contribute to the impaired alveolar macrophage function. Exposure to IGF-1 ex vivo, results in improved function of CF alveolar macrophages. Further studies are needed to determine whether alveolar macrophage function can be enhanced in vivo with IGF-1 treatment. PMID:23698746

The Pathway for Oxygen: Tutorial Modelling on Oxygen Transport from Air to Mitochondrion: The Pathway for Oxygen.

PubMed

Bassingthwaighte, James B; Raymond, Gary M; Dash, Ranjan K; Beard, Daniel A; Nolan, Margaret

2016-01-01

The 'Pathway for Oxygen' is captured in a set of models describing quantitative relationships between fluxes and driving forces for the flux of oxygen from the external air source to the mitochondrial sink at cytochrome oxidase. The intervening processes involve convection, membrane permeation, diffusion of free and heme-bound O2 and enzymatic reactions. While this system's basic elements are simple: ventilation, alveolar gas exchange with blood, circulation of the blood, perfusion of an organ, uptake by tissue, and consumption by chemical reaction, integration of these pieces quickly becomes complex. This complexity led us to construct a tutorial on the ideas and principles; these first PathwayO2 models are simple but quantitative and cover: (1) a 'one-alveolus lung' with airway resistance, lung volume compliance, (2) bidirectional transport of solute gasses like O2 and CO2, (3) gas exchange between alveolar air and lung capillary blood, (4) gas solubility in blood, and circulation of blood through the capillary syncytium and back to the lung, and (5) blood-tissue gas exchange in capillaries. These open-source models are at Physiome.org and provide background for the many respiratory models there.

[Oxidative stress in patients on mechanical ventilation].

PubMed

Marjanović, Vesna; Dordević, Vidosava; Marjanović, Goran

2009-01-01

The appearance and intensity of oxidative stress were analyzed in the course of mechanical ventilation and parameters that could point toward potential lung damage. In three time intervals on day 1, 3 and 7 of mechanical ventilation, parameters such as: triglycerides, cholesterol, lactate, serum lactic dehydrogenase, acid-base balance and lipid peroxidation products--thiobarbituric acid reactive substances, were followed in 30 patients with head injuries. A decrease in the level of partial oxygen pressure (PaO2) (p < 0.01) and PaO2/FiO2 index (p < 0.05) in arterial blood was recorded on day 3 of mechanical ventilation. This was accompanied with an increase in alveolar-arterial difference (AaDO2) (p < 0.05), thiobarbituric acid reactive substances (p < 0.001) and lactic dehydrogenase (p < 0.001) comparing to day 1 of mechanical ventilation. The patients with initial PaO2 > 120 mmHg, had significant increase of thiobarbituric acid reactive substances and AaDO2 (p < 0.05) and fall of PaO2 (p < 0.001) on day 3 of mechanical ventilation. Oxidative stress and lipid peroxide production are increased during third day of mechanical ventilation leading to disruption of oxygen diffusion through alveolar-capillary membrane and reduction of parameters of oxygenation.

The Pathway for Oxygen: Tutorial Modelling on Oxygen Transport from Air to Mitochondrion

PubMed Central

Bassingthwaighte, James B.; Raymond, Gary M.; Dash, Ranjan K.; Beard, Daniel A.; Nolan, Margaret

2016-01-01

The ‘Pathway for Oxygen’ is captured in a set of models describing quantitative relationships between fluxes and driving forces for the flux of oxygen from the external air source to the mitochondrial sink at cytochrome oxidase. The intervening processes involve convection, membrane permeation, diffusion of free and heme-bound O2 and enzymatic reactions. While this system’s basic elements are simple: ventilation, alveolar gas exchange with blood, circulation of the blood, perfusion of an organ, uptake by tissue, and consumption by chemical reaction, integration of these pieces quickly becomes complex. This complexity led us to construct a tutorial on the ideas and principles; these first PathwayO2 models are simple but quantitative and cover: 1) a ‘one-alveolus lung’ with airway resistance, lung volume compliance, 2) bidirectional transport of solute gasses like O2 and CO2, 3) gas exchange between alveolar air and lung capillary blood, 4) gas solubility in blood, and circulation of blood through the capillary syncytium and back to the lung, and 5) blood-tissue gas exchange in capillaries. These open-source models are at Physiome.org and provide background for the many respiratory models there. PMID:26782201

Preliminary observations on the effect of hypoxic and hyperbaric stress on pulmonary gas exchange in breath-hold divers.

PubMed

Garbella, Erika; Piarulli, Andrea; Fornai, Edo; Pingitore, Alessandro; Prediletto, Renato

2011-06-01

To evaluate pulmonary alveolar-capillary membrane integrity and ventilation/perfusion mismatch after breath-hold diving. Pulmonary diffusing capacity to carbon monoxide (DLCO) and nitric oxide (DLNO), haemoglobin (Hb) and haematocrit (Hct) were measured in six elite divers before and at 2, 10 and 25 minutes after a maximal breath-hold dive to a depth of 10 metres' sea water. Compared to pre-dive, DLCO showed a slight increase at 2 minutes in five subjects and a tendency to decrease at 25 minutes (P < 0.001) in all subjects. DLNO showed an increase at 10 minutes in three divers and a slight decrease at 25 minutes in five subjects. There was a small but significant (P < 0.001) increase in Hb and Hct at 2 minutes, possibly affecting the DLCO measurements. An early but transient increase in DLCO in five divers may reflect the central shift in blood volume during a breath-hold dive. The late parallel decrease in DLCO and DLNO likely reflects alveolar-capillary distress (interstitial oedema). The DLNO increase in three subjects at 10 minutes may suggest ventilation/perfusion mismatch.

Osteoclastogenesis in Local Alveolar Bone in Early Decortication-Facilitated Orthodontic Tooth Movement

PubMed Central

Liu, Chang; Jiang, Yu-Xi; Qu, Hong; Li, Cui-Ying; Jiang, Jiu-Hui

2016-01-01

Objective In the current study, we aimed to investigate the effects of alveolar decortication on local bone remodeling, and to explore the possible mechanism by which decortication facilitates tooth movement. Materials and Methods Forty rabbits were included in the experiment. The left mandible was subjected to decortication-facilitated orthodontics, and the right mandible underwent traditional orthodontics as a control. The animals were sacrificed on the days 1, 3, 5, 7 and 14, after undergoing orthodontic procedures. Tooth movement was measured by Micro-CT, and the local periodontal tissues were investigated using H&E, Masson's trichrome and tartrate-resistant acid phosphatase (TRAP) staining. The mRNA levels of genes related to bone remodeling in the alveolar bone were analyzed using real-time PCR. Result On days 3, 5, 7 and 14, tooth movement was statistically accelerated by decortication (P < 0.05) and was accompanied by increased hyperemia. Despite the lack of new bone formation in both groups, more osteoclasts were noted in the decorticated group, with two peak counts (P < 0.05). The first peak count was consistent with the maximum values of ctsk and TRAP expression, and the second peak counts accompanied the maximum nfatc1 and jdp2 expression. The increased fra2 expression and the ratio of rankl/opg also accompanied the second peak counts. Conclusions Following alveolar decortication, osteoclastogenesis was initially induced to a greater degree than the new bone formation which was thought to have caused a regional acceleratory phenomenon (RAP). The amount of steoclastogenesis in the decorticated alveolar bone was found to have two peaks, perhaps due to attenuated local resistance. The first peak count in osteoclasts may have been due to previously existing osteoclast precursors, whereas the second may represent the differentiation of peripheral blood mononuclear cells which came from circulation as the result of hyperemia. PMID:27096621

Zoledronate Effects on Systemic and Jaw Osteopenias in Ovariectomized Periostin-Deficient Mice

PubMed Central

Bonnet, Nicolas; Lesclous, Philippe; Saffar, Jean Louis; Ferrari, Serge

2013-01-01

Osteoporosis and periodontal disease (PD) are frequently associated in the elderly, both concurring to the loss of jaw alveolar bone and finally of teeth. Bisphosphonates improve alveolar bone loss but have also been associated with osteonecrosis of the jaw (ONJ), particularly using oncological doses of zoledronate. The effects and therapeutic margin of zoledronate on jaw bone therefore remain uncertain. We reappraised the efficacy and safety of Zoledronate (Zol) in ovariectomized (OVX) periostin (Postn)-deficient mice, a unique genetic model of systemic and jaw osteopenia. Compared to vehicle, Zol 1M (100 µg/kg/month) and Zol 1W (100 µg/kg/week) for 3 months both significantly improved femur BMD, trabecular bone volume on tissue volume (BV/TV) and cortical bone volume in both OVX Postn+/+ and Postn−/− (all p<0.01). Zol 1M and Zol 1W also improved jaw alveolar and basal BV/TV, although the highest dose (Zol 1W) was less efficient, particularly in Postn−/−. Zol decreased osteoclast number and bone formation indices, i.e. MAR, MPm/BPm and BFR, independently in Postn−/− and Postn+/+, both in the long bones and in deep jaw alveolar bone, without differences between Zol doses. Zol 1M and Zol 1W did not reactivate inflammation nor increase fibrous tissue in the bone marrow of the jaw, whereas the distance between the root and the enamel of the incisor (DRI) remained high in Postn−/− vs Postn+/+ confirming latent inflammation and lack of crestal alveolar bone. Zol 1W and Zol 1M decreased osteocyte numbers in Postn−/− and Postn+/+ mandible, and Zol 1W increased the number of empty lacunae in Postn−/−, however no areas of necrotic bone were observed. These results demonstrate that zoledronate improves jaw osteopenia and suggest that in Postn−/− mice, zoledronate is not sufficient to induce bone necrosis. PMID:23505553

Biological Effects of Orthodontic Tooth Movement Into the Grafted Alveolar Cleft.

PubMed

Sun, Jian; Zhang, Xiaoyue; Li, Renmei; Chen, Zhengxi; Huang, Yuanliang; Chen, Zhenqi

2018-03-01

Functional stimulus during orthodontic tooth movement into the grafted bone can lead to better alveolar bone grafting outcomes. The aim of this study was to analyze the biological effects of orthodontic tooth movement into the grafted alveolar cleft area with histologic staining, fluorescence staining, and real-time polymerase chain reaction (PCR). An animal model of orthodontic tooth movement into the grafted alveolar cleft area was established in 8-week-old Sprague-Dawley rats. The animals were divided into the experimental group and the control group. Four checkpoints were observed: before orthodontic stimuli, day 1 after orthodontic stimuli, day 3 after orthodontic stimuli, and day 5 after orthodontic stimuli. The cleft bone formation conditions, including the collagen fibers and the activities of the osteoclasts and osteoblasts, were evaluated by histologic staining. The expression of tartrate-resistant acid phosphatase (TRAP), receptor activator nuclear factor κB ligand, and Runt-related transcription factor 2 was detected by real-time PCR in both groups. Hematoxylin-eosin staining showed that the remodeling process of iliac autografts was completed when the orthodontic stress was applied, whereas the bone tissues first showed osteoclastogenesis and then osteogenesis. On the basis of TRAP staining, the osteoclasts increased to the maximal amount on day 3 and decreased thereafter. Evidence from tetracycline fluorescence staining indicated that no obvious changes in osteoblast activity were detected at the early stage; however, it gradually increased, especially in the region close to the root surface. According to real-time PCR, the expression of TRAP increased in both the early and middle stages, that of receptor activator nuclear factor κB ligand increased in the early stage, and that of Runt-related transcription factor 2 increased in the late stage. Moreover, the results showed significant differences between the experimental and control groups. Orthodontic tooth movement into the alveolar cleft bone graft area promoted bone remodeling of embedded bone, thus inducing bone resorption and subsequent deposition. Copyright © 2017. Published by Elsevier Inc.

Raised protein levels and altered cellular expression of factor VII activating protease (FSAP) in the lungs of patients with acute respiratory distress syndrome (ARDS)

PubMed Central

Wygrecka, Malgorzata; Markart, Philipp; Fink, Ludger; Guenther, Andreas; Preissner, Klaus T

2007-01-01

Background The acute respiratory distress syndrome (ARDS) is characterised by inflammation of the lung parenchyma and changes in alveolar haemostasis with extravascular fibrin deposition. Factor VII activating protease (FSAP) is a recently described serine protease in plasma and tissues known to be involved in haemostasis, cell proliferation and migration. Methods The level of FSAP protein expression was examined by western blotting/ELISA/immunohistochemistry and its activity was investigated by coagulation/fibrinolysis assays in plasma, bronchoalveolar lavage (BAL) fluid and lung tissue of mechanically ventilated patients with early ARDS and compared with patients with cardiogenic pulmonary oedema and healthy controls. Cell culture experiments were performed to assess the influence of different inflammatory stimuli on FSAP expression by various cell populations of the lung. Results FSAP protein level and activity were markedly increased in the plasma and BAL fluid of patients with ARDS with a significant contribution to the increased alveolar procoagulant activity. Immunoreactivity for FSAP was observed in alveolar macrophages, bronchial epithelial and endothelial cells of lungs of patients with ARDS, while in controls the immunoreactivity for FSAP was restricted to alveolar macrophages. Only a low basal level of FSAP expression was detected in these cell populations. However, FSAP‐specific mRNA expression was induced by lipopolysaccharide and interleukin‐8 in human lung microvascular endothelial cells and in bronchial epithelial cells. FSAP was also found to be taken up by alveolar macrophages and degraded within the lysosomal compartment. Conclusions Increased levels of FSAP and an altered cellular expression pattern are found in the lungs of patients with ARDS. This may represent a novel pathological mechanism which contributes to pulmonary extravascular fibrin deposition and may also modulate inflammation in the acutely injured lung via haemostasis‐independent cellular activities of FSAP. PMID:17483138

[Effects of Tetrandrine Prenatal Intervention on Alveolar Epithelial Cells Type I Differentiation in Rat Model of Nitrofen-induced Congenital Diaphragmatic Hernia].

PubMed

Xiao, Bin; Xu, Chang; Liu, Min; Ji, Yi; Yang Li-xun; Li, Tai-ming; Jiang, Jun; He, Tao-zhen

2016-03-01

To investigate the effects of Tetrandrine (TET) prenatal intervention on the differentiation of alveolar epithelial cells type I (AEC I) in rat model of Nitrofen-induced congenital diaphragmatic hernia (CDH). Timed-pregnant Sprague-Dawley rats were divided into three groups, namely control, CDH and TET group on day 9.5 of gestation. The rats in TET group and CDH group were given 125 mg of Nitrofen by gavage one time, while the rats in control group were given the same dose of seed fat. After that, the rats in TET group was given 30 mg/kg of TET by gavage once a day for three days from day 18.5 of gestation, while the rats in CDH and control group were given the same dose of normal saline. On day 21.5 of gestation, all fetuses were delivered by cesarean, the lungs of fetuses were histologically evaluated by microscope and electron microscope. The expressions of type I cell-specific protein (RT140) and thyroid transcription factor 1 (TTF1) in alveolar fluid content were analyzed by RT-PCR and immunohistochemistry staining. To detect the number of AEC I and AEC II of each group by transmission electron microscopy and calculate the percentage of AEC I and AEC II (I/II%). The microscope and electron microscope study found the lungs of fetuses in CDH group showed marked hypoplasia, in contrast to the improvement of hypoplasia in TET fetuses. The pulmonary alveolar area had significant difference statistically (P < 0.01) in each group, which present as control > TET > CDH. I/II% had significant difference statistically (P < 0.01) in each group, which present as control > TET > CDH. The expression level of TTF1 was up-regulated in both CDH and TET groups, and it was higher in CDH group (P < 0.01). The expression level of RT140 were down-regulated in CDH and TET groups, which was lower in CDH group (P < 0.01). The development of AEC I was interfered in CDH rat model, TET prenatal treatment could improve the lung development of CDH.

Intra-operative protective mechanical ventilation in lung transplantation: a randomised, controlled trial.

PubMed

Verbeek, G L; Myles, P S; Westall, G P; Lin, E; Hastings, S L; Marasco, S F; Jaffar, J; Meehan, A C

2017-08-01

Primary graft dysfunction occurs in up to 25% of patients after lung transplantation. Contributing factors include ventilator-induced lung injury, cardiopulmonary bypass, ischaemia-reperfusion injury and excessive fluid administration. We evaluated the feasibility, safety and efficacy of an open-lung protective ventilation strategy aimed at reducing ventilator-induced lung injury. We enrolled adult patients scheduled to undergo bilateral sequential lung transplantation, and randomly assigned them to either a control group (volume-controlled ventilation with 5 cmH 2 O, positive end-expiratory pressure, low tidal volumes (two-lung ventilation 6 ml.kg -1 , one-lung ventilation 4 ml.kg -1 )) or an alveolar recruitment group (regular step-wise positive end-expiratory pressure-based alveolar recruitment manoeuvres, pressure-controlled ventilation set at 16 cmH 2 O with 10 cmH 2 O positive end-expiratory pressure). Ventilation strategies were commenced from reperfusion of the first lung allograft and continued for the duration of surgery. Regular PaO 2 /F I O 2 ratios were calculated and venous blood samples collected for inflammatory marker evaluation during the procedure and for the first 24 h of intensive care stay. The primary end-point was the PaO 2 /F I O 2 ratio at 24 h after first lung reperfusion. Thirty adult patients were studied. The primary outcome was not different between groups (mean (SD) PaO 2 /F I O 2 ratio control group 340 (111) vs. alveolar recruitment group 404 (153); adjusted p = 0.26). Patients in the control group had poorer mean (SD) PaO 2 /F I O 2 ratios at the end of the surgical procedure and a longer median (IQR [range]) time to tracheal extubation compared with the alveolar recruitment group (308 (144) vs. 402 (154) (p = 0.03) and 18 (10-27 [5-468]) h vs. 15 (11-36 [5-115]) h (p = 0.01), respectively). An open-lung protective ventilation strategy during surgery for lung transplantation is feasible, safe and achieves favourable ventilation parameters. © 2017 The Association of Anaesthetists of Great Britain and Ireland.

Three-dimensional analysis of alveolar wall destruction in the early stage of pulmonary emphysema.

PubMed

Kobayashi, Yukihiro; Uehara, Takeshi; Kawasaki, Kenji; Sugano, Mitsutoshi; Matsumoto, Takehisa; Matsumoto, Gou; Honda, Takayuki

2015-03-01

The morphological mechanism of alveolar wall destruction during pulmonary emphysema has not been clarified. The aim of this study was to elucidate this process three-dimensionally. Lung specimens from five patients with pulmonary emphysema were used, and five controls with normal alveolar structure were also examined. Sections 150 μm thick were stained with hematoxylin and eosin, elastica, and silver impregnation, and immunostained with selected antibodies. We examined these sections three-dimensionally using a laser confocal microscope and a light microscope. There were only a few Kohn's pores and no fenestrae in the normal alveoli from the controls. In the lungs of the emphysema patients a small rupture appeared in the extremely thin alveolar wall among the alveolar capillaries. This rupture enlarged to form a circle surrounded by the capillaries, which was called an alveolar fenestra. Two neighboring fenestrae fused by breakdown of the collapsed or cord-like capillary between them to form a large fenestra. The large fenestrae fused repeatedly to become larger, and these were bordered by thick elastic fibers constructing an alveolar framework. Alveolar wall destruction during emphysema could start from small ruptures of the alveolar wall that become fenestrae surrounded by capillaries, which fuse repeatedly to become larger fenestrae rimmed with elastic fibers. The alveolar capillary network could initially prevent enlargement of the fenestrae, and the thick elastic fibers constituting the alveolar framework could secondarily prevent destruction of the alveolar wall structure. © 2014 Wiley Periodicals, Inc.

Effect of Alveolar Segmental Sandwich Osteotomy on Alveolar Height: A Preliminary Study.

PubMed

Mehta, Karan S; Prasad, Kavitha; Shetty, Vibha; Ranganath, Krishnappa; Lalitha, R M; Dexith, Jayashree; Munoyath, Sejal K; Kumar, Vineeth

2017-12-01

Bone loss following extraction is maximum in horizontal dimension. Height is also reduced which is pronounced on the buccal aspect. Various surgical procedures are available to correct the bone volume viz. GBR, onlay bone grafting, alveolar distraction and sandwich osteotomy. Sandwich osteotomy has been found to increase the vertical alveolar bone height successfully. The objective of the study was to assess the effect of alveolar segmental sandwich osteotomy on alveolar height and crestal width. A prospective study was undertaken from December 2012 to August 2014. Seven patients with 12 implant sites with a mean age of 36 years were recruited. All seven patients with 12 implant sites underwent alveolar segmental sandwich osteotomy and interpositional bone grafting. Alveolar bone height was assessed radiographically preoperatively, immediate post-op, and at 3 months post-op. Alveolar bone width was assessed radiographically preoperatively and at 3 months post-op. Statistical significance was inferred at p  < 0.05. The mean vertical augmentation at immediate post-op was 6.58 mm ( p  = 0.001). The vertical augmentation that was achieved 3 months post-op was a mean of 3.75 mm which was statistically significant ( p  = 0.004). The change in alveolar height from immediate post-op to 3 month post-op was a mean 1.69 mm. The mean change in alveolar crestal width at 3 months was a mean of -0.29 mm ( p  = 0.57). Sandwich osteotomy can be used as an alternative technique to increase alveolar bone height prior to implant placement. Moderate alveolar deficiency can be predictably corrected by this technique.

Rate of disappearance of labeled carbon dioxide from the lungs of humans during breath holding: a method for studying the dynamics of pulmonary CO2 exchange

PubMed Central

Hyde, Richard W.; Puy, Ricardo J. M.; Raub, William F.; Forster, Robert E.

1968-01-01

The dynamics of CO2 exchange in the lungs of man was studied by observing the rate of disappearance of a stable isotope of CO2 (13CO2) from the alveolar gas during breath holding. Over 50% of the inspired isotope disappeared within the first 3 sec followed by a moderately rapid logarithmic decline in which one-half of the remaining 13CO2 disappeared every 10 sec. The large initial disappearance of 13CO2 indicated that alveolar 13CO2 equilibrated in less than 3 sec with the CO2 stored in the pulmonary tissues and capillary blood. The volume of CO2 in the pulmonary tissues calculated from this initial disappearance was 200 ml or 0.33 ml of CO2 per milliliter of pulmonary tissue volume. The alveolar to end-capillary gradient for 13CO2 was calculated by comparing the simultaneous disappearance rates of 13CO2 and acetylene. At rest and during exercise this gradient for 13CO2 was either very small or not discernible, and diffusing capacity for CO2 (DLCO2) exceeded 200 ml/(min × mm Hg). After the administration of a carbonic anhydrase inhibitor the rate of disappearance of 13CO2 decreased markedly. DLCO2 fell to 42 ml/(min × mm Hg) and at least 70% of the exchange of 13CO2 with the CO2 stores in the pulmonary tissues and blood was blocked by the inhibitor. These changes were attributed to impairment of exchange of 13CO2 with the bicarbonate in the pulmonary tissues and blood. The pH of the pulmonary tissues (Vtis) was determined by a method based on the premise that the CO2 space in the pulmonary tissues blocked by the inhibitor represented total bicarbonate content. At an alveolar PCO2 of 40 mm Hg pH of Vtis equalled 6.97 ± 0.09. PMID:5658586

The large lungs of elite swimmers: an increased alveolar number?

PubMed

Armour, J; Donnelly, P M; Bye, P T

1993-02-01

In order to obtain further insight into the mechanisms relating to the large lung volumes of swimmers, tests of mechanical lung function, including lung distensibility (K) and elastic recoil, pulmonary diffusion capacity, and respiratory mouth pressures, together with anthropometric data (height, weight, body surface area, chest width, depth and surface area), were compared in eight elite male swimmers, eight elite male long distance athletes and eight control subjects. The differences in training profiles of each group were also examined. There was no significant difference in height between the subjects, but the swimmers were younger than both the runners and controls, and both the swimmers and controls were heavier than the runners. Of all the training variables, only the mean total distance in kilometers covered per week was significantly greater in the runners. Whether based on: (a) adolescent predicted values; or (b) adult male predicted values, swimmers had significantly increased total lung capacity ((a) 145 +/- 22%, (mean +/- SD) (b) 128 +/- 15%); vital capacity ((a) 146 +/- 24%, (b) 124 +/- 15%); and inspiratory capacity ((a) 155 +/- 33%, (b) 138 +/- 29%), but this was not found in the other two groups. Swimmers also had the largest chest surface area and chest width. Forced expiratory volume in one second (FEV1) was largest in the swimmers ((b) 122 +/- 17%) and FEV1 as a percentage of forced vital capacity (FEV1/FVC)% was similar for the three groups. Pulmonary diffusing capacity (DLCO) was also highest in the swimmers (117 +/- 18%). All of the other indices of lung function, including pulmonary distensibility (K), elastic recoil and diffusion coefficient (KCO), were similar. These findings suggest that swimmers may have achieved greater lung volumes than either runners or control subjects, not because of greater inspiratory muscle strength, or differences in height, fat free mass, alveolar distensibility, age at start of training or sternal length or chest depth, but by developing physically wider chests, containing an increased number of alveoli, rather than alveoli of increased size. However, in this cross-sectional study, hereditary factors cannot be ruled out, although we believe them to be less likely.

Up-Regulation and Profibrotic Role of Osteopontin in Human Idiopathic Pulmonary Fibrosis

PubMed Central

Pardo, Annie; Gibson, Kevin; Cisneros, José; Richards, Thomas J; Yang, Yinke; Becerril, Carina; Yousem, Samueal; Herrera, Iliana; Ruiz, Victor; Selman, Moisés; Kaminski, Naftali

2005-01-01

Background Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal disorder characterized by fibroproliferation and excessive accumulation of extracellular matrix in the lung. Methods and Findings Using oligonucleotide arrays, we identified osteopontin as one of the genes that significantly distinguishes IPF from normal lungs. Osteopontin was localized to alveolar epithelial cells in IPF lungs and was also significantly elevated in bronchoalveolar lavage from IPF patients. To study the fibrosis-relevant effects of osteopontin we stimulated primary human lung fibroblasts and alveolar epithelial cells (A549) with recombinant osteopontin. Osteopontin induced a significant increase of migration and proliferation in both fibroblasts and epithelial cells. Epithelial growth was inhibited by the pentapeptide Gly-Arg-Gly-Asp-Ser (GRGDS) and antibody to CD44, while fibroproliferation was inhibited by GRGDS and antibody to αvβ3 integrin. Fibroblast and epithelial cell migration were inhibited by GRGDS, anti-CD44, and anti-αvβ3. In fibroblasts, osteopontin up-regulated tissue inhibitor of metalloprotease-1 and type I collagen, and down-regulated matrix metalloprotease-1 (MMP-1) expression, while in A549 cells it caused up-regulation of MMP-7. In human IPF lungs, osteopontin colocalized with MMP-7 in alveolar epithelial cells, and application of weakest link statistical models to microarray data suggested a significant interaction between osteopontin and MMP-7. Conclusions Our results provide a potential mechanism by which osteopontin secreted from the alveolar epithelium may exert a profibrotic effect in IPF lungs and highlight osteopontin as a potential target for therapeutic intervention in this incurable disease. PMID:16128620

The effects of alveolar bone loss and miniscrew position on initial tooth displacement during intrusion of the maxillary anterior teeth: Finite element analysis

PubMed Central

Cho, Sun-Mi; Choi, Sung-Hwan; Sung, Sang-Jin; Yu, Hyung-Seog

2016-01-01

Objective The aim of this study was to determine the optimal loading conditions for pure intrusion of the six maxillary anterior teeth with miniscrews according to alveolar bone loss. Methods A three-dimensional finite element model was created for a segment of the six anterior teeth, and the positions of the miniscrews and hooks were varied after setting the alveolar bone loss to 0, 2, or 4 mm. Under 100 g of intrusive force, initial displacement of the individual teeth in three directions and the degree of labial tilting were measured. Results The degree of labial tilting increased with reduced alveolar bone height under the same load. When a miniscrew was inserted between the two central incisors, the amounts of medial-lateral and anterior-posterior displacement of the central incisor were significantly greater than in the other conditions. When the miniscrews were inserted distally to the canines and an intrusion force was applied distal to the lateral incisors, the degree of labial tilting and the amounts of displacement of the six anterior teeth were the lowest, and the maximum von Mises stress was distributed evenly across all the teeth, regardless of the bone loss. Conclusions Initial tooth displacement similar to pure intrusion of the six maxillary anterior teeth was induced when miniscrews were inserted distal to the maxillary canines and an intrusion force was applied distal to the lateral incisors. In this condition, the maximum von Mises stresses were relatively evenly distributed across all the teeth, regardless of the bone loss. PMID:27668194

Effect of CPAP in a Mouse Model of Hyperoxic Neonatal Lung Injury

PubMed Central

Reyburn, Brent; Fiore, Juliann M. Di; Raffay, Thomas; Martin, Richard J.; Y.S., Prakash; Jafri, Anjum; MacFarlane, Peter M.

2015-01-01

Background Continuous positive airway pressure [CPAP] and supplemental oxygen have become the mainstay of neonatal respiratory support in preterm infants. Although oxygen therapy is associated with respiratory morbidities including bronchopulmonary dysplasia [BPD], the long-term effects of CPAP on lung function are largely unknown. We used a hyperoxia-induced mouse model of BPD to explore the effects of daily CPAP during the first week of life on later respiratory system mechanics. Objective To test the hypothesis that daily CPAP in a newborn mouse model of BPD improves longer term respiratory mechanics. Methods Mouse pups from C57BL/6 pregnant dams were exposed to room air [RA] or hyperoxia [50% O2, 24hrs/day] for the first postnatal week with or without exposure to daily CPAP [6cmH2O, 3hrs/day]. Respiratory system resistance [Rrs] and compliance [Crs] were measured following a subsequent 2 week period of room RA recovery. Additional measurements included radial alveolar counts and macrophage counts. Results Mice exposed to hyperoxia had significantly elevated Rrs, decreased Crs, reduced alveolarization, and increased macrophage counts at three weeks compared to RA treated mice. Daily CPAP treatment significantly improved Rrs, Crs and alveolarization, and decreased lung macrophage infiltration in hyperoxia-exposed pups. Conclusions We have demonstrated that daily CPAP had a longer term benefit on baseline respiratory system mechanics in a neonatal mouse model of BPD. We speculate that this beneficial effect of CPAP was the consequence of a decrease in the inflammatory response and resultant alveolar injury associated with hyperoxic newborn lung injury. PMID:26394387

Vitamin D deficiency contributes directly to the acute respiratory distress syndrome (ARDS).

PubMed

Dancer, Rachel C A; Parekh, Dhruv; Lax, Sian; D'Souza, Vijay; Zheng, Shengxing; Bassford, Chris R; Park, Daniel; Bartis, D G; Mahida, Rahul; Turner, Alice M; Sapey, Elizabeth; Wei, Wenbin; Naidu, Babu; Stewart, Paul M; Fraser, William D; Christopher, Kenneth B; Cooper, Mark S; Gao, Fang; Sansom, David M; Martineau, Adrian R; Perkins, Gavin D; Thickett, David R

2015-07-01

Vitamin D deficiency has been implicated as a pathogenic factor in sepsis and intensive therapy unit mortality but has not been assessed as a risk factor for acute respiratory distress syndrome (ARDS). Causality of these associations has never been demonstrated. To determine if ARDS is associated with vitamin D deficiency in a clinical setting and to determine if vitamin D deficiency in experimental models of ARDS influences its severity. Human, murine and in vitro primary alveolar epithelial cell work were included in this study. Vitamin D deficiency (plasma 25(OH)D levels <50 nmol/L) was ubiquitous in patients with ARDS and present in the vast majority of patients at risk of developing ARDS following oesophagectomy. In a murine model of intratracheal lipopolysaccharide challenge, dietary-induced vitamin D deficiency resulted in exaggerated alveolar inflammation, epithelial damage and hypoxia. In vitro, vitamin D has trophic effects on primary human alveolar epithelial cells affecting >600 genes. In a clinical setting, pharmacological repletion of vitamin D prior to oesophagectomy reduced the observed changes of in vivo measurements of alveolar capillary damage seen in deficient patients. Vitamin D deficiency is common in people who develop ARDS. This deficiency of vitamin D appears to contribute to the development of the condition, and approaches to correct vitamin D deficiency in patients at risk of ARDS should be developed. UKCRN ID 11994. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Investigation of alveolar tissue deformations using OCT combined with fluorescence microscopy

NASA Astrophysics Data System (ADS)

Gaertner, Maria; Cimalla, Peter; Knels, Lilla; Meissner, Sven; Schnabel, Christian; Kuebler, Wolfgang M.; Koch, Edmund

2011-06-01

In critical care medicine, artificial ventilation is a life saving tool providing sufficient blood oxygenation to patients suffering from respiratory failure. Essential for their survival is the use of protective ventilation strategies to prevent further lung damage due to ventilator induced lung injury (VILI). Since there is only little known about implications of lung tissue overdistension on the alveolar level, especially in the case of diseased lungs, this research deals with the investigation of lung tissue deformation on a microscale. A combined setup utilizing optical coherence tomography (OCT) and confocal fluorescence microscopy, is used to study the elastic behavior of the alveolar tissue. Three-dimensional geometrical information with voxel sizes of 6 μm × 6 μm × 11 μm (in air) is provided by OCT, structural information about localization of elastin fibers is elucidated via confocal fluorescence microscopy with a lateral resolution of around 1 μm. Imaging depths of 90 μm for OCT and 20 μm for confocal fluorescence microscopy were obtained. Dynamic studies of subpleural tissue were carried out on the basis of an in vivo mouse model post mortem, mimicking the physiological environment of an intact thorax and facilitating a window for the application of optical methods. Morphological changes were recorded by applying constant positive airway pressures of different values. With this, alveolar volume changes could clearly be recognized and quantified to form a compliance value of 3.5 • 10-6(see manuscript). The distribution of elastin fibers was detected and will be subject to further elasticity analysis.

Injury of the Inferior Alveolar Nerve during Implant Placement: a Literature Review

PubMed Central

Wang, Hom-Lay; Sabalys, Gintautas

2011-01-01

ABSTRACT Objectives The purpose of present article was to review aetiological factors, mechanism, clinical symptoms, and diagnostic methods as well as to create treatment guidelines for the management of inferior alveolar nerve injury during dental implant placement. Material and Methods Literature was selected through a search of PubMed, Embase and Cochrane electronic databases. The keywords used for search were inferior alveolar nerve injury, inferior alveolar nerve injuries, inferior alveolar nerve injury implant, inferior alveolar nerve damage, inferior alveolar nerve paresthesia and inferior alveolar nerve repair. The search was restricted to English language articles, published from 1972 to November 2010. Additionally, a manual search in the major anatomy, dental implant, periodontal and oral surgery journals and books were performed. The publications there selected by including clinical, human anatomy and physiology studies. Results In total 136 literature sources were obtained and reviewed. Aetiological factors of inferior alveolar nerve injury, risk factors, mechanism, clinical sensory nerve examination methods, clinical symptoms and treatment were discussed. Guidelines were created to illustrate the methods used to prevent and manage inferior alveolar nerve injury before or after dental implant placement. Conclusions The damage of inferior alveolar nerve during the dental implant placement can be a serious complication. Clinician should recognise and exclude aetiological factors leading to nerve injury. Proper presurgery planning, timely diagnosis and treatment are the key to avoid nerve sensory disturbances management. PMID:24421983

The effect of experimentally induced hypothyroidism on the isoflurane minimum alveolar concentration in dogs.

PubMed

Berry, Stephanie H; Panciera, David L

2015-01-01

To determine the effect of experimentally induced hypothyroidism on isoflurane (ISO) minimum alveolar concentration (MAC) in dogs. Prospective experimental study. Eighteen adult female mongrel dogs, age 2-4 years and weighing 8.2-13.1 kg. Hypothyroidism was induced in nine dogs by the intravenous administration of 1 mCi kg(-1) of (131) Iodine. The remaining nine dogs served as controls. Dogs were studied 9-12 months after the induction of hypothyroidism. Anesthesia was induced with ISO in oxygen via a mask. The trachea was intubated, and anesthesia was maintained using ISO in oxygen using a semi-closed rebreathing circle system. The dogs were mechanically ventilated to maintain an end-tidal carbon dioxide concentration between 35 and 45 mmHg. End-tidal ISO concentrations were measured with an infrared gas analyzer. The MAC was determined in duplicate using a tail clamp technique. The mean values for the groups were compared using a two sample t-test. The mean ± SD MAC of isoflurane in the hypothyroid and euthyroid dogs was 0.98 ± 0.31% and 1.11 ± 0.26%, respectively. The mean MAC of isoflurane in hypothyroid dogs was not significantly different from the mean MAC of isoflurane in the control dogs (p = 0.3553). The MAC of ISO in dogs was not significantly affected by experimentally induced hypothyroidism. The dose of ISO in dogs with hypothyroidism does not need to be altered. © 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.

Effect of inducer inlet and diffuser throat areas on performance of a low pressure ratio sweptback centrifugal compressor

NASA Technical Reports Server (NTRS)

Klassen, H. A.

1975-01-01

A low-pressure-ratio centrifugal compressor was tested with nine combinations of three diffuser throat areas and three impeller inducer inlet areas which were 75, 100, and 125 percent of design values. For a given inducer inlet area, increases in diffuser area within the range investigated resulted in increased mass flow and higher peak efficiency. Changes in both diffuser and inducer areas indicated that efficiencies within one point of the maximum efficiency were obtained over a compressor specific speed range of 27 percent. The performance was analyzed of an assumed two-spool open-cycle engine using the 75 percent area inducer with a variable area diffuser.

Sex steroid receptor expression in idiopathic pulmonary fibrosis.

PubMed

Mehrad, Mitra; Trejo Bittar, Humberto E; Yousem, Samuel A

2017-08-01

Usual interstitial pneumonia (UIP) is characterized by progressive scarring of the lungs and is associated with high morbidity and mortality despite therapeutic interventions. Sex steroid receptors have been demonstrated to play an important role in chronic lung conditions; however, their significance is unknown in patients with UIP. We retrospectively reviewed 40 idiopathic UIP cases for the expression of hormonal receptors. Forty cases including 10 normal lung, 10 cryptogenic organizing pneumonia, 10 idiopathic organizing diffuse alveolar damage, 7 hypersensitivity pneumonitis, and 3 nonspecific interstitial pneumonitis served as controls. Immunohistochemistry for estrogen receptor α, progesterone receptor (PR), and androgen receptor was performed in all groups. Expression of these receptors was assessed in 4 anatomic/pathologic compartments: alveolar and bronchiolar epithelium, arteries/veins, fibroblastic foci/airspace organization, and old scar. All UIPs (100%) stained positive for PR in myofibroblasts in the scarred areas, whereas among the control cases, only 1 nonspecific interstitial pneumonitis case stained focally positive and the rest were negative. PR was positive in myocytes of the large-sized arteries within the fibrotic areas in 31 cases (77.5%). PR was negative within the alveolar and bronchial epithelium, airspace organization, and center of fibroblastic foci; however, weak PR positivity was noted in the peripheral fibroblasts of the fibroblastic foci where they merged with dense fibrous connective tissue scar. All UIP and control cases were negative for androgen receptor and estrogen receptor α. This is the first study to show the expression of PR within the established fibrotic areas of UIP, indicating that progesterone may have profibrotic effects in UIP patients. Hormonal therapy by targeting PR could be of potential benefit in patients with UIP/IPF. Copyright © 2017 Elsevier Inc. All rights reserved.

Unexpected death of a ventilator-dependent amyotrophic lateral sclerosis patient.

PubMed

di Paolo, M; Evangelisti, L; Ambrosino, N

2013-01-01

Amyotrophic lateral sclerosis (ALS) is a fatal, progressive, neurodegenerative disease and most patients affected die of respiratory compromise and/or pneumonia within 2-3 years of diagnosis. As ALS progresses, ventilator assistance is required. In the end stages of the disease, patients suffer from respiratory failure and may become ventilator-dependent. Deaths due to malfunction of mechanical ventilators are reported but there are very few forensic autopsy records. We report the case of a 69-year-old ALS female ventilator-dependent, trachostomised patient who was found dead by her husband, with the ventilator in "stand-by" mode. A forensic autopsy was performed. Samples of internal organs were taken for histological and toxicological examination. The ventilator internal memory was also analysed and tested in order to find possible malfunction. Gross examination did not reveal any sign of trauma but showed brain and lung congestion. Pulmonary histological examination revealed thickening of peribronchial interstitial space, alveolar over-distension, break of inter-alveolar walls and diffuse alveolar haemorrhages. Focal microhemorrhages were also detected in other organs. Analysis of the ventilator internal memory showed that during the night of death, there had been several voltage drops. Specific tests revealed malfunction of the internal battery which was unable to provide the necessary voltage, as a consequence the ventilator switched off, stopping ventilation. Battery malfunction reduced the volume of the ventilator alarm, which was not heard by the caregiver. Histological pattern, with acute pulmonary emphysema and focal polivisceral haemorrhages, is strongly suggestive of a death due to "acute" asphyxia. The authors also discuss the need for strict supervision and follow up of these ventilatory dependent patients and their devices. Copyright © 2012 Sociedade Portuguesa de Pneumologia. Published by Elsevier España. All rights reserved.

[Lipoid pneumonia related to workplace exposure to paint].

PubMed

Abad Fernández, A; de Miguel Díez, J; López Vime, R; Gómez Santos, D; Nájera Botello, L; Jara Chinarro, B

2003-03-01

A 49-year-old man with no known history of pulmonary disease was treated at our hospital after observation of an interstitial pattern on a chest film. The patient was a smoker and professional painter. Computed tomography of the chest showed a diffuse bilateral ground-glass pattern. The lung biopsy showed intra-alveolar lipid accumulation in the form of vacuoles of varying sizes surrounded by numerous focally multinucleated macrophages, establishing a definitive diagnosis of exogenous lipoid pneumonia. Given the patient's profession, he was recommended to avoid workplace exposure to paraffins and oily sprays. The clinical course was favorable after exposure was stopped, with improved lung function and symptoms.

Effects of Polymethoxyflavonoids on Bone Loss Induced by Estrogen Deficiency and by LPS-Dependent Inflammation in Mice.

PubMed

Matsumoto, Shigeru; Tominari, Tsukasa; Matsumoto, Chiho; Yoshinouchi, Shosei; Ichimaru, Ryota; Watanabe, Kenta; Hirata, Michiko; Grundler, Florian M W; Miyaura, Chisato; Inada, Masaki

2018-01-20

Polymethoxyflavonoids (PMFs) are a family of the natural compounds that mainly compise nobiletin, tangeretin, heptamethoxyflavone (HMF), and tetramethoxyflavone (TMF) in citrus fruits. PMFs have shown various biological functions, including anti-oxidative effects. We previously showed that nobiletin, tangeretin, and HMF all inhibited interleukin (IL)-1-mediated osteoclast differentiation via the inhibition of prostaglandin E2 synthesis. In this study, we created an original mixture of PMFs (nobiletin, tangeretin, HMF, and TMF) and examined whether or not PMFs exhibit co-operative inhibitory effects on osteoclastogenesis and bone resorption. In a coculture of bone marrow cells and osteoblasts, PMFs dose-dependently inhibited IL-1-induced osteoclast differentiation and bone resorption. The optimum concentration of PMFs was lower than that of nobiletin alone in the suppression of osteoclast differentiation, suggesting that the potency of PMFs was stronger than that of nobiletin in vitro. The oral administration of PMFs recovered the femoral bone loss induced by estrogen deficiency in ovariectomized mice. We further tested the effects of PMFs on lipopolysaccharide-induced bone resorption in mouse alveolar bone. In an ex vivo experimental model for periodontitis, PMFs significantly suppressed the bone-resorbing activity in organ cultures of mouse alveolar bone. These results indicate that a mixture of purified nobiletin, tangeretin, HMF, and TMF exhibits a co-operative inhibitory effect for the protection against bone loss in a mouse model of bone disease, suggesting that PMFs may be potential candidates for the prevention of bone resorption diseases, such as osteoporosis and periodontitis.

The role of purinergic signaling on deformation induced injury and repair responses of alveolar epithelial cells.

PubMed

Belete, Hewan A; Hubmayr, Rolf D; Wang, Shaohua; Singh, Raman-Deep

2011-01-01

Cell wounding is an important driver of the innate immune response of ventilator-injured lungs. We had previously shown that the majority of wounded alveolus resident cells repair and survive deformation induced insults. This is important insofar as wounded and repaired cells may contribute to injurious deformation responses commonly referred to as biotrauma. The central hypothesis of this communication states that extracellular adenosine-5' triphosphate (ATP) promotes the repair of wounded alveolus resident cells by a P2Y2-Receptor dependent mechanism. Using primary type 1 alveolar epithelial rat cell models subjected to micropuncture injury and/or deforming stress we show that 1) stretch causes a dose dependent increase in cell injury and ATP media concentrations; 2) enzymatic depletion of extracellular ATP reduces the probability of stretch induced wound repair; 3) enriching extracellular ATP concentrations facilitates wound repair; 4) purinergic effects on cell repair are mediated by ATP and not by one of its metabolites; and 5) ATP mediated cell salvage depends at least in part on P2Y2-R activation. While rescuing cells from wounding induced death may seem appealing, it is possible that survivors of membrane wounding become governors of a sustained pro-inflammatory state and thereby perpetuate and worsen organ function in the early stages of lung injury syndromes. Means to uncouple P2Y2-R mediated cytoprotection from P2Y2-R mediated inflammation and to test the preclinical efficacy of such an undertaking deserve to be explored.

Loperamide Restricts Intracellular Growth of Mycobacterium tuberculosis in Lung Macrophages.

PubMed

Juárez, Esmeralda; Carranza, Claudia; Sánchez, Guadalupe; González, Mitzi; Chávez, Jaime; Sarabia, Carmen; Torres, Martha; Sada, Eduardo

2016-12-01

New approaches for improving tuberculosis (TB) control using adjunct host-directed cellular and repurposed drug therapies are needed. Autophagy plays a crucial role in the response to TB, and a variety of autophagy-inducing drugs that are currently available for various medical conditions may serve as an adjunct treatment in pulmonary TB. Here, we evaluated the potential of loperamide, carbamazepine, valproic acid, verapamil, and rapamycin to enhance the antimicrobial immune response to Mycobacterium tuberculosis (Mtb). Human monocyte-derived macrophages (MDMs) and murine alveolar cells (MACs) were infected with Mtb and treated with loperamide, carbamazepine, valproic acid, verapamil, and rapamycin in vitro. Balb/c mice were intraperitoneally administered loperamide, valproic acid, and verapamil, and MACs were infected in vitro with Mtb. The induction of autophagy, the containment of Mtb within autophagosomes and the intracellular Mtb burden were determined. Autophagy was induced by all of the drugs in human and mouse macrophages, and loperamide significantly increased the colocalization of microtubule-associated protein 1 light chain 3 with Mtb in MDMs. Carbamazepine, loperamide, and valproic acid induced microtubule-associated protein 1 light chain 3 and autophagy related 16- like protein 1 gene expression in MDMs and in MACs. Loperamide also induced a reduction in TNF-α production. Loperamide and verapamil induced autophagy, which was associated with a significant reduction in the intracellular growth of Mtb in MACs and alveolar macrophages. The intraperitoneal administration of loperamide and valproic acid induced autophagy in freshly isolated MACs. The antimycobacterial activity in MACs was higher after loperamide treatment and was associated with the degradation of p62. In conclusion, loperamide shows potential as an adjunctive therapy for the treatment of TB.

Syndecan-2 Attenuates Radiation-induced Pulmonary Fibrosis and Inhibits Fibroblast Activation by Regulating PI3K/Akt/ROCK Pathway via CD148.

PubMed

Tsoyi, Konstantin; Chu, Sarah G; Patino-Jaramillo, Nasly G; Wilder, Julie; Villalba, Julian; Doyle-Eisele, Melanie; McDonald, Jacob; Liu, Xiaoli; El-Chemaly, Souheil; Perrella, Mark A; Rosas, Ivan O

2018-02-01

Radiation-induced pulmonary fibrosis is a severe complication of patients treated with thoracic irradiation. We have previously shown that syndecan-2 reduces fibrosis by exerting alveolar epithelial cytoprotective effects. Here, we investigate whether syndecan-2 attenuates radiation-induced pulmonary fibrosis by inhibiting fibroblast activation. C57BL/6 wild-type mice and transgenic mice that overexpress human syndecan-2 in alveolar macrophages were exposed to 14 Gy whole-thoracic radiation. At 24 weeks after irradiation, lungs were collected for histological, protein, and mRNA evaluation of pulmonary fibrosis, profibrotic gene expression, and α-smooth muscle actin (α-SMA) expression. Mouse lung fibroblasts were activated with transforming growth factor (TGF)-β1 in the presence or absence of syndecan-2. Cell proliferation, migration, and gel contraction were assessed at different time points. Irradiation resulted in significantly increased mortality and pulmonary fibrosis in wild-type mice that was associated with elevated lung expression of TGF-β1 downstream target genes and cell death compared with irradiated syndecan-2 transgenic mice. In mouse lung fibroblasts, syndecan-2 inhibited α-SMA expression, cell contraction, proliferation, and migration induced by TGF-β1. Syndecan-2 attenuated phosphoinositide 3-kinase/serine/threonine kinase/Rho-associated coiled-coil kinase signaling and serum response factor binding to the α-SMA promoter. Syndecan-2 attenuates pulmonary fibrosis in mice exposed to radiation and inhibits TGF-β1-induced fibroblast-myofibroblast differentiation, migration, and proliferation by down-regulating phosphoinositide 3-kinase/serine/threonine kinase/Rho-associated coiled-coil kinase signaling and blocking serum response factor binding to the α-SMA promoter via CD148. These findings suggest that syndecan-2 has potential as an antifibrotic therapy in radiation-induced lung fibrosis.

[Lung protective ventilation - pathophysiology and diagnostics].

PubMed

Uhlig, Stefan; Frerichs, Inéz

2008-06-01

Mechanical ventilation may lead to lung injury depending on the ventilatory settings (e.g. pressure amplitudes, endexpiratory pressures, frequency) and the length of mechanical ventilation. Particularly in the inhomogeneously injured lungs of ARDS patients, alveolar overextension results in volutrauma, cyclic opening and closure of alveolar units in atelectrauma. Particularly important appears to be the fact that these processes may also cause biotrauma, i.e. the ventilator-induced hyperactivation of inflammatory responses in the lung. These side effects are reduced, but not eliminated with the currently recommended ventilation strategy with a tidal volume of 6 ml/kg idealized body weight. It is our hope that in the future optimization of ventilator settings will be facilated by bedside monitoring of novel indices of respiratory mechanics such as the stress index or the Slice technique, and by innovative real-time imaging technologies such as electrical impedance tomography.

In vivo lung morphometry with hyperpolarized 3He diffusion MRI: Theoretical background

NASA Astrophysics Data System (ADS)

Sukstanskii, A. L.; Yablonskiy, D. A.

2008-02-01

MRI-based study of 3He gas diffusion in lungs may provide important information on lung microstructure. Lung acinar airways can be described in terms of cylinders covered with alveolar sleeve [Haefeli-Bleuer, Weibel, Anat. Rec. 220 (1988) 401]. For relatively short diffusion times (on the order of a few ms) this geometry allows description of the 3He diffusion attenuated MR signal in lungs in terms of two diffusion coefficients—longitudinal (D) and transverse (D) with respect to the individual acinar airway axis [Yablonskiy et al., PNAS 99 (2002) 3111]. In this paper, empirical relationships between D and D and the geometrical parameters of airways and alveoli are found by means of computer Monte Carlo simulations. The effects of non-Gaussian signal behavior (dependence of D and D on b-value) are also taken into account. The results obtained are quantitatively valid in the physiologically important range of airway parameters characteristic of healthy lungs and lungs with mild emphysema. In lungs with advanced emphysema, the results provide only "apparent" characteristics but still could potentially be used to evaluate emphysema progression. This creates a basis for in vivo lung morphometry—evaluation of the geometrical parameters of acinar airways from hyperpolarized 3He diffusion MRI, despite the airways being too small to be resolved by direct imaging. These results also predict a rather substantial dependence of 3He ADC on the experimentally-controllable diffusion time, Δ. If Δ is decreased from 3 ms to 1 ms, the ADC in normal human lungs may increase by almost 50%. This effect should be taken into account when comparing experimental data obtained with different pulse sequences.

Lipopolysaccharide modulation of a CD14-like molecule on porcine alveolar macrophages

NASA Technical Reports Server (NTRS)

Kielian, T. L.; Ross, C. R.; McVey, D. S.; Chapes, S. K.; Blecha, F.; Spooner, B. S. (Principal Investigator)

1995-01-01

Cluster of differentiation antigen 14 (CD14) functions as a receptor for lipopolysaccharide (LPS) LPS-binding protein (LBP) complexes. Because LPS has varying effects on CD14 expression in vitro, we evaluated CD14 expression in response to LPS with a fully differentiated macrophage phenotype, the alveolar macrophage. By using flow microfluorometric analysis and a radioimmunoassay with an anti-human CD14 monoclonal antibody (My4) that cross-reacts with porcine CD14, we found that macrophages stimulated with LPS for 24 h exhibited a two- to fivefold increase in CD14-like antigen compared with unstimulated cells. At low concentrations of LPS, up-regulation of the CD14-like antigen was dependent on serum; at higher concentrations of LPS, serum was not required. In the absence of serum a 10-fold higher dose of LPS (10 ng/ml) was required to increase CD14-like expression. In addition, LPS-induced CD14-like up-regulation correlated with secretion of tumor necrosis factor-alpha, regardless of serum concentration. Blockade with My4 antibody significantly inhibited LPS-induced tumor necrosis factor-alpha secretion at 1 ng/ml of LPS. However, inhibition decreased as we increased the LPS concentration, suggesting the existence of CD14-independent pathways of macrophage activation in response to LPS. Alternatively, My4 may have a lower affinity for the porcine CD14 antigen than LPS, which may have only partially blocked the LPS-LBP binding site at high concentrations of LPS. Therefore, these data suggest that LPS activation of porcine alveolar macrophages for 24 h increased CD14-like receptor expression. The degree of CD14-like up-regulation was related to LPS concentration, however, activation did not require the presence of serum at high concentrations of LPS.

DJ-1 Modulates Nuclear Erythroid 2-Related Factor-2-Mediated Protection in Human Primary Alveolar Type II Cells in Smokers.

PubMed

Bahmed, Karim; Messier, Elise M; Zhou, Wenbo; Tuder, Rubin M; Freed, Curt R; Chu, Hong Wei; Kelsen, Steven G; Bowler, Russell P; Mason, Robert J; Kosmider, Beata

2016-09-01

Cigarette smoke (CS) is a main source of oxidative stress and a key risk factor for emphysema, which consists of alveolar wall destruction. Alveolar type (AT) II cells are in the gas exchange regions of the lung. We isolated primary ATII cells from deidentified organ donors whose lungs were not suitable for transplantation. We analyzed the cell injury obtained from nonsmokers, moderate smokers, and heavy smokers. DJ-1 protects cells from oxidative stress and induces nuclear erythroid 2-related factor-2 (Nrf2) expression, which activates the antioxidant defense system. In ATII cells isolated from moderate smokers, we found DJ-1 expression by RT-PCR, and Nrf2 and heme oxygenase (HO)-1 translocation by Western blotting and immunocytofluorescence. In ATII cells isolated from heavy smokers, we detected Nrf2 and HO-1 cytoplasmic localization. Moreover, we found high oxidative stress, as detected by 4-hydroxynonenal (4-HNE) (immunoblotting), inflammation by IL-8 and IL-6 levels by ELISA, and apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay in ATII cells obtained from heavy smokers. Furthermore, we detected early DJ-1 and late Nrf2 expression after ATII cell treatment with CS extract. We also overexpressed DJ-1 by adenovirus construct and found that this restored Nrf2 and HO-1 expression and induced nuclear translocation in heavy smokers. Moreover, DJ-1 overexpression also decreased ATII cell apoptosis caused by CS extract in vitro. Our results indicate that DJ-1 activates the Nrf2-mediated antioxidant defense system. Furthermore, DJ-1 overexpression can restore the impaired Nrf2 pathway, leading to ATII cell protection in heavy smokers. This suggests a potential therapeutic strategy for targeting DJ-1 in CS-related lung diseases.

Prenatal retinoic acid treatment upregulates late gestation lung protein 1 in the nitrofen-induced hypoplastic lung in late gestation.

PubMed

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

2011-02-01

Pulmonary hypoplasia (PH), the leading cause of mortality in congenital diaphragmatic hernia (CDH), is associated with arrested alveolarization. Late gestation lung protein 1 (LGL1) plays a crucial role in the regulation of alveolarization. Inhibition of LGL1 impairs alveolar maturation in fetal rat lungs. LGL1 heterozygotus knockout mice display delayed lung maturation. It is well known that prenatal administration of retinoic acid (RA) stimulates alveologenesis in nitrofen-induced PH. In vitro studies have reported that RA is a key modulator of LGL1 during alveologenesis. We hypothesized, that pulmonary gene expression of LGL1 is downregulated in the late stage of lung development, and that prenatal administration of RA upregulates pulmonary LGL1 expression in the nitrofen CDH model. Pregnant rats were exposed to nitrofen on day 9 (D9) of gestation. RA was given intraperitoneally on D18, D19 and D20. Fetal lungs were dissected on D21 and divided into control, control + RA, CDH and CDH + RA group. Expression levels of LGL1 were determined using RT-PCR and immunohistochemistry. On D21, LGL1 relative mRNA expression levels were significantly downregulated in CDH group compared to controls. After RA treatment, gene expression levels of LGL1 were significantly upregulated in CDH + RA and control + RA compared to CDH group. Immunohistochemical studies confirmed these results. Downregulation of pulmonary LGL1 gene expression in the late stage of lung development may interfere with normal alveologenesis. Upregulation of LGL1 pulmonary gene expression after RA treatment may promote lung growth by stimulating alveologenesis in the nitrofen CDH model.

Experimental progressive emphysema in BALB/cJ mice as a model for chronic alveolar destruction in humans

PubMed Central

Limjunyawong, Nathachit; Craig, John M.; Lagassé, H. A. Daniel; Scott, Alan L.

2015-01-01

Emphysema, one of the major components of chronic obstructive pulmonary disease (COPD), is characterized by the progressive and irreversible loss of alveolar lung tissue. Even though >80% of COPD cases are associated with cigarette smoking, only a relatively small proportion of smokers develop emphysema, suggesting a potential role for genetic factors in determining individual susceptibility to emphysema. Although strain-dependent effects have been shown in animal models of emphysema, the molecular basis underlying this intrinsic susceptibility is not fully understood. In this present study, we investigated emphysema development using the elastase-induced experimental emphysema model in two commonly used mouse strains, C57BL/6J and BALB/cJ. The results demonstrate that mice with different genetic backgrounds show disparate susceptibility to the development of emphysema. BALB/cJ mice were found to be much more sensitive than C57BL/6J to elastase injury in both a dose-dependent and time-dependent manner, as measured by significantly higher mortality, greater body weight loss, greater decline in lung function, and a greater loss of alveolar tissue. The more susceptible BALB/cJ strain also showed the persistence of inflammatory cells in the lung, especially macrophages and lymphocytes. A comparative gene expression analysis following elastase-induced injury showed BALB/cJ mice had elevated levels of il17A mRNA and a number of classically (M1) and alternatively (M2) activated macrophage genes, whereas the C57BL/6J mice demonstrated augmented levels of interferon-γ. These findings suggest a possible role for these cellular and molecular mediators in modulating the severity of emphysema and highlight the possibility that they might contribute to the heterogeneity observed in clinical emphysema outcomes. PMID:26232300

Experimental progressive emphysema in BALB/cJ mice as a model for chronic alveolar destruction in humans.

PubMed

Limjunyawong, Nathachit; Craig, John M; Lagassé, H A Daniel; Scott, Alan L; Mitzner, Wayne

2015-10-01

Emphysema, one of the major components of chronic obstructive pulmonary disease (COPD), is characterized by the progressive and irreversible loss of alveolar lung tissue. Even though >80% of COPD cases are associated with cigarette smoking, only a relatively small proportion of smokers develop emphysema, suggesting a potential role for genetic factors in determining individual susceptibility to emphysema. Although strain-dependent effects have been shown in animal models of emphysema, the molecular basis underlying this intrinsic susceptibility is not fully understood. In this present study, we investigated emphysema development using the elastase-induced experimental emphysema model in two commonly used mouse strains, C57BL/6J and BALB/cJ. The results demonstrate that mice with different genetic backgrounds show disparate susceptibility to the development of emphysema. BALB/cJ mice were found to be much more sensitive than C57BL/6J to elastase injury in both a dose-dependent and time-dependent manner, as measured by significantly higher mortality, greater body weight loss, greater decline in lung function, and a greater loss of alveolar tissue. The more susceptible BALB/cJ strain also showed the persistence of inflammatory cells in the lung, especially macrophages and lymphocytes. A comparative gene expression analysis following elastase-induced injury showed BALB/cJ mice had elevated levels of il17A mRNA and a number of classically (M1) and alternatively (M2) activated macrophage genes, whereas the C57BL/6J mice demonstrated augmented levels of interferon-γ. These findings suggest a possible role for these cellular and molecular mediators in modulating the severity of emphysema and highlight the possibility that they might contribute to the heterogeneity observed in clinical emphysema outcomes. Copyright © 2015 the American Physiological Society.

Activated prostaglandin D2 receptors on macrophages enhance neutrophil recruitment into the lung

PubMed Central

Jandl, Katharina; Stacher, Elvira; Bálint, Zoltán; Sturm, Eva Maria; Maric, Jovana; Peinhaupt, Miriam; Luschnig, Petra; Aringer, Ida; Fauland, Alexander; Konya, Viktoria; Dahlen, Sven-Erik; Wheelock, Craig E.; Kratky, Dagmar; Olschewski, Andrea; Marsche, Gunther; Schuligoi, Rufina; Heinemann, Akos

2016-01-01

Background Prostaglandin (PG) D2 is an early-phase mediator in inflammation, but its action and the roles of the 2 D-type prostanoid receptors (DPs) DP1 and DP2 (also called chemoattractant receptor–homologous molecule expressed on TH2 cells) in regulating macrophages have not been elucidated to date. Objective We investigated the role of PGD2 receptors on primary human macrophages, as well as primary murine lung macrophages, and their ability to influence neutrophil action in vitro and in vivo. Methods In vitro studies, including migration, Ca2+ flux, and cytokine secretion, were conducted with primary human monocyte-derived macrophages and neutrophils and freshly isolated murine alveolar and pulmonary interstitial macrophages. In vivo pulmonary inflammation was assessed in male BALB/c mice. Results Activation of DP1, DP2, or both receptors on human macrophages induced strong intracellular Ca2+ flux, cytokine release, and migration of macrophages. In a murine model of LPS-induced pulmonary inflammation, activation of each PGD2 receptor resulted in aggravated airway neutrophilia, tissue myeloperoxidase activity, cytokine contents, and decreased lung compliance. Selective depletion of alveolar macrophages abolished the PGD2-enhanced inflammatory response. Activation of PGD2 receptors on human macrophages enhanced the migratory capacity and prolonged the survival of neutrophils in vitro. In human lung tissue specimens both DP1 and DP2 receptors were located on alveolar macrophages along with hematopoietic PGD synthase, the rate-limiting enzyme of PGD2 synthesis. Conclusion For the first time, our results show that PGD2 markedly augments disease activity through its ability to enhance the proinflammatory actions of macrophages and subsequent neutrophil activation. PMID:26792210

Activated prostaglandin D2 receptors on macrophages enhance neutrophil recruitment into the lung.

PubMed

Jandl, Katharina; Stacher, Elvira; Bálint, Zoltán; Sturm, Eva Maria; Maric, Jovana; Peinhaupt, Miriam; Luschnig, Petra; Aringer, Ida; Fauland, Alexander; Konya, Viktoria; Dahlen, Sven-Erik; Wheelock, Craig E; Kratky, Dagmar; Olschewski, Andrea; Marsche, Gunther; Schuligoi, Rufina; Heinemann, Akos

2016-03-01

Prostaglandin (PG) D2 is an early-phase mediator in inflammation, but its action and the roles of the 2 D-type prostanoid receptors (DPs) DP1 and DP2 (also called chemoattractant receptor-homologous molecule expressed on T(H)2 cells) in regulating macrophages have not been elucidated to date. We investigated the role of PGD2 receptors on primary human macrophages, as well as primary murine lung macrophages, and their ability to influence neutrophil action in vitro and in vivo. In vitro studies, including migration, Ca(2+) flux, and cytokine secretion, were conducted with primary human monocyte-derived macrophages and neutrophils and freshly isolated murine alveolar and pulmonary interstitial macrophages. In vivo pulmonary inflammation was assessed in male BALB/c mice. Activation of DP1, DP2, or both receptors on human macrophages induced strong intracellular Ca(2+) flux, cytokine release, and migration of macrophages. In a murine model of LPS-induced pulmonary inflammation, activation of each PGD2 receptor resulted in aggravated airway neutrophilia, tissue myeloperoxidase activity, cytokine contents, and decreased lung compliance. Selective depletion of alveolar macrophages abolished the PGD2-enhanced inflammatory response. Activation of PGD2 receptors on human macrophages enhanced the migratory capacity and prolonged the survival of neutrophils in vitro. In human lung tissue specimens both DP1 and DP2 receptors were located on alveolar macrophages along with hematopoietic PGD synthase, the rate-limiting enzyme of PGD2 synthesis. For the first time, our results show that PGD2 markedly augments disease activity through its ability to enhance the proinflammatory actions of macrophages and subsequent neutrophil activation. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

DJ-1 Modulates Nuclear Erythroid 2–Related Factor-2–Mediated Protection in Human Primary Alveolar Type II Cells in Smokers

PubMed Central

Bahmed, Karim; Messier, Elise M.; Zhou, Wenbo; Tuder, Rubin M.; Freed, Curt R.; Chu, Hong Wei; Kelsen, Steven G.; Bowler, Russell P.; Mason, Robert J.

2016-01-01

Cigarette smoke (CS) is a main source of oxidative stress and a key risk factor for emphysema, which consists of alveolar wall destruction. Alveolar type (AT) II cells are in the gas exchange regions of the lung. We isolated primary ATII cells from deidentified organ donors whose lungs were not suitable for transplantation. We analyzed the cell injury obtained from nonsmokers, moderate smokers, and heavy smokers. DJ-1 protects cells from oxidative stress and induces nuclear erythroid 2–related factor-2 (Nrf2) expression, which activates the antioxidant defense system. In ATII cells isolated from moderate smokers, we found DJ-1 expression by RT-PCR, and Nrf2 and heme oxygenase (HO)-1 translocation by Western blotting and immunocytofluorescence. In ATII cells isolated from heavy smokers, we detected Nrf2 and HO-1 cytoplasmic localization. Moreover, we found high oxidative stress, as detected by 4-hydroxynonenal (4-HNE) (immunoblotting), inflammation by IL-8 and IL-6 levels by ELISA, and apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay in ATII cells obtained from heavy smokers. Furthermore, we detected early DJ-1 and late Nrf2 expression after ATII cell treatment with CS extract. We also overexpressed DJ-1 by adenovirus construct and found that this restored Nrf2 and HO-1 expression and induced nuclear translocation in heavy smokers. Moreover, DJ-1 overexpression also decreased ATII cell apoptosis caused by CS extract in vitro. Our results indicate that DJ-1 activates the Nrf2-mediated antioxidant defense system. Furthermore, DJ-1 overexpression can restore the impaired Nrf2 pathway, leading to ATII cell protection in heavy smokers. This suggests a potential therapeutic strategy for targeting DJ-1 in CS-related lung diseases. PMID:27093578

Maternal deprivation decelerates postnatal morphological lung development of F344 rats.

PubMed

Hupa, Katharina Luise; Schmiedl, Andreas; Pabst, Reinhard; Von Hörsten, Stephan; Stephan, Michael

2014-02-01

Intensive medical care at premature born infants is often associated with separation of neonates from their mothers. Here, early artificial prolonged separation of rat pups from their dams (Maternal Deprivation, MD) was used to study potential impact on morphological lung maturation. Furthermore, we investigated the influence of an endogenous deficiency of the neuropeptide-cleaving dipeptidyl peptidase IV (DPP4), since the effects of MD are known to be partly mediated via neuropeptidergic effects, hypothesizing that MD will lead to a retardation of postnatal lung development, DPP4-dependendly. We used wild type and CD26/DPP4 deficient rats. For MD, the dam was placed each day into a separate cage for 2 h, while the pups remained in the nest on their own. Morphological lung maturation and cell proliferation at the postnatal days 7, 10, 14, and 21 were determined morphometrically. Maternally deprived wild types showed a retarded postnatal lung development compared with untreated controls in both substrains. During alveolarization, an increased thickness of alveolar septa and a decreased surface of septa about 50% were found. At the end of the morphological lung maturation, the surface of the alveolar septa was decreased at about 25% and the septal thickness remained increased about 20%. The proliferation rate was also decreased about 50% on day 14. However, the MD induced effects were less pronounced in DPP4-deficient rats, due to a significant deceleration already induced by DPP4-deficiency. Thus, MD as a model for postnatal stress experience influences remarkably postnatal development of rats, which is significantly modulated by the DPP4-system. Copyright © 2013 Wiley Periodicals, Inc.

Maternal PUFA ω-3 Supplementation Prevents Neonatal Lung Injuries Induced by Hyperoxia in Newborn Rats.

PubMed

Sharma, Dyuti; Nkembi, Armande Subayi; Aubry, Estelle; Houeijeh, Ali; Butruille, Laura; Houfflin-Debarge, Véronique; Besson, Rémi; Deruelle, Philippe; Storme, Laurent

2015-09-14

Bronchopulmonary dysplasia (BPD) is one of the most common complications of prematurity, occurring in 30% of very low birth weight infants. The benefits of dietary intake of polyunsaturated fatty acids ω-3 (PUFA ω-3) during pregnancy or the perinatal period have been reported. The aim of this study was to assess the effects of maternal PUFA ω-3 supplementation on lung injuries in newborn rats exposed to prolonged hyperoxia. Pregnant female Wistar rats (n = 14) were fed a control diet (n = 2), a PUFA ω-6 diet (n = 6), or a PUFA ω-3 diet (n = 6), starting with the 14th gestation day. At Day 1, female and newborn rats (10 per female) were exposed to hyperoxia (O₂, n = 70) or to the ambient air (Air, n = 70). Six groups of newborns rats were obtained: PUFA ω-6/O₂ (n = 30), PUFA ω-6/air (n = 30), PUFA ω-3/O₂ (n = 30), PUFA ω-3/air (n = 30), control/O₂ (n = 10), and control/air (n = 10). After 10 days, lungs were removed for analysis of alveolarization and pulmonary vascular development. Survival rate was 100%. Hyperoxia reduced alveolarization and increased pulmonary vascular wall thickness in both control (n = 20) and PUFA ω-6 groups (n = 60). Maternal PUFA ω-3 supplementation prevented the decrease in alveolarization caused by hyperoxia (n = 30) compared to PUFA ω-6/O₂ (n = 30) or to the control/O₂ (n = 10), but did not significantly increase the thickness of the lung vascular wall. Therefore, maternal PUFA ω-3 supplementation may protect newborn rats from lung injuries induced by hyperoxia. In clinical settings, maternal PUFA ω-3 supplementation during pregnancy and during lactation may prevent BPD development after premature birth.

Selective targeting of alveolar type II respiratory epithelial cells by anti-surfactant protein-C antibody-conjugated lipoplexes

PubMed Central

Wu, Yun; Ma, Junyu; Woods, Parker S.; Chesarino, Nicholas M.; Liu, Chang; Lee, L. James; Nana-Sinkam, Serge P.; Davis, Ian C.

2015-01-01

Alveolar type II (ATII) respiratory epithelial cells are essential to normal lung function. They may be also central to the pathogenesis of diseases such as acute lung injury, pulmonary fibrosis, and pulmonary adenocarcinoma. Hence, ATII cells are important therapeutic targets. However, effective ATII cell-specific drug delivery in vivo requires carriers of an appropriate size, which can cross the hydrophobic alveolar surfactant film and polar aqueous layer overlying ATII cells, and be taken up without inducing ATII cell dysfunction, pulmonary inflammation, lung damage, or excessive systemic spread and side-effects. We have developed lipoplexes as a versatile nanoparticle carrier system for drug/RNA delivery. To optimize their pulmonary localization and ATII cell specificity, lipoplexes were conjugated to an antibody directed against the ATII cell-specific antigen surfactant protein-C (SP-C) then administered to C57BL/6 mice via the nares. Intranasally-administered, anti-SP-C-conjugated lipoplexes targeted mouse ATII cells with >70% specificity in vivo, were retained within ATII cells for at least 48 hours, and did not accumulate at significant levels in other lung cell types or viscera. 48 hours after treatment with anti-SP-C-conjugated lipoplexes containing the test microRNA miR-486, expression of mature miR-486 was approximately 4-fold higher in ATII cells than whole lung by qRT-PCR, and was undetectable in other viscera. Lipoplexes induced no weight loss, hypoxemia, lung dysfunction, pulmonary edema, or pulmonary inflammation over a 6-day period. These findings indicate that ATII cell-targeted lipoplexes exhibit all the desired characteristics of an effective drug delivery system for treatment of pulmonary diseases that result primarily from ATII cell dysfunction. PMID:25687308

An automatic early stage alveolar-bone-resorption evaluation method on digital dental panoramic radiographs

NASA Astrophysics Data System (ADS)

Zhang, Min; Katsumata, Akitoshi; Muramatsu, Chisako; Hara, Takeshi; Suzuki, Hiroki; Fujita, Hiroshi

2014-03-01

Periodontal disease is a kind of typical dental diseases, which affects many adults. The presence of alveolar bone resorption, which can be observed from dental panoramic radiographs, is one of the most important signs of the progression of periodontal disease. Automatically evaluating alveolar-bone resorption is of important clinic meaning in dental radiology. The purpose of this study was to propose a novel system for automated alveolar-bone-resorption evaluation from digital dental panoramic radiographs for the first time. The proposed system enables visualization and quantitative evaluation of alveolar bone resorption degree surrounding the teeth. It has the following procedures: (1) pre-processing for a test image; (2) detection of tooth root apices with Gabor filter and curve fitting for the root apex line; (3) detection of features related with alveolar bone by using image phase congruency map and template matching and curving fitting for the alveolar line; (4) detection of occlusion line with selected Gabor filter; (5) finally, evaluation of the quantitative alveolar-bone-resorption degree in the area surrounding teeth by simply computing the average ratio of the height of the alveolar bone and the height of the teeth. The proposed scheme was applied to 30 patient cases of digital panoramic radiographs, with alveolar bone resorption of different stages. Our initial trial on these test cases indicates that the quantitative evaluation results are correlated with the alveolar-boneresorption degree, although the performance still needs further improvement. Therefore it has potential clinical practicability.

Molecular and cellular characteristics of ABCA3 mutations associated with diffuse parenchymal lung diseases in children

PubMed Central

Flamein, Florence; Riffault, Laure; Muselet-Charlier, Céline; Pernelle, Julie; Feldmann, Delphine; Jonard, Laurence; Durand-Schneider, Anne-Marie; Coulomb, Aurore; Maurice, Michèle; Nogee, Lawrence M.; Inagaki, Nobuya; Amselem, Serge; Dubus, Jean Christophe; Rigourd, Virginie; Brémont, François; Marguet, Christophe; Brouard, Jacques; de Blic, Jacques; Clement, Annick; Epaud, Ralph; Guillot, Loïc

2012-01-01

ABCA3 (ATP-binding cassette subfamily A, member 3) is expressed in the lamellar bodies of alveolar type II cells and is crucial to pulmonary surfactant storage and homeostasis. ABCA3 gene mutations have been associated with neonatal respiratory distress (NRD) and pediatric interstitial lung disease (ILD). The objective of this study was to look for ABCA3 gene mutations in patients with severe NRD and/or ILD. The 30 ABCA3 coding exons were screened in 47 patients with severe NRD and/or ILD. ABCA3 mutations were identified in 10 out of 47 patients, including 2 homozygous, 5 compound heterozygous and 3 heterozygous patients. SP-B and SP-C expression patterns varied across patients. Among patients with ABCA3 mutations, five died shortly after birth and five developed ILD (including one without NRD). Functional studies of p.D253H and p.T1173R mutations revealed that p.D253H and p.T1173R induced abnormal lamellar bodies. Additionally, p.T1173R increased IL-8 secretion in vitro. In conclusion, we identified new ABCA3 mutations in patients with life-threatening NRD and/or ILD. Two mutations associated with ILD acted via different pathophysiological mechanisms despite similar clinical phenotypes. PMID:22068586

Trace metals in fluids lining the respiratory system of patients with idiopathic pulmonary fibrosis and diffuse lung diseases.

PubMed

Bargagli, Elena; Lavorini, Federico; Pistolesi, Massimo; Rosi, Elisabetta; Prasse, Antje; Rota, Emilia; Voltolini, Luca

2017-07-01

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease with a poor prognosis and an undefined etiopathogenesis. Oxidative stress contributes to alveolar injury and fibrosis development and, because transition metals are essential to the functioning of most proteins involved in redox reactions, a better knowledge of metal concentrations and metabolism in the respiratory system of IPF patients may provide a valuable complementary approach to prevent and manage a disease which is often misdiagnosed or diagnosed in later stages. The present review summarizes and discusses literature data on the elemental composition of bronchoalveolar lavage (BAL), induced sputum and exhaled breath condensate (EBC) from patients affected by IPF and healthy subjects. Available data are scanty and the lack of consistent methods for the collection and analysis of lung and airways lining fluids makes it difficult to compare the results of different studies. However, the elemental composition of BAL samples from IPF patients seems to have a specific profile that can be distinguished from that of patients with other interstitial lung diseases (ILD) or control subjects. Suggestions are given towards standard sampling and analytical procedures of BAL samples, in the aim to assess typical element concentration patterns and their potential role as biomarkers of IPF. Copyright © 2017 Elsevier GmbH. All rights reserved.

Mechanisms of Severe Acute Respiratory Syndrome Coronavirus-Induced Acute Lung Injury

PubMed Central

Gralinski, Lisa E.; Bankhead, Armand; Jeng, Sophia; Menachery, Vineet D.; Proll, Sean; Belisle, Sarah E.; Matzke, Melissa; Webb-Robertson, Bobbie-Jo M.; Luna, Maria L.; Shukla, Anil K.; Ferris, Martin T.; Bolles, Meagan; Chang, Jean; Aicher, Lauri; Waters, Katrina M.; Smith, Richard D.; Metz, Thomas O.; Law, G. Lynn; Katze, Michael G.; McWeeney, Shannon; Baric, Ralph S.

2013-01-01

ABSTRACT Systems biology offers considerable promise in uncovering novel pathways by which viruses and other microbial pathogens interact with host signaling and expression networks to mediate disease severity. In this study, we have developed an unbiased modeling approach to identify new pathways and network connections mediating acute lung injury, using severe acute respiratory syndrome coronavirus (SARS-CoV) as a model pathogen. We utilized a time course of matched virologic, pathological, and transcriptomic data within a novel methodological framework that can detect pathway enrichment among key highly connected network genes. This unbiased approach produced a high-priority list of 4 genes in one pathway out of over 3,500 genes that were differentially expressed following SARS-CoV infection. With these data, we predicted that the urokinase and other wound repair pathways would regulate lethal versus sublethal disease following SARS-CoV infection in mice. We validated the importance of the urokinase pathway for SARS-CoV disease severity using genetically defined knockout mice, proteomic correlates of pathway activation, and pathological disease severity. The results of these studies demonstrate that a fine balance exists between host coagulation and fibrinolysin pathways regulating pathological disease outcomes, including diffuse alveolar damage and acute lung injury, following infection with highly pathogenic respiratory viruses, such as SARS-CoV. PMID:23919993

Extracorporeal Membrane Oxygenation for Refractory Severe Respiratory Failure in Acute Interstitial Pneumonia.

PubMed

Gonçalves-Venade, Gabriela; Lacerda-Príncipe, Nuno; Roncon-Albuquerque, Roberto; Paiva, José Artur

2018-05-01

Acute interstitial pneumonia (AIP) is a rare idiopathic interstitial lung disease with rapid progressive respiratory failure and high mortality. In the present report, three cases of AIP complicated by refractory respiratory failure supported with extracorporeal membrane oxygenation (ECMO) are presented. One male and two female patients (ages 27-59) were included. Venovenous ECMO support was provided using miniaturized systems, with two-site femoro-jugular circuit configuration. Despite lung protective ventilation, prone position and neuromuscular blockade, refractory respiratory failure of unknown etiology supervened (ratio of arterial oxygen partial pressure to fractional inspired oxygen 46-130) and ECMO was initiated after 3-7 days of mechanical ventilation. AIP diagnosis was established after exclusion of infectious and noninfectious acute respiratory distress syndrome on the basis of clinical and analytical data, bronchoalveolar lavage analysis and lung imaging, with a confirmatory surgical lung biopsy revealing diffuse alveolar damage of unknown etiology. Immunosuppressive treatment consisted in high-dose corticosteroids and cyclophosphamide in one case. Two patients survived to hospital discharge. ECMO allowed AIP diagnosis and treatment in the presence of refractory respiratory failure, therefore reducing ventilator-induced lung injury and bridging lung recovery in two patients. ECMO referral should be considered in refractory respiratory failure if AIP is suspected. © 2018 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

Evolution and development of gas exchange structures in Mammalia: the placenta and the lung.

PubMed

Mess, Andrea M; Ferner, Kirsten J

2010-08-31

Appropriate oxygen supply is crucial for organisms. Here we examine the evolution of structures associated with the delivery of oxygen in the pre- and postnatal phases in mammals. There is an enormous structural and functional variability in the placenta that has facilitated the evolution of specialized reproductive strategies, such as precociality. In particular the cell layers separating fetal and maternal blood differ markedly: a non-invasive epitheliochorial placenta, which increases the diffusion distance, represents a derived state in ungulates. Rodents and their relatives have an invasive haemochorial placental type as optimum for the diffusion distance. In contrast, lung development is highly conserved and differences in the lungs of neonates can be explained by different developmental rates. Monotremes and marsupials have altricial stages with lungs at the early saccular phase, whereas newborn eutherians have lungs at the late saccular or alveolar phase. In conclusion, the evolution of exchange structures in the pre- and postnatal periods does not follow similar principles. Copyright (c) 2010 Elsevier B.V. All rights reserved.