A nocturnal decline of salivary pH associated with airway hyperresponsiveness in asthma.

PubMed

Watanabe, Masanari; Sano, Hiroyuki; Tomita, Katsuyuki; Yamasaki, Akira; Kurai, Jun; Hasegawa, Yasuyuki; Igishi, Tadashi; Okazaki, Ryota; Tohda, Yuji; Burioka, Naoto; Shimizu, Eiji

2010-08-01

Salivary pH is associated with esophageal acid reflux and neutralization of esophageal acid. In this study, we assessed the association between nocturnal decline of salivary pH and airway hyperresponsiveness. Salivary pH was serially assessed in 9 patients with mild asthma (7 men and 2 women; mean age 33.3 years; mean %predicted FEV(1.0) 89.4%) and 10 healthy volunteers (6 men and 4 women; mean age 31.2 years) using a pH indicator tape. The buffering capacity of saliva was defined as the median effective dose (ED(50)) for acidification of saliva with 0.01 N HCl, and airway responsiveness was defined as the dose of methacholine producing a 35% fall in Grs (PD(35)-Grs). There was a significant correlation between the values obtained from the pH indicator tape and those obtained from the electrometric pH meter. Using the indicator tape for sequential monitoring, we observed a nocturnal fall (ΔpH) in salivary pH in all subjects. A significant correlation was found between airway hyperresponsiveness (PD(35)-Grs) and either ΔpH or ED(50) in mildly asthmatic patients. Vagal reflux dysfunction might contribute to nocturnal salivary pH as well as to airway hyperresponsiveness in mild asthmatics.

Diesel exhaust particulate induces airway hyperresponsiveness in a murine model: essential role of GM-CSF.

PubMed

Ohta, K; Yamashita, N; Tajima, M; Miyasaka, T; Nakano, J; Nakajima, M; Ishii, A; Horiuchi, T; Mano, K; Miyamoto, T

1999-11-01

Inhaled pollutants were recently shown to be responsible for an increased incidence of airway allergic diseases, including asthma. A common feature of all forms of asthma is airway hyperresponsiveness. Our purpose was to elucidate the effects of diesel exhaust particulate (DEP), one of the most prevalent inhaled pollutants, on airway responsiveness. A/J and C57Bl/6 mice were used; the former are genetically predisposed to be hyperresponsive to acetylcholine, whereas the latter are not. DEP was administered intranasally for 2 weeks, after which pulmonary function was analyzed by whole-body plethysmography. Intranasal administration of DEP increased airway responsiveness to acetylcholine in both A/J and C57Bl/6 mice and induced displacement of ciliated epithelial cells by mucus-secreting Clara cells. The effect was mediated by M(3) muscarinic receptors. Acetylcholine-evoked bronchial constriction was reversed by administration of terbutaline, a beta(2)-adrenergic antagonist, which is also characteristic of human asthma. Intranasal administration of antibody raised against GM-CSF abolished DEP-evoked increases in airway responsiveness and Clara cell hyperplasia. The antibody raised against IL-4 also inhibited DEP-evoked increases in airway responsiveness. However, it was to a lesser extent compared with antibody against GM-CSF. In addition, DEP stimulated GM-CSF messenger RNA expression in the lung. DEP induces airway hyperresponsiveness by stimulating GM-CSF synthesis.

Inhibition of TRPC3 downregulates airway hyperresponsiveness, remodeling of OVA-sensitized mouse.

PubMed

Wang, Lingwei; Li, Jie; Zhang, Jian; He, Qi; Weng, Xuanwen; Huang, Yanmei; Guan, Minjie; Qiu, Chen

2017-02-26

Airway hyperresponsiveness (AHR), airway remodeling and inflammation are the fundamental pathological alterations that occur in asthma. Transient receptor potential canonical 3 (TRPC3) has been implicated in diverse functions of airway smooth muscle cells (ASMCs) in asthma. However, the underlying mechanisms remain incompletely understood. We investigated the mRNA and protein expression of TRPC3 in ASMCs from normal and OVA-sensitized mouse. And the effects of inhibition or knockdown of TRPC3 with Ethyl-1- (4- (2,3,3-trichloroacrylamide) phenyl) -5 - (trifluoromethyl) -1H -pyrazole -4-carboxylate (Pyr3) and lentiviral shRNA on OVA-sensitized mouse AHR, airway remodeling, circulating inflammatory cytokines, cell proliferation and migration. We found that TRPC3 mRNA and protein expression levels were significantly increased in ASMCs from OVA-sensitized mouse. Inhibiting TRPC3 with continuous subcutaneous administration of Pyr3 decreased enhanced pause (Penh) of OVA-sensitized mouse. Meanwhile, both Pyr3 and lentiviral shRNA treatment of ASMCs in OVA-sensitized mouse significantly decreased their proliferation and migration. These results suggest that TRPC3 plays a critical role in asthma and represents a promising new target for asthma treatment. Copyright © 2016 Elsevier Inc. All rights reserved.

Inhibition of TRPC3 downregulates airway hyperresponsiveness, remodeling of OVA-sensitized mouse

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

Wang, Lingwei; Li, Jie; Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou

Airway hyperresponsiveness (AHR), airway remodeling and inflammation are the fundamental pathological alterations that occur in asthma. Transient receptor potential canonical 3 (TRPC3) has been implicated in diverse functions of airway smooth muscle cells (ASMCs) in asthma. However, the underlying mechanisms remain incompletely understood. We investigated the mRNA and protein expression of TRPC3 in ASMCs from normal and OVA-sensitized mouse. And the effects of inhibition or knockdown of TRPC3 with Ethyl-1- (4- (2,3,3-trichloroacrylamide) phenyl) −5 - (trifluoromethyl) -1H -pyrazole -4-carboxylate (Pyr3) and lentiviral shRNA on OVA-sensitized mouse AHR, airway remodeling, circulating inflammatory cytokines, cell proliferation and migration. We found that TRPC3 mRNAmore » and protein expression levels were significantly increased in ASMCs from OVA-sensitized mouse. Inhibiting TRPC3 with continuous subcutaneous administration of Pyr3 decreased enhanced pause (Penh) of OVA-sensitized mouse. Meanwhile, both Pyr3 and lentiviral shRNA treatment of ASMCs in OVA-sensitized mouse significantly decreased their proliferation and migration. These results suggest that TRPC3 plays a critical role in asthma and represents a promising new target for asthma treatment. - Highlights: • Penh, airway remodeling and the gene expression and protein of TRPC3 are increased in OVA-sensitized mice. • Inhibition of TRPC3 suppresses the OVA-sensitized mice Penh and airway remodeling. • Inhibition of TRPC3 decreases OVA-sensitized mice ASMC proliferation and migration.« less

S100A8 protein attenuates airway hyperresponsiveness by suppressing the contraction of airway smooth muscle.

PubMed

Xu, Yu-Dong; Wang, Yu; Yin, Lei-Miao; Park, Gyoung-Hee; Ulloa, Luis; Yang, Yong-Qing

2017-02-26

Airway hyperresponsiveness (AHR) is a major clinical problem in allergic asthma mainly caused by the hypercontractility of airway smooth muscles (ASM). S100A8 is an important member of the S100 calcium-binding protein family with a potential to regulate cell contractility. Here, we analyze the potential of S100A8 to regulate allergen-induced AHR and ASM contraction. Treatment with recombinant S100A8 (rS100A8) diminished airway hyperresponsiveness in OVA-sensitized rats. ASM contraction assays showed that rS100A8 reduced hypercontractility in both isolated tracheal rings and primary ASM cells treated by acetylcholine. rS100A8 markedly rescued the phosphorylation level of myosin light chain induced by acetylcholine in ASM cells. These results show that rS100A8 plays a protective role in regulating AHR in asthma by inhibiting ASM contraction. These results support S100A8 as a novel therapeutic target to control ASM contraction in asthma. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Retinoic acid reverses the airway hyperresponsiveness but not the parenchymal defect that is associated with vitamin A deficiency.

PubMed

McGowan, Stephen E; Holmes, Amey Jo; Smith, Jennifer

2004-02-01

Airway hyperresponsiveness (AHR) is influenced by structural components of the bronchial wall, including the smooth muscle and connective tissue elements and the neuromuscular function. AHR is also influenced by parenchymally derived tethering forces on the bronchial wall, which maintain airway caliber by producing outward radial traction. Our previous work has shown that vitamin A-deficient (VAD) rats exhibit cholinergic hyperresponsiveness and a decrease in the expression and function of the muscarinic-2 receptors (M2R). We hypothesized that if decreases in radial traction from airway or parenchymal structures contributed to the VAD-related increase in AHR, then the radial traction would normalize more slowly than VAD-related alterations in neurotransmitter signaling. Rats remained vitamin A sufficient (VAS) or were rendered VAD and then maintained on the VAD diet in the presence or absence of supplementation with all-trans retinoic acid (RA). VAD was associated with an approximately twofold increase in respiratory resistance and elastance compared with VAS rats. Exposure to RA for 12 days but not 4 days restored resistance and elastance to control (VAS) levels. In VAD rats, AHR was accompanied by decreases in bronchial M2R gene expression and function, which were restored after 12 days of RA supplementation. Subepithelial bronchial elastic fibers were decreased by approximately 50% in VAD rats and were significantly restored by RA. The increase in AHR that is associated with VAD is accompanied by decreases in M2R expression and function that can be restored by RA and a reduction in airway elastic fibers that can be partially restored by RA.

A 'Good' muscle in a 'Bad' environment: the importance of airway smooth muscle force adaptation to airway hyperresponsiveness.

PubMed

Bossé, Ynuk; Chapman, David G; Paré, Peter D; King, Gregory G; Salome, Cheryl M

2011-12-15

Asthma is characterized by airway inflammation, with a consequent increase in spasmogens, and exaggerated airway narrowing in response to stimuli, termed airway hyperresponsiveness (AHR). The nature of any relationship between inflammation and AHR is less clear. Recent ex vivo data has suggested a novel mechanism by which inflammation may lead to AHR, in which increased basal ASM-tone, due to the presence of spasmogens in the airways, may "strengthen" the ASM and ultimately lead to exaggerated airway narrowing. This phenomenon was termed "force adaptation" [Bossé, Y., Chin, L.Y., Paré, P.D., Seow, C.Y., 2009. Adaptation of airway smooth muscle to basal tone: relevance to airway hyperresponsiveness. Am. J. Respir. Cell Mol. Biol. 40, 13-18]. However, it is unknown whether the magnitude of the effect of force adaptation ex vivo could contribute to exaggerated airway narrowing in vivo. Our aim was to utilize a computational model of ASM shortening in order to quantify the potential effect of force adaptation on airway narrowing when all other mechanical factors were kept constant. The shortening in the model is dictated by a balance between physiological loads and ASM force-generating capacity at different lengths. The results suggest that the magnitude of the effect of force adaptation on ASM shortening would lead to substantially more airway narrowing during bronchial challenge at any given airway generation. We speculate that the increased basal ASM-tone in asthma, due to the presence of inflammation-derived spasmogens, produces an increase in the force-generating capacity of ASM, predisposing to AHR during subsequent challenge. Copyright © 2011 Elsevier B.V. All rights reserved.

Genetic deletion of apolipoprotein A-I increases airway hyperresponsiveness, inflammation, and collagen deposition in the lung

PubMed Central

Wang, Weiling; Xu, Hao; Shi, Yang; Nandedkar, Sandhya; Zhang, Hao; Gao, Haiqing; Feroah, Thom; Weihrauch, Dorothee; Schulte, Marie L.; Jones, Deron W.; Jarzembowski, Jason; Sorci-Thomas, Mary; Pritchard, Kirkwood A.

2010-01-01

The relationship between high-density lipoprotein and pulmonary function is unclear. To determine mechanistic relationships we investigated the effects of genetic deletion of apolipoprotein A-I (apoA-I) on plasma lipids, paraoxonase (PON1), pro-inflammatory HDL (p-HDL), vasodilatation, airway hyperresponsiveness and pulmonary oxidative stress, and inflammation. ApoA-I null (apoA-I−/−) mice had reduced total and HDL cholesterol but increased pro-inflammatory HDL compared with C57BL/6J mice. Although PON1 protein was increased in apoA-I−/− mice, PON1 activity was decreased. ApoA-I deficiency did not alter vasodilatation of facialis arteries, but it did alter relaxation responses of pulmonary arteries. Central airway resistance was unaltered. However, airway resistance mediated by tissue dampening and elastance were increased in apoA-I−/− mice, a finding also confirmed by positive end-expiratory pressure (PEEP) studies. Inflammatory cells, collagen deposition, 3-nitrotyrosine, and 4-hydroxy-2-nonenal were increased in apoA-I−/− lungs but not oxidized phospholipids. Colocalization of 4-hydroxy-2-nonenal with transforming growth factor β-1 (TGFβ-1 was increased in apoA-I−/− lungs. Xanthine oxidase, myeloperoxidase and endothelial nitric oxide synthase were increased in apoA-I−/− lungs. Dichlorodihydrofluorescein-detectable oxidants were increased in bronchoalveolar lavage fluid (BALF) in apoA-I−/− mice. In contrast, BALF nitrite+nitrate levels were decreased in apoA-I−/− mice. These data demonstrate that apoA-I plays important roles in limiting pulmonary inflammation and oxidative stress, which if not prevented, will decrease pulmonary artery vasodilatation and increase airway hyperresponsiveness. PMID:20498409

pcDNA-IL-12 vaccination blocks eosinophilic inflammation but not airway hyperresponsiveness following murine Toxocara canis infection.

PubMed

Malheiro, Adriana; Aníbal, Fernanda F; Martins-Filho, Olindo Assis; Teixeira-Carvalho, Andréa; Perini, Adenir; Martins, Milton A; Medeiros, Alexandra I; Turato, Walter M; Acencio, Milene P M; Brandão, Izaíra T; Nomizo, Auro; Silva, Célio L; Faccioli, Lúcia H

2008-01-17

We have investigated the effect of pcDNA3-CpG and pcDNA-IL-12, delivered by intradermal gene gun administration, on the blood/lung eosinophilia, airway hyperresponsiveness as well as the immune response in a murine model of toxocariasis. Our results demonstrated that pcDNA-IL-12 but not pcDNA3-CpG vaccination led to a persistent lower blood/bronchoalveolar eosinophilia following Toxocara canis infection, as pcDNA3-CpG led only to an early transient blockage of eosinophil transmigration into bronchoalveolar fluid following T. canis infection. Prominent Type-1 immune response was pointed out as the hallmark of T. canis infection following pcDNA-IL-12 vaccination. Outstanding IFN-gamma/IL-4 ratio besides low levels of IgG1 with subsequent high IgG2a/IgG1 ratio further characterized a Type-1 polarized immunological profile in pcDNA-IL-12-vaccinated animals. Nevertheless, only pcDNA3-CpG was able to prevent airway hyperresponsiveness induced by T. canis infection. The persistent airway hyperresponsiveness observed in pcDNA-IL-12-vaccinated animals demonstrated that the airway constriction involved other immunological mediator than those blocked by pcDNA-IL-12. Together, these data indicated that pcDNA-IL-12 and pcDNA3-CpG vaccines have distinct therapeutic benefits regarding the eosinophilic inflammation/airway hyperresponsiveness triggered by T. canis infection, suggesting their possible use in further combined therapeutic interventions.

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

Sensitivity to the house dust mite and airway hyperresponsiveness in a young adult population.

PubMed

Obase, Y; Shimoda, T; Mitsuta, K; Matsuo, N; Matsuse, H; Kohno, S

1999-10-01

The pathogenic mechanisms of airway hyperresponsiveness (AHR) in asthma are unknown and only a few studies have examined the importance of sensitivity to antigens in AHR in young adults. We investigated the correlation between AHR and sensitivity to specific antigens, atopy, history of childhood asthma and spirometry in a young adult population. Based on the results of interviews with 447 students at our university, 308 non-smoker students were classified into six groups. Group 1 comprised subjects with intermittent mild bronchial asthma; group 2, subjects with history of childhood asthma; group 3, subjects with atopic disease, and a RAST score for Dermatophagoides farinae (Def) of > or = 2; group 4, normal subjects with a RAST score for Def of > or = 2; group 5, subjects with cedar pollinosis; and group 6, normal subjects. We measured AHR to methacholine (MCh), spirometry, immunoglobulin E-radioimmunosorbent test (IgE-RIST), IgE-radioallergosorbent test to six common antigens, eosinophil cationic protein (ECP), and eosinophil count in peripheral blood in each subject. Airway hyperresponsiveness to MCh did not correlate with IgE-RIST, eosinophil count, or ECP. The highest AHR to MCh was present in groups 1 and 2 and lowest in groups 5 and 6. Multiple regression analysis showed that sensitivity to Def was the only factor that significantly influenced AHR to MCh. Airway hyperresponsiveness to MCh of groups with a RAST score for Def of 0/1 was lower than groups with a RAST score of 2 to 6. Airway hyperresponsiveness to MCh did not correlate with the degree of positivity to Def antigen among positive sensitized groups (RAST score 2 to 6). Sensitivity to mite antigen may be important in the pathogenesis of AHR and Def is a major contributing antigen in young adults in Japan. Once asthma occurs, AHR remains positive for a long time even after the disappearance of asthma-related symptoms.

The contribution of airway smooth muscle to airway narrowing and airway hyperresponsiveness in disease.

PubMed

Martin, J G; Duguet, A; Eidelman, D H

2000-08-01

Airway hyperresponsiveness (AHR), the exaggerated response to constrictor agonists in asthmatic subjects, is incompletely understood. Changes in either the quantity or properties of airway smooth muscle (ASM) are possible explanations for AHR. Morphometric analyses demonstrate structural changes in asthmatic airways, including subepithelial fibrosis, gland hyperplasia/hypertrophy, neovascularization and an increase in ASM mass. Mathematical modelling of airway narrowing suggests that, of all the changes in structure, the increase in ASM mass is the most probable cause of AHR. An increase in ASM mass in the large airways is more closely associated with a greater likelihood of dying from asthma than increases in ASM mass in other locations within the airway tree. ASM contraction is opposed by the elastic recoil of the lungs and airways, which appears to limit the degree of bronchoconstriction in vivo. The cyclical nature of tidal breathing applies stresses to the airway wall that enhance the bronchodilating influence of the lung tissues on the contracting ASM, in all probability by disrupting cross-bridges. However, the increase in ASM mass in asthma may overcome the limitation resulting from the impedances to ASM shortening imposed by the lung parenchyma and airway wall tissues. Additionally, ASM with the capacity to shorten rapidly may achieve shorter lengths and cause a greater degree of bronchoconstriction when stimulated to contract than slower ASM. Changes in ASM properties are induced by the process of sensitization and allergen-exposure such as enhancement of phospholipase C activity and inositol phosphate turnover, and increases in myosin light chain kinase activity. Whether changes in ASM mass or biochemical/biomechanical properties form the basis for asthma remains to be determined.

Impaired activation of adenylyl cyclase in lung of the Basenji-greyhound model of airway hyperresponsiveness: decreased numbers of high affinity beta-adrenoceptors.

PubMed Central

Emala, C. W.; Aryana, A.; Hirshman, C. A.

1996-01-01

1. To evaluate mechanisms involved in the impaired beta-adrenoceptor stimulation of adenylyl cyclase in tissues from the Basenji-greyhound (BG) dog model of airway hyperresponsiveness, we compared agonist and antagonist binding affinity of beta-adrenoceptors, beta-adrenoceptor subtypes, percentage of beta-adrenoceptors sequestered, and coupling of the beta-adrenoceptor to Gs alpha in lung membranes from BG and control mongrel dogs. We found that lung membranes from the BG dog had higher total numbers of beta-adrenoceptors with a greater percentage of receptors of the beta 2 subtype as compared to mongrel lung membranes. 2. Agonist and antagonist binding affinity and the percentage of beta-adrenoceptors sequestered were not different in BG and mongrel dog lung membranes. However, the percentage of beta-adrenoceptors in the high affinity state for agonist was decreased in BG lung membranes suggesting an uncoupling of the receptor from Gs alpha. 3. Impaired coupling between the beta-adrenoceptor and G protein documented by the decreased numbers of beta-adrenoceptors in the high affinity state in BG lung membranes, is a plausible explanation for the reduced stimulation of adenylyl cyclase and the resultant reduction in airway smooth muscle relaxation in this model. PMID:8864536

Airway hyperresponsiveness; smooth muscle as the principal actor

PubMed Central

Lauzon, Anne-Marie; Martin, James G.

2016-01-01

Airway hyperresponsiveness (AHR) is a defining characteristic of asthma that refers to the capacity of the airways to undergo exaggerated narrowing in response to stimuli that do not result in comparable degrees of airway narrowing in healthy subjects. Airway smooth muscle (ASM) contraction mediates airway narrowing, but it remains uncertain as to whether the smooth muscle is intrinsically altered in asthmatic subjects or is responding abnormally as a result of the milieu in which it sits. ASM in the trachea or major bronchi does not differ in its contractile characteristics in asthmatics, but the more pertinent peripheral airways await complete exploration. The mass of ASM is increased in many but not all asthmatics and therefore cannot be a unifying hypothesis for AHR, although when increased in mass it may contribute to AHR. The inability of a deep breath to reverse or prevent bronchial narrowing in asthma may reflect an intrinsic difference in the mechanisms that lead to softening of contracted ASM when subjected to stretch. Cytokines such as interleukin-13 and tumor necrosis factor-α promote a more contractile ASM phenotype. The composition and increased stiffness of the matrix in which ASM is embedded promotes a more proliferative and pro-inflammatory ASM phenotype, but the expected dedifferentiation and loss of contractility have not been shown. Airway epithelium may drive ASM proliferation and/or molecular remodeling in ways that may lead to AHR. In conclusion, AHR is likely multifactorial in origin, reflecting the plasticity of ASM properties in the inflammatory environment of the asthmatic airway. PMID:26998246

Airway hyper-responsiveness to neurokinin A and bradykinin following Mycoplasma pneumoniae infection associated with reduced epithelial neutral endopeptidase.

PubMed

Tamaoki, J; Chiyotani, A; Tagaya, E; Araake, M; Nagai, A

1998-09-01

To determine whether mycoplasma infection produces airway hyper-responsiveness to tachykinins and bradykinin and, if so, to elucidate the role of neutral endopeptidase (NEP), isolated hamster tracheal segments were studied under isometric conditions in vitro. Nasal inoculation with Mycoplasma pneumoniae potentiated contractile responses to neurokinin A and bradykinin, causing a leftward shift of the dose-response curves to a lower concentration by 1 log unit for each agonist, whereas there was no response with acetylcholine. Pretreatment of tissues with the NEP inhibitor phosphoramidon augmented neurokinin A- and bradykinin-induced contractions in saline-treated control tissues, but did not further potentiate the responsiveness in M. pneumoniae-infected tissues. NEP activity in the tracheal epithelium, but not in epithelium-denuded tissues, was decreased in infected animals. These results suggest that M. pneumoniae infection causes airway bronchoconstrictor hyper-responsiveness to neurokinin A and bradykinin and that this effect may be associated with an inhibition of epithelial NEP activity.

How the airway smooth muscle in cystic fibrosis reacts in proinflammatory conditions: implications for airway hyper-responsiveness and asthma in cystic fibrosis.

PubMed

McCuaig, Sarah; Martin, James G

2013-04-01

Among patients with cystic fibrosis there is a high prevalence (40-70%) of asthma signs and symptoms such as cough and wheezing and airway hyper-responsiveness to inhaled histamine or methacholine. Whether these abnormal airway responses are due to a primary deficiency in the cystic fibrosis transmembrane conductance regulator (CFTR) or are secondary to the inflammatory environment in the cystic fibrosis lungs is not clear. A role for the CFTR in smooth muscle function is emerging, and alterations in contractile signalling have been reported in CFTR-deficient airway smooth muscle. Persistent bacterial infection, especially with Pseudomonas aeruginosa, stimulates interleukin-8 release from the airway epithelium, resulting in neutrophilic inflammation. Increased neutrophilia and skewing of CFTR-deficient T-helper cells to type 2 helper T cells creates an inflammatory environment characterised by high concentrations of tumour necrosis factor α, interleukin-8, and interleukin-13, which might all contribute to increased contractility of airway smooth muscle in cystic fibrosis. An emerging role of interleukin-17, which is raised in patients with cystic fibrosis, in airway smooth muscle proliferation and hyper-responsiveness is apparent. Increased understanding of the molecular mechanisms responsible for the altered smooth muscle physiology in patients with cystic fibrosis might provide insight into airway dysfunction in this disease. Copyright © 2013 Elsevier Ltd. All rights reserved.

Concomitant Exposure to Ovalbumin and Endotoxin Augments Airway Inflammation but Not Airway Hyperresponsiveness in a Murine Model of Asthma

PubMed Central

Mac Sharry, John; Shalaby, Karim H.; Marchica, Cinzia; Farahnak, Soroor; Chieh-Li, Tien; Lapthorne, Susan; Qureshi, Salman T.; Shanahan, Fergus; Martin, James G.

2014-01-01

Varying concentrations of lipopolysaccharide (LPS) in ovalbumin (OVA) may influence the airway response to allergic sensitization and challenge. We assessed the contribution of LPS to allergic airway inflammatory responses following challenge with LPS-rich and LPS-free commercial OVA. BALB/c mice were sensitized with LPS-rich OVA and alum and then underwent challenge with the same OVA (10 µg intranasally) or an LPS-free OVA. Following challenge, bronchoalveolar lavage (BAL), airway responsiveness to methacholine and the lung regulatory T cell population (Treg) were assessed. Both OVA preparations induced BAL eosinophilia but LPS-rich OVA also evoked BAL neutrophilia. LPS-free OVA increased interleukin (IL)-2, IL-4 and IL-5 whereas LPS-rich OVA additionally increased IL-1β, IL-12, IFN-γ, TNF-α and KC. Both OVA-challenged groups developed airway hyperresponsiveness. TLR4-deficient mice challenged with either OVA preparation showed eosinophilia but not neutrophilia and had increased IL-5. Only LPS-rich OVA challenged mice had increased lung Tregs and LPS-rich OVA also induced in vitro Treg differentiation. LPS-rich OVA also induced a Th1 cytokine response in human peripheral blood mononuclear cells.We conclude that LPS-rich OVA evokes mixed Th1, Th2 and innate immune responses through the TLR-4 pathway, whereas LPS-free OVA evokes only a Th2 response. Contaminating LPS is not required for induction of airway hyperresponsiveness but amplifies the Th2 inflammatory response and is a critical mediator of the neutrophil, Th1 and T regulatory cell responses to OVA. PMID:24968337

Endogenous osteopontin promotes ozone-induced neutrophil recruitment to the lungs and airway hyperresponsiveness to methacholine

PubMed Central

Barreno, Ramon X.; Richards, Jeremy B.; Schneider, Daniel J.; Cromar, Kevin R.; Nadas, Arthur J.; Hernandez, Christopher B.; Hallberg, Lance M.; Price, Roger E.; Hashmi, Syed S.; Blackburn, Michael R.; Haque, Ikram U.

2013-01-01

Inhalation of ozone (O3), a common environmental pollutant, causes pulmonary injury, pulmonary inflammation, and airway hyperresponsiveness (AHR) in healthy individuals and exacerbates many of these same sequelae in individuals with preexisting lung disease. However, the mechanisms underlying these phenomena are poorly understood. Consequently, we sought to determine the contribution of osteopontin (OPN), a hormone and a pleiotropic cytokine, to the development of O3-induced pulmonary injury, pulmonary inflammation, and AHR. To that end, we examined indices of these aforementioned sequelae in mice genetically deficient in OPN and in wild-type, C57BL/6 mice 24 h following the cessation of an acute (3 h) exposure to filtered room air (air) or O3 (2 parts/million). In wild-type mice, O3 exposure increased bronchoalveolar lavage fluid (BALF) OPN, whereas immunohistochemical analysis demonstrated that there were no differences in the number of OPN-positive alveolar macrophages between air- and O3-exposed wild-type mice. O3 exposure also increased BALF epithelial cells, protein, and neutrophils in wild-type and OPN-deficient mice compared with genotype-matched, air-exposed controls. However, following O3 exposure, BALF neutrophils were significantly reduced in OPN-deficient compared with wild-type mice. When airway responsiveness to inhaled acetyl-β-methylcholine chloride (methacholine) was assessed using the forced oscillation technique, O3 exposure caused hyperresponsiveness to methacholine in the airways and lung parenchyma of wild-type mice, but not OPN-deficient mice. These results demonstrate that OPN is increased in the air spaces following acute exposure to O3 and functionally contributes to the development of O3-induced pulmonary inflammation and airway and lung parenchymal hyperresponsiveness to methacholine. PMID:23666750

Interleukin-1beta-induced airway hyperresponsiveness enhances substance P in intrinsic neurons of ferret airway.

PubMed

Wu, Z-X; Satterfield, B E; Fedan, J S; Dey, R D

2002-11-01

Interleukin (IL)-1beta causes airway inflammation, enhances airway smooth muscle responsiveness, and alters neurotransmitter expression in sensory, sympathetic, and myenteric neurons. This study examines the role of intrinsic airway neurons in airway hyperresponsiveness (AHR) induced by IL-1beta. Ferrets were instilled intratracheally with IL-1beta (0.3 microg/0.3 ml) or saline (0.3 ml) once daily for 5 days. Tracheal smooth muscle contractility in vitro and substance P (SP) expression in tracheal neurons were assessed. Tracheal smooth muscle reactivity to acetylcholine (ACh) and methacholine (MCh) and smooth muscle contractions to electric field stimulation (EFS) both increased after IL-1beta. The IL-1beta-induced AHR was maintained in tracheal segments cultured for 24 h, a procedure that depletes SP from sensory nerves while maintaining viability of intrinsic airway neurons. Pretreatment with CP-99994, an antagonist of neurokinin 1 receptor, attenuated the IL-1beta-induced hyperreactivity to ACh and MCh and to EFS in cultured tracheal segments. SP-containing neurons in longitudinal trunk, SP innervation of superficial muscular plexus neurons, and SP nerve fiber density in tracheal smooth muscle all increased after treatment with IL-1beta. These results show that IL-1beta-enhanced cholinergic airway smooth muscle contractile responses are mediated by the actions of SP released from intrinsic airway neurons.

Airways Hyperresponsiveness Following a Single Inhalation Exposure to Doxorubicin-Induced Heart Failure Prevents Airways Transition Metal-Rich Particulate Matter in Hypertensive Rats

EPA Science Inventory

Exposure to particulate matter (PM) air pollution results in airways hyperresponsiveness (AHR), however it also results in adverse cardiovascular effects, particularly in individuals with underlying cardiovascular disease. The impact of pre-existing cardiac deficit on PM-induced ...

Early treatment of chlorine-induced airway hyperresponsiveness and inflammation with corticosteroids

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

Jonasson, Sofia, E-mail: sofia.jonasson@foi.se; Wigenstam, Elisabeth; Department of Public Health and Clinical Medicine, Unit of Respiratory Medicine, Umeå University, Umeå

Chlorine (Cl{sub 2}) is an industrial gas that is highly toxic and irritating when inhaled causing tissue damage and an acute inflammatory response in the airways followed by a long-term airway dysfunction. The aim of this study was to evaluate whether early anti-inflammatory treatment can protect against the delayed symptoms in Cl{sub 2}-exposed mice. BALB/c mice were exposed by nose-only inhalation using 200 ppm Cl{sub 2} during 15 min. Assessment of airway hyperresponsiveness (AHR), inflammatory cell counts in bronchoalveolar lavage, occurrence of lung edema and lung fibrosis were analyzed 24 h or 14 days post-exposure. A single dose of themore » corticosteroid dexamethasone (10 or 100 mg/kg) was administered intraperitoneally 1, 3, 6, or 12 h following Cl{sub 2} exposure. High-dose of dexamethasone reduced the acute inflammation if administered within 6 h after exposure but treated animals still displayed a significant lung injury. The effect of dexamethasone administered within 1 h was dose-dependent; high-dose significantly reduced acute airway inflammation (100 mg/kg) but not treatment with the relatively low-dose (10 mg/kg). Both doses reduced AHR 14 days later, while lung fibrosis measured as collagen deposition was not significantly reduced. The results point out that the acute inflammation in the lungs due to Cl{sub 2} exposure only partly is associated with the long-term AHR. We hypothesize that additional pathogenic mechanisms apart from the inflammatory reactions contribute to the development of long-term airway dysfunction. By using this mouse model, we have validated early administration of corticosteroids in terms of efficacy to prevent acute lung injury and delayed symptoms induced by Cl{sub 2} exposure. - Highlights: • Inhalation of Cl{sub 2} may lead to a long-standing airway hyperresponsiveness. • The symptoms in Cl{sub 2}-exposed mice are similar to those described for RADS in humans. • Corticosteroids prevent delayed symptoms such as

Influence of pirfenidone on airway hyperresponsiveness and inflammation in a Brown-Norway rat model of asthma.

PubMed

Mansoor, Jim K; Decile, Kendra C; Giri, Shri N; Pinkerton, Kent E; Walby, William F; Bratt, Jennifer M; Grewal, Harinder; Margolin, Solomon B; Schelegle, Edward S

2007-01-01

Pirfenidone was administered to sensitized Brown Norway rats prior to a series of ovalbumin challenges. Airway hyperresponsiveness, inflammatory cell infiltration, mucin and collagen content, and the degree of epithelium and smooth muscle staining for TGF-beta were examined in control, sensitized, and sensitized/challenged rats fed a normal diet or pirfenidone diet. Pirfenidone had no effect on airway hyperresponsiveness, but reduced distal bronchiolar cell infiltration and proximal and distal mucin content. Statistical analysis showed that the control group and sensitized/challenged pirfenidone diet group TGF-beta staining intensity scores were not significantly different from isotype controls, but that the staining intensity scores for the sensitized/challenged normal diet group was significantly different from isotype controls. These results suggest that pirfenidone treatment is effective in reducing some of the components of acute inflammation induced by allergen challenge.

Additive Effect of Diesel Exhaust Particulates and Ozone on Airway Hyperresponsiveness and Inflammation in a Mouse Model of Asthma

PubMed Central

Choi, Inseon-S; Takizawa, Hajime; Rhim, TaiYoun; Lee, June-Hyuk; Park, Sung-Woo; Park, Choon-Sik

2005-01-01

Allergic airway diseases are related to exposure to atmospheric pollutants, which have been suggested to be one factor in the increasing prevalence of asthma. Little is known about the effect of ozone and diesel exhaust particulates (DEP) on the development or aggravation of asthma. We have used a mouse asthma model to determine the effect of ozone and DEP on airway hyperresponsiveness and inflammation. Methacholine enhanced pause (Penh) was measured. Levels of IL-4 and IFN-γ were quantified in bronchoalveolar lavage fluids by enzyme immunoassays. The OVA-sensitized-challenged and ozone and DEP exposure group had higher Penh than the OVA-sensitized-challenged group and the OVA-sensitized-challenged and DEP exposure group, and the OVA-sensitized-challenged and ozone exposure group. Levels of IFN-γ were decreased in the OVA-sensitized-challenged and DEP exposure group and the OVA-sensitized-challenged and ozone and DEP exposure group compared to the OVA-sensitized-challenged and ozone exposure group. Levels of IL-4 were increased in the OVA-sensitized-challenged and ozone exposure group and the OVA-sensitized-challenged and DEP exposure group, and the OVA-sensitized-challenged and ozone and DEP exposure group compared to OVA-sensitized-challenged group. Co-exposure of ozone and DEP has additive effect on airway hyperresponsiveness by modulation of IL-4 and IFN-γ suggesting that DEP amplify Th2 immune response. PMID:16224148

Smooth muscle myosin isoform expression and LC20 phosphorylation in innate rat airway hyperresponsiveness.

PubMed

Gil, Fulvio R; Zitouni, Nedjma B; Azoulay, Eric; Maghni, Karim; Lauzon, Anne-Marie

2006-11-01

Four smooth muscle myosin heavy chain (SMMHC) isoforms are generated by alternative mRNA splicing of a single gene. Two of these isoforms differ by the presence [(+)insert] or absence [(-)insert] of a 7-amino acid insert in the motor domain. The rate of actin filament propulsion of the (+)insert SMMHC isoform, as measured in the in vitro motility assay, is twofold greater than that of the (-)insert isoform. We hypothesized that a greater expression of the (+)insert SMMHC isoform and greater regulatory light chain (LC(20)) phosphorylation contribute to airway hyperresponsiveness. We measured airway responsiveness to methacholine in Fischer hyperresponsive and Lewis normoresponsive rats and determined SMMHC isoform mRNA and protein expression, as well as essential light chain (LC(17)) isoforms, h-caldesmon, and alpha-actin protein expression in their tracheae. We also measured tracheal muscle strip contractility in response to methacholine and corresponding LC(20) phosphorylation. We found Fischer rats have more (+)insert mRNA (69.4 +/- 2.0%) (mean +/- SE) than Lewis rats (53.0 +/- 2.4%; P < 0.05) and a 44% greater content of (+)insert isoform relative to total myosin protein. No difference was found for LC(17) isoform, h-caldesmon, and alpha-actin expression. The contractility experiments revealed a greater isometric force for Fischer trachealis segments (4.2 +/- 0.8 mN) than Lewis (1.9 +/- 0.4 mN; P < 0.05) and greater LC(20) phosphorylation level in Fischer (55.1 +/- 6.4) than in Lewis (41.4 +/- 6.1; P < 0.05) rats. These results further support the contention that innate airway hyperresponsiveness is a multifactorial disorder in which increased expression of the fast (+)insert SMMHC isoform and greater activation of LC(20) lead to smooth muscle hypercontractility.

20-HETE mediates ozone-induced, neutrophil-independent airway hyper-responsiveness in mice.

PubMed

Cooper, Philip R; Mesaros, A Clementina; Zhang, Jie; Christmas, Peter; Stark, Christopher M; Douaidy, Karim; Mittelman, Michael A; Soberman, Roy J; Blair, Ian A; Panettieri, Reynold A

2010-04-20

Ozone, a pollutant known to induce airway hyper-responsiveness (AHR), increases morbidity and mortality in patients with obstructive airway diseases and asthma. We postulate oxidized lipids mediate in vivo ozone-induced AHR in murine airways. Male BALB/c mice were exposed to ozone (3 or 6 ppm) or filtered air (controls) for 2 h. Precision cut lung slices (PCLS; 250 microm thickness) containing an intrapulmonary airway ( approximately 0.01 mm(2) lumen area) were prepared immediately after exposure or 16 h later. After 24 h, airways were contracted to carbachol (CCh). Log EC(50) and E(max) values were then calculated by measuring the airway lumen area with respect to baseline. In parallel studies, dexamethasone (2.5 mg/kg), or 1-aminobenzotriazol (ABT) (50 mg/kg) were given intraperitoneal injection to naïve mice 18 h prior to ozone exposure. Indomethacin (10 mg/kg) was administered 2 h prior. Cell counts, cytokine levels and liquid chromatography-mass spectrometry (LC-MS) for lipid analysis were assessed in bronchoalveolar lavage (BAL) fluid from ozone exposed and control mice. Ozone acutely induced AHR to CCh. Dexamethasone or indomethacin had little effect on the ozone-induced AHR; while, ABT, a cytochrome P450 inhibitor, markedly attenuated airway sensitivity. BAL fluid from ozone exposed animals, which did not contain an increase in neutrophils or interleukin (IL)-6 levels, increased airway sensitivity following in vitro incubation with a naïve PCLS. In parallel, significant increases in oxidized lipids were also identified using LC-MS with increases of 20-HETE that were decreased following ABT treatment. These data show that ozone acutely induces AHR to CCh independent of inflammation and is insensitive to steroid treatment or cyclooxygenase (COX) inhibition. BAL fluid from ozone exposed mice mimicked the effects of in vivo ozone exposure that were associated with marked increases in oxidized lipids. 20-HETE plays a pivotal role in mediating acute ozone

Epithelium-generated neuropeptide Y induces smooth muscle contraction to promote airway hyperresponsiveness.

PubMed

Li, Shanru; Koziol-White, Cynthia; Jude, Joseph; Jiang, Meiqi; Zhao, Hengjiang; Cao, Gaoyuan; Yoo, Edwin; Jester, William; Morley, Michael P; Zhou, Su; Wang, Yi; Lu, Min Min; Panettieri, Reynold A; Morrisey, Edward E

2016-05-02

Asthma is one of the most common chronic diseases globally and can be divided into presenting with or without an immune response. Current therapies have little effect on nonimmune disease, and the mechanisms that drive this type of asthma are poorly understood. Here, we have shown that loss of the transcription factors forkhead box P1 (Foxp1) and Foxp4, which are critical for lung epithelial development, in the adult airway epithelium evokes a non-Th2 asthma phenotype that is characterized by airway hyperresponsiveness (AHR) without eosinophilic inflammation. Transcriptome analysis revealed that loss of Foxp1 and Foxp4 expression induces ectopic expression of neuropeptide Y (Npy), which has been reported to be present in the airways of asthma patients, but whose importance in disease pathogenesis remains unclear. Treatment of human lung airway explants with recombinant NPY increased airway contractility. Conversely, loss of Npy in Foxp1- and Foxp4-mutant airway epithelium rescued the AHR phenotype. We determined that NPY promotes AHR through the induction of Rho kinase activity and phosphorylation of myosin light chain, which induces airway smooth muscle contraction. Together, these studies highlight the importance of paracrine signals from the airway epithelium to the underlying smooth muscle to induce AHR and suggest that therapies targeting epithelial induction of this phenotype may prove useful in treatment of noneosinophilic asthma.

Graphene Oxide Attenuates Th2-Type Immune Responses, but Augments Airway Remodeling and Hyperresponsiveness in a Murine Model of Asthma

PubMed Central

2015-01-01

Several lines of evidence indicate that exposure to nanoparticles (NPs) is able to modify airway immune responses, thus facilitating the development of respiratory diseases. Graphene oxide (GO) is a promising carbonaceous nanomaterial with unique physicochemical properties, envisioned for a multitude of medical and industrial applications. In this paper, we determined how exposure to GO modulates the allergic pulmonary response. Using a murine model of ovalbumin (OVA)-induced asthma, we revealed that GO, given at the sensitization stage, augmented airway hyperresponsiveness and airway remodeling in the form of goblet cell hyperplasia and smooth muscle hypertrophy. At the same time, the levels of the cytokines IL-4, IL-5, and IL-13 were reduced in broncho-alveolar lavage (BAL) fluid in GO-exposed mice. Exposure to GO during sensitization with OVA decreased eosinophil accumulation and increased recruitment of macrophages in BAL fluid. In line with the cytokine profiles, sensitization with OVA in the presence of GO stimulated the production of OVA-specific IgG2a and down-regulated the levels of IgE and IgG1. Moreover, exposure to GO increased the macrophage production of the mammalian chitinases, CHI3L1 and AMCase, whose expression is associated with asthma. Finally, molecular modeling has suggested that GO may directly interact with chitinase, affecting AMCase activity, which has been directly proven in our studies. Thus, these data show that GO exposure attenuates Th2 immune response in a model of OVA-induced asthma, but leads to potentiation of airway remodeling and hyperresponsiveness, with the induction of mammalian chitinases. PMID:24847914

Airway Hyperresponsiveness through Synergy of γδ T Cells and NKT Cells1

PubMed Central

Jin, Niyun; Miyahara, Nobuaki; Roark, Christina L.; French, Jena D.; Aydintug, M. Kemal; Matsuda, Jennifer L.; Gapin, Laurent; O'Brien, Rebecca L.; Gelfand, Erwin W.; Born, Willi K.

2015-01-01

Mice sensitized and challenged with OVA were used to investigate the role of innate T cells in the development of allergic airway hyperresponsiveness (AHR). AHR, but not eosinophilic airway inflammation, was induced in T cell-deficient mice by small numbers of cotransferred γδ T cells and invariant NKT cells, whereas either cell type alone was not effective. Only Vγ1+Vδ5+ γδ T cells enhanced AHR. Surprisingly, OVA-specific αβ T cells were not required, revealing a pathway of AHR development mediated entirely by innate T cells. The data suggest that lymphocytic synergism, which is key to the Ag-specific adaptive immune response, is also intrinsic to T cell-dependent innate responses. PMID:17709511

Role of tachykinins in ozone-induced airway hyperresponsiveness to cigarette smoke in guinea pigs.

PubMed

Wu, Z X; Morton, R F; Lee, L Y

1997-09-01

Acute exposure to ozone (O3) induces airway hyperresponsiveness to various inhaled bronchoactive substances. Inhalation of cigarette smoke, a common inhaled irritant in humans, is known to evoke a transient bronchoconstrictive effect. To examine whether O3 increases airway responsiveness to cigarette smoke, effects of smoke inhalation challenge on total pulmonary resistance (RL) and dynamic lung compliance (Cdyn) were compared before and after exposure to O3 (1.5 ppm, 1 h) in anesthetized guinea pigs. Before O3 exposure, inhalation of two breaths of cigarette smoke (7 ml) at a low concentration (33%) induced a mild and reproducible bronchoconstriction that slowly developed and reached its peak (DeltaRL = 67 +/- 19%, DeltaCdyn = -29 +/- 6%) after a delay of >1 min. After exposure to O3 the same cigarette smoke inhalation challenge evoked an intense bronchoconstriction that occurred more rapidly, reaching its peak (DeltaRL = 620 +/- 224%, DeltaCdyn = -35 +/- 7%) within 20 s, and was sustained for >2 min. By contrast, sham exposure to room air did not alter the bronchomotor response to cigarette smoke challenge. Pretreatment with CP-99994 and SR-48968, the selective antagonists of neurokinin type 1 and 2 receptors, respectively, completely blocked the enhanced responses of RL and Cdyn to cigarette smoke challenge induced by O3. These results show that O3 exposure induces airway hyperresponsiveness to inhaled cigarette smoke and that the enhanced responses result primarily from the bronchoconstrictive effect of endogenous tachykinins.

Sensory neuropeptides modulate cigarette smoke-induced decrease in neutral endopeptidase activity in guinea pig airways.

PubMed

Kuo, H P; Lu, L C

1995-01-01

Cigarette smoke (CS) inhalation stimulates C-fibers to release sensory neuropeptides which mediate airway reflex responses to prevent irritants from entering the lower airways. When CS is inhaled via the upper airways, these airway defense responses may modulate the effect of CS on airway NEP activity and related airway hyperresponsiveness. To examine this possibility, we exposed guinea pigs to 1:10 diluted mid-tar cigarette smoke 100 puffs per day for 7 days and recorded pulmonary resistance of cumulative doses of neurokinin A (NKA, 10(-12)-10(-8) mol/kg, i.v.) or methacholine (Mch, 1-50 micrograms/kg, i.v.). NEP activity in the tracheobronchi was measured using fluorometric assay. Exposure of CS alone failed to alter the dose-response to NKA or Mch compared with air control. NEP activity in the airways after CS exposure was slightly but significantly lower than that of air control. Capsaicin pretreatment 1 week before CS exposure significantly shifted the dose-response curves of NKA, but not Mch, to the left and decreased NEP activity in the airways to a greater extent compared with CS exposure alone group. Capsaicin pretreatment alone failed to alter the responsiveness to NKA or NEP activity. CS also induced a significant increase in neutrophil counts in airways. Capsaicin pretreatment enhanced the effect of CS on neutrophil recruitment. We conclude that sensory neuropeptides may have a protective role in modulation of airways NEP activity downregulation induced by CS, probably by preventing CS from entering the lower airways or the chronic release of sensory neuropeptides induced by CS providing increased amount of substrata for NEP upregulation, and therefore modify the direct effect of CS on NEP activity and related airway hyperresponsiveness.

Interaction of ozone exposure with airway hyperresponsiveness and inflammation induced by trimellitic anhydride in sensitized guinea pigs

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

Sun, Jian; Chung, K.Fan

1997-09-01

The effect of prior ozone (O{sub 3}) exposure on airway hyperresponsiveness and inflammation induced by trimellitic anhydride (TMA) has been investigated in TMA-sensitized guinea pigs. Airway responsiveness was measured as the concentration of acetylcholine needed to increase baseline lung resistance (RL) by 300% (PC300). Ozone (3 ppm, for 3 h) caused an increase in-log PC300 at 1 h after exposure, with return of -log PC300 to control levels at 8 h. Ozone also increased baseline RL at 8 h. TMA challenge increase -log PC300 in TMA-sensitized guinea pigs at 8 h after challenge from 3.85 {+-} 0.09 to 4.11 {+-}more » 0.09. Ozone exposure prior to TMA challenge prevented the induction of airway hyperresponsiveness with a mean -log PC300 of 3.51 {+-} 0.20, which was not different from that of control TMA-Sensitized group. Baseline RL was significantly higher in ozone-pretreated animals after TMA challenge when compared to those of either control or challenged with TMA alone. Ozone had no effect on TMA challenge-induced BAL eosinophilia and neutrophilia. We conclude that a single exposure to ozone inhibits the increase in airway responsiveness, but increases the bronchoconstrictor response induced by TMA in TMA-Sensitized guinea pigs; however, the inflammatory airway response to TMA is unchanged by preexposure to ozone. 29 refs., 2 figs., 1 tab.« less

Role of IL-4 receptor α-positive CD4(+) T cells in chronic airway hyperresponsiveness.

PubMed

Kirstein, Frank; Nieuwenhuizen, Natalie E; Jayakumar, Jaisubash; Horsnell, William G C; Brombacher, Frank

2016-06-01

TH2 cells and their cytokines are associated with allergic asthma in human subjects and with mouse models of allergic airway disease. IL-4 signaling through the IL-4 receptor α (IL-4Rα) chain on CD4(+) T cells leads to TH2 cell differentiation in vitro, implying that IL-4Rα-responsive CD4(+) T cells are critical for the induction of allergic asthma. However, mechanisms regulating acute and chronic allergen-specific TH2 responses in vivo remain incompletely understood. This study defines the requirements for IL-4Rα-responsive CD4(+) T cells and the IL-4Rα ligands IL-4 and IL-13 in the development of allergen-specific TH2 responses during the onset and chronic phase of experimental allergic airway disease. Development of acute and chronic ovalbumin (OVA)-induced allergic asthma was assessed weekly in CD4(+) T cell-specific IL-4Rα-deficient BALB/c mice (Lck(cre)IL-4Rα(-/lox)) and respective control mice in the presence or absence of IL-4 or IL-13. During acute allergic airway disease, IL-4 deficiency did not prevent the onset of TH2 immune responses and OVA-induced airway hyperresponsiveness or goblet cell hyperplasia, irrespective of the presence or absence of IL-4Rα-responsive CD4(+) T cells. In contrast, deficiency of IL-13 prevented allergic asthma, irrespective of the presence or absence of IL-4Rα-responsive CD4(+) T cells. Importantly, chronic allergic inflammation and airway hyperresponsiveness were dependent on IL-4Rα-responsive CD4(+) T cells. Deficiency in IL-4Rα-responsive CD4(+) T cells resulted in increased numbers of IL-17-producing T cells and, consequently, increased airway neutrophilia. IL-4-responsive T helper cells are dispensable for acute OVA-induced airway disease but crucial in maintaining chronic asthmatic pathology. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Substance P released from intrinsic airway neurons contributes to ozone-enhanced airway hyperresponsiveness in ferret trachea.

PubMed

Wu, Zhong-Xin; Satterfield, Brian E; Dey, Richard D

2003-08-01

Exposure to ozone (O3) induces airway hyperresponsiveness mediated partly through the release of substance P (SP) from nerve terminals in the airway wall. Although substantial evidence suggests that SP is released by sensory nerves, SP is also present in neurons of airway ganglia. The purpose of this study was to investigate the role of intrinsic airway neurons in O3-enhanced airway responsiveness in ferret trachea. To remove the effects of sensory innervation, segments of ferret trachea were maintained in culture conditions for 24 h before in vitro exposure to 2 parts/million of O3 or air for 1 h. Sensory nerve depletion was confirmed by showing that capsaicin did not affect tracheal smooth muscle responsiveness to cholinergic agonist or contractility responses to electrical field stimulation (EFS). Contractions of isolated tracheal smooth muscle to EFS were significantly increased after in vitro O3 exposure, but the constrictor response to cholinergic agonist was not altered. Pretreatment with CP-99994, an antagonist of the neurokinin 1 receptor, attenuated the increased contraction to EFS after O3 exposure but had no effect in the air exposure group. The number of SP-positive neurons in longitudinal trunk ganglia, the extent of SP innervation to superficial muscular plexus nerve cell bodies, and SP nerve fiber density in tracheal smooth muscle all increased significantly after O3 exposure. The results show that release of SP from intrinsic airway neurons contributes to O3-enhanced tracheal smooth muscle responsiveness by facilitating acetylcholine release from cholinergic nerve terminals.

Inhibition of neutrophil elastase attenuates airway hyperresponsiveness and inflammation in a mouse model of secondary allergen challenge: neutrophil elastase inhibition attenuates allergic airway responses

PubMed Central

2013-01-01

Background Chronic asthma is often associated with neutrophilic infiltration in the airways. Neutrophils contain elastase, a potent secretagogue in the airways, nonetheless the role for neutrophil elastase as well as neutrophilic inflammation in allergen-induced airway responses is not well defined. In this study, we have investigated the impact of neutrophil elastase inhibition on the development of allergic airway inflammation and airway hyperresponsiveness (AHR) in previously sensitized and challenged mice. Methods BALB/c mice were sensitized and challenged (primary) with ovalbumin (OVA). Six weeks later, a single OVA aerosol (secondary challenge) was delivered and airway inflammation and airway responses were monitored 6 and 48 hrs later. An inhibitor of neutrophil elastase was administered prior to secondary challenge. Results Mice developed a two-phase airway inflammatory response after secondary allergen challenge, one neutrophilic at 6 hr and the other eosinophilic, at 48 hr. PAR-2 expression in the lung tissues was enhanced following secondary challenge, and that PAR-2 intracellular expression on peribronchial lymph node (PBLN) T cells was also increased following allergen challenge of sensitized mice. Inhibition of neutrophil elastase significantly attenuated AHR, goblet cell metaplasia, and inflammatory cell accumulation in the airways following secondary OVA challenge. Levels of IL-4, IL-5 and IL-13, and eotaxin in BAL fluid 6 hr after secondary allergen challenge were significantly suppressed by the treatment. At 48 hr, treatment with the neutrophil elastase inhibitor significantly reduced the levels of IL-13 and TGF-β1 in the BAL fluid. In parallel, in vitro IL-13 production was significantly inhibited in spleen cells from sensitized mice. Conclusion These data indicate that neutrophil elastase plays an important role in the development of allergic airway inflammation and hyperresponsiveness, and would suggest that the neutrophil elastase inhibitor

Abrogation of Airway Hyperresponsiveness but not Inflammation by Rho kinase Insufficiency

PubMed Central

Kasahara, David I.; Ninin, Fernanda M.C.; Wurmbrand, Allison P.; Liao, James K.; Shore, Stephanie A.

2015-01-01

Background Major features of allergic asthma include airway hyperresponsiveness (AHR), eosinophilic inflammation, and goblet cell metaplasia. Rho kinase (ROCK) is a serine/threonine protein kinase that regulates the actin cytoskeleton. By doing so, it can modulate airway smooth muscle cell contraction and leukocyte migration and proliferation. This study was designed to determine the contributions of the two ROCK isoforms, ROCK1 and ROCK2, to AHR, inflammation and goblet cell metaplasia in a mast-cell dependent model of allergic airways disease. Methods and Results Repeated intranasal challenges with OVA caused AHR, eosinophilic inflammation, and goblet cell hyperplasia in wildtype (WT) mice. OVA-induced AHR was partially or completely abrogated in mice haploinsufficient for ROCK2 (ROCK2+/−) or ROCK1 (ROCK1+/−), respectively. In contrast, there was no effect of ROCK insufficiency on allergic airways inflammation, although both ROCK1 and ROCK2 insufficiency attenuated mast cell degranulation. Goblet cell hyperplasia, as indicated by PAS staining, was not different in ROCK1+/− versus WT mice. However, in ROCK2+/− mice, goblet cell hyperplasia was reduced in medium but not large airways. Maximal acetylcholine-induced force generation was reduced in tracheal rings from ROCK1+/− and ROCK2+/− versus WT mice. The ROCK inhibitor, fasudil, also reduced airway responsiveness in OVA-challenged mice, without affecting inflammatory responses. Conclusion In a mast cell model of allergic airways disease, ROCK1 and ROCK2 both contribute to AHR, likely through direct effects on smooth muscle cell and effects on mast-cell degranulation. In addition, ROCK2 but not ROCK1 plays a role in allergen-induced goblet cell hyperplasia. PMID:25323425

Stability of FeNO and airway hyperresponsiveness to mannitol in untreated asthmatics.

PubMed

Udesen, Pernille Bækgaard; Westergaard, Christian Grabow; Porsbjerg, Celeste; Backer, Vibeke

2017-06-01

Airway hyperresponsiveness and airway inflammation are important hallmarks of asthma and are useful in asthma diagnosing, monitoring and treatment. The aim of the study was to assess whether two commonly used clinical tests, the mannitol challenge and Fraction of exhaled NO (FeNO), were stable clinical indicators over time in stable untreated asthmatics. 54 non-smoking, asthma patients not treated with steroids were enrolled in the study and assessed at baseline and a median of 6 months later. At baseline and follow-up, FeNO and airway hyperesponsiveness to mannitol were measured, and asthma control was assessed with the Asthma Control Questionnaire (ACQ). A total of 41 subjects completed both visits. Mean (SD) FEV1% at baseline was 94.1% (17.7) and at re-examination 94.6% (19.7) (ns). The ACQ score was unchanged from baseline (Mean (SD): 0.90 (± 0.73)) to follow-up 0.90 (± 0.74) (ns), as was the FEV 1 % (94.1% (±17.1%) vs 94.6% (19.7%)(ns) indicating that patients were clinically stable during follow-up. The response to mannitol was unchanged at follow-up (Geometric mean (CI) of Response Dose Ratio (RDR) to mannitol: 0.026(0.013-0.046) vs 0.026(0.012-0.050) (ns). There was a slight decrease in FeNO at follow-up (25.5 ppb (19.7-32.9) to 21.9 ppb (17.1-28.2) (p < 0.001). In steroid-free non-smoking asthmatics with constant symptom scores and lung function, airway responsiveness to mannitol remained at the same level over a period of months, while a minor change in exhaled FeNO was reported. These results suggest that mannitol is a stable, reliable marker of clinical disease activity.

Aggravation of airway inflammation and hyper-responsiveness following nasal challenge with Dermatophagoides pteronyssinus in perennial allergic rhinitis without symptoms of asthma.

PubMed

Wang, W; Xian, M; Xie, Y; Zheng, J; Li, J

2016-03-01

House dust mites are the most prevalent allergen causing sensitizations in patients with rhinitis and asthma in China. We aimed to investigate the changes in both upper and lower airway inflammation and responsiveness following Dermatophagoides pteronyssinus (Der-p) nasal provocation test (NPT) in rhinitis patients. Study subjects included 15 nonasthmatic Der-p-sensitized rhinitis (AR) patients with airway hyper-responsiveness (AHR) (AR+AHR+), 15 AR patients without AHR (AR+AHR-), 15 healthy controls (HCs) with Der-p sensitization (HC+DP+), and 15 HC without Der-p sensitization (HC+DP-). All subjects underwent Der-p NPT. Visual analogue scale (VAS) scores of nasal symptoms, nasal lavage and nasal airway resistance (NAR) measurement, sputum induction, and forced expiratory volume in 1 second (FEV1 ) were performed. Airway responsiveness to histamine bronchoprovocation (PD20 -FEV1 ) and exhaled nitric oxide (FeNO) was determined. NAR increased significantly in all subjects with the greatest effect seen in AR+AHR+ individuals. VAS increased in all subjects at 30 min and returned to baseline at 6 h, with significantly higher levels in AR+AHR+ and AR+AHR- subjects (P < 0.05). Eosinophils in nasal lavage fluid and sputum increased significantly after NPT in AR+AHR+ and AR+AHR- subjects (P < 0.001). FEV1 % and PD20 -FEV1 decreased and FeNO increased significantly after NPT only in AR+AHR+ subjects (P < 0.05). Nasal lavage eosinophil count was positively correlated with sputum eosinophil count and the level of FeNO and negatively correlated with FEV1 and PD20 . House dust mite nasal provocation test induces and aggravates both upper and lower airway inflammation and hyper-responsiveness in patients with persistent allergic rhinitis without asthmatic symptoms. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Glutathione redox regulates airway hyperresponsiveness and airway inflammation in mice.

PubMed

Koike, Yoko; Hisada, Takeshi; Utsugi, Mitsuyoshi; Ishizuka, Tamotsu; Shimizu, Yasuo; Ono, Akihiro; Murata, Yukie; Hamuro, Junji; Mori, Masatomo; Dobashi, Kunio

2007-09-01

Glutathione is the major intracellular redox buffer. We have shown that glutathione redox status, which is the balance between intracellular reduced (GSH) and oxidized (GSSG) glutathione, in antigen-presenting cells (APC) regulates the helper T cell type 1 (Th1)/Th2 balance due to the production of IL-12. Bronchial asthma is a typical Th2 disease. Th2 cells and Th2 cytokines are characteristic of asthma and trigger off an inflammation. Accordingly, we studied the effects of the intracellular glutathione redox status on airway hyperresponsiveness (AHR) and allergen-induced airway inflammation in a mouse model of asthma. We used gamma-Glutamylcysteinylethyl ester (gamma-GCE), which is a membrane-permeating GSH precursor, to elevate the intracellular GSH level and GSH/GSSG ratio of mice. In vitro, gamma-GCE pretreatment of human monocytic THP-1 cells elevated the GSH/GSSG ratio and enhanced IL-12(p70) production induced by LPS. In the mouse asthma model, intraperitoneal injection of gamma-GCE elevated the GSH/GSSG ratio of lung tissue and reduced AHR. gamma-GCE reduced levels of IL-4, IL-5, IL-10, and the chemokines eotaxin and RANTES (regulated on activation, normal T cell expressed and secreted) in bronchoalveolar lavage fluid, whereas it enhanced the production of IL-12 and IFN-gamma. Histologically, gamma-GCE suppressed eosinophils infiltration. Interestingly, we also found that gamma-GCE directly inhibited chemokine-induced eosinophil chemotaxis without affecting eotaxin receptor chemokine receptor 3 (CCR3) expressions. Taken together, these findings suggest that changing glutathione redox balance, increase in GSH level, and the GSH/GSSG ratio by gamma-GCE, ameliorate bronchial asthma by altering the Th1/Th2 imbalance through IL-12 production from APC and suppressing chemokine production and eosinophil migration itself.

Airway Hyperresponsiveness in Children With Sickle Cell Anemia

PubMed Central

Field, Joshua J.; Stocks, Janet; Kirkham, Fenella J.; Rosen, Carol L.; Dietzen, Dennis J.; Semon, Trisha; Kirkby, Jane; Bates, Pamela; Seicean, Sinziana; DeBaun, Michael R.; Redline, Susan

2011-01-01

Background: The high prevalence of airway hyperresponsiveness (AHR) among children with sickle cell anemia (SCA) remains unexplained. Methods: To determine the relationship between AHR, features of asthma, and clinical characteristics of SCA, we conducted a multicenter, prospective cohort study of children with SCA. Dose response slope (DRS) was calculated to describe methacholine responsiveness, because 30% of participants did not achieve a 20% decrease in FEV1 after inhalation of the highest methacholine concentration, 25 mg/mL. Multiple linear regression analysis was done to identify independent predictors of DRS. Results: Methacholine challenge was performed in 99 children with SCA aged 5.6 to 19.9 years (median, 12.8 years). Fifty-four (55%) children had a provocative concentration of methacholine producing a 20% decrease in FEV1 < 4 mg/mL. In a multivariate analysis, independent associations were found between increased methacholine responsiveness and age (P < .001), IgE (P = .009), and lactate dehydrogenase (LDH) levels (P = .005). There was no association between methacholine responsiveness and a parent report of a doctor diagnosis of asthma (P = .986). Other characteristics of asthma were not associated with methacholine responsiveness, including positive skin tests to aeroallergens, exhaled nitric oxide, peripheral blood eosinophil count, and pulmonary function measures indicating airflow obstruction. Conclusions: In children with SCA, AHR to methacholine is prevalent. Younger age, serum IgE concentration, and LDH level, a marker of hemolysis, are associated with AHR. With the exception of serum IgE, no signs or symptoms of an allergic diathesis are associated with AHR. Although the relationship between methacholine responsiveness and LDH suggests that factors related to SCA may contribute to AHR, these results will need to be validated in future studies. PMID:20724735

A semisynthetic diterpenoid lactone inhibits NF-κB signalling to ameliorate inflammation and airway hyperresponsiveness in a mouse asthma model

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

Lim, J.C.-W.

Andrographolide (AGP) and 14-deoxy-11,12-didehydroandrographolide (DDAG), two main diterpenoid constituents of Andrographis paniculata were previously shown to ameliorate asthmatic symptoms in a mouse model. However, due to inadequacies of both compounds in terms of drug-likeness, DDAG analogues were semisynthesised for assessment of their anti-asthma activity. A selected analogue, 3,19-diacetyl-14-deoxy-11,12-didehydroandrographolide (SRS27), was tested for inhibitory activity of NF-κB activation in TNF-α-induced A549 cells and was subsequently evaluated in a mouse model of ovalbumin (OVA)-induced asthma. Female BALB/c mice, 6–8 weeks old were sensitized on days 0 and 14, and challenged on days 22, 23 and 24 with OVA. Compound or vehicle (3%more » dimethyl sulfoxide) was administered intraperitoneally 1 h before and 11 h after each OVA aerosol challenge. On day 25, pulmonary eosinophilia, airway hyperresponsiveness, mucus hypersecretion, inflammatory cytokines such as IL-4, -5 and -13 in BAL fluid, gene expression of inflammatory mediators such as 5-LOX, E-selectin, VCAM-1, CCL5, TNF-α, AMCase, Ym2, YKL-40, Muc5ac, CCL2 and iNOS in animal lung tissues, and serum IgE were determined. SRS27 at 30 μM was found to suppress NF-κB nuclear translocation in A549 cells. In the ovalbumin-induced mouse asthma model, SRS27 at 3 mg/kg displayed a substantial decrease in pulmonary eosinophilia, BAL fluid inflammatory cytokines level, serum IgE production, mucus hypersecretion and gene expression of inflammatory mediators in lung tissues. SRS27 is the first known DDAG analogue effective in ameliorating inflammation and airway hyperresponsiveness in the ovalbumin-induced mouse asthma model. - Highlights: • SRS27 was synthesised to overcome inadequacies of its parent compound in terms of drug-likeness. • SRS27 was tested in TNF-α-induced A549 lung cells and ovalbumin (OVA)-induced mouse asthma model. • SRS27 suppressed NF-κB nuclear translocation in A549 cells. �

Early treatment of chlorine-induced airway hyperresponsiveness and inflammation with corticosteroids.

PubMed

Jonasson, Sofia; Wigenstam, Elisabeth; Koch, Bo; Bucht, Anders

2013-09-01

Chlorine (Cl2) is an industrial gas that is highly toxic and irritating when inhaled causing tissue damage and an acute inflammatory response in the airways followed by a long-term airway dysfunction. The aim of this study was to evaluate whether early anti-inflammatory treatment can protect against the delayed symptoms in Cl2-exposed mice. BALB/c mice were exposed by nose-only inhalation using 200ppm Cl2 during 15min. Assessment of airway hyperresponsiveness (AHR), inflammatory cell counts in bronchoalveolar lavage, occurrence of lung edema and lung fibrosis were analyzed 24h or 14days post-exposure. A single dose of the corticosteroid dexamethasone (10 or 100mg/kg) was administered intraperitoneally 1, 3, 6, or 12h following Cl2 exposure. High-dose of dexamethasone reduced the acute inflammation if administered within 6h after exposure but treated animals still displayed a significant lung injury. The effect of dexamethasone administered within 1h was dose-dependent; high-dose significantly reduced acute airway inflammation (100mg/kg) but not treatment with the relatively low-dose (10mg/kg). Both doses reduced AHR 14days later, while lung fibrosis measured as collagen deposition was not significantly reduced. The results point out that the acute inflammation in the lungs due to Cl2 exposure only partly is associated with the long-term AHR. We hypothesize that additional pathogenic mechanisms apart from the inflammatory reactions contribute to the development of long-term airway dysfunction. By using this mouse model, we have validated early administration of corticosteroids in terms of efficacy to prevent acute lung injury and delayed symptoms induced by Cl2 exposure. Copyright © 2013 Elsevier Inc. All rights reserved.

A Multi-Scale Approach to Airway Hyperresponsiveness: From Molecule to Organ

PubMed Central

Lauzon, Anne-Marie; Bates, Jason H. T.; Donovan, Graham; Tawhai, Merryn; Sneyd, James; Sanderson, Michael J.

2012-01-01

Airway hyperresponsiveness (AHR), a characteristic of asthma that involves an excessive reduction in airway caliber, is a complex mechanism reflecting multiple processes that manifest over a large range of length and time scales. At one extreme, molecular interactions determine the force generated by airway smooth muscle (ASM). At the other, the spatially distributed constriction of the branching airways leads to breathing difficulties. Similarly, asthma therapies act at the molecular scale while clinical outcomes are determined by lung function. These extremes are linked by events operating over intermediate scales of length and time. Thus, AHR is an emergent phenomenon that limits our understanding of asthma and confounds the interpretation of studies that address physiological mechanisms over a limited range of scales. A solution is a modular computational model that integrates experimental and mathematical data from multiple scales. This includes, at the molecular scale, kinetics, and force production of actin-myosin contractile proteins during cross-bridge and latch-state cycling; at the cellular scale, Ca2+ signaling mechanisms that regulate ASM force production; at the tissue scale, forces acting between contracting ASM and opposing viscoelastic tissue that determine airway narrowing; at the organ scale, the topographic distribution of ASM contraction dynamics that determine mechanical impedance of the lung. At each scale, models are constructed with iterations between theory and experimentation to identify the parameters that link adjacent scales. This modular model establishes algorithms for modeling over a wide range of scales and provides a framework for the inclusion of other responses such as inflammation or therapeutic regimes. The goal is to develop this lung model so that it can make predictions about bronchoconstriction and identify the pathophysiologic mechanisms having the greatest impact on AHR and its therapy. PMID:22701430

RGS4 Overexpression in Lung Attenuates Airway Hyperresponsiveness in Mice.

PubMed

Madigan, Laura A; Wong, Gordon S; Gordon, Elizabeth M; Chen, Wei-Sheng; Balenga, Nariman; Koziol-White, Cynthia J; Panettieri, Reynold A; Levine, Stewart J; Druey, Kirk M

2018-01-01

A cardinal feature of asthma is airway hyperresponsiveness (AHR) to spasmogens, many of which activate G protein-coupled receptors (GPCRs) on airway smooth muscle (ASM) cells. Asthma subtypes associated with allergy are characterized by eosinophilic inflammation in the lung due to the type 2 immune response to allergens and proinflammatory mediators that promote AHR. The degree to which intrinsic abnormalities of ASM contribute to this phenotype remains unknown. The regulators of G protein signaling (RGS) proteins are a large group of intracellular proteins that inhibit GPCR signaling pathways. RGS2- and RGS5-deficient mice develop AHR spontaneously. Although RGS4 is upregulated in ASM from patients with severe asthma, the effects of increased RGS4 expression on AHR in vivo are unknown. Here, we examined the impact of forced RGS4 overexpression in lung on AHR using transgenic (Tg) mice. Tg RGS4 was expressed in bronchial epithelium and ASM in vivo, and protein expression in lung was increased at least 4-fold in Tg mice compared with wild-type (WT) mice. Lung slices from Tg mice contracted less in response to the m3 muscarinic receptor agonist methacholine compared with the WT, although airway resistance in live, unchallenged mice of both strains was similar. Tg mice were partially protected against AHR induced by fungal allergen challenge due to weakened contraction signaling in ASM and reduced type 2 cytokine (IL-5 and IL-13) levels in Tg mice compared with the WT. These results provide support for the hypothesis that increasing RGS4 expression and/or function could be a viable therapeutic strategy for asthma.

Cigarette smoke induces bronchoconstrictor hyperresponsiveness to substance P and inactivates airway neutral endopeptidase in the guinea pig. Possible role of free radicals.

PubMed

Dusser, D J; Djokic, T D; Borson, D B; Nadel, J A

1989-09-01

We examined the effects of acute exposure to cigarette smoke on the airway responses to substance P in anesthetized guinea pigs and on the activity of airway neutral endopeptidase (NEP). After exposure to air or to cigarette smoke we measured the change in total pulmonary resistance (RL) induced by increasing concentrations of aerosolized substance P in the absence or presence of the NEP inhibitor phosphoramidon. In the absence of phosphramidon the bronchoconstrictor responses to substance P were greater in cigarette smoke-exposed guinea pigs than in air-exposed animals. Phosphoramidon did not further potentiate the responses to substance P in smoke-exposed guinea pigs, whereas it did so in air-exposed animals. In the presence of phosphoramidon, bronchoconstrictor responses to substance P in animals exposed to air or to cigarette smoke were not different. Aerosols of SOD delivered before cigarette smoke exposures dramatically reduced smoke-induced hyperresponsiveness to substance P, whereas heat-inactivated SOD had no effect on smoke-induced hyper-responsiveness to substance P. Cigarette smoke solution inhibited NEP activity from tracheal homogenate in a concentration-dependent fashion, an inhibitory effect that was mostly due to the gas phase of the smoke, but not to nicotine. The mild chemical oxidant N-chlorosuccinimide mimicked the concentration-dependent inhibitory effect of smoke solution on airway NEP activity. We conclude that cigarette smoke causes enhanced airway responsiveness to substance P in vivo by inactivating airway NEP. We suggest that cigarette smoke-induced inhibition of airway NEP is due to effects of free radicals.

Cigarette smoke induces bronchoconstrictor hyperresponsiveness to substance P and inactivates airway neutral endopeptidase in the guinea pig. Possible role of free radicals.

PubMed Central

Dusser, D J; Djokic, T D; Borson, D B; Nadel, J A

1989-01-01

We examined the effects of acute exposure to cigarette smoke on the airway responses to substance P in anesthetized guinea pigs and on the activity of airway neutral endopeptidase (NEP). After exposure to air or to cigarette smoke we measured the change in total pulmonary resistance (RL) induced by increasing concentrations of aerosolized substance P in the absence or presence of the NEP inhibitor phosphoramidon. In the absence of phosphramidon the bronchoconstrictor responses to substance P were greater in cigarette smoke-exposed guinea pigs than in air-exposed animals. Phosphoramidon did not further potentiate the responses to substance P in smoke-exposed guinea pigs, whereas it did so in air-exposed animals. In the presence of phosphoramidon, bronchoconstrictor responses to substance P in animals exposed to air or to cigarette smoke were not different. Aerosols of SOD delivered before cigarette smoke exposures dramatically reduced smoke-induced hyperresponsiveness to substance P, whereas heat-inactivated SOD had no effect on smoke-induced hyper-responsiveness to substance P. Cigarette smoke solution inhibited NEP activity from tracheal homogenate in a concentration-dependent fashion, an inhibitory effect that was mostly due to the gas phase of the smoke, but not to nicotine. The mild chemical oxidant N-chlorosuccinimide mimicked the concentration-dependent inhibitory effect of smoke solution on airway NEP activity. We conclude that cigarette smoke causes enhanced airway responsiveness to substance P in vivo by inactivating airway NEP. We suggest that cigarette smoke-induced inhibition of airway NEP is due to effects of free radicals. PMID:2474576

Could an increase in airway smooth muscle shortening velocity cause airway hyperresponsiveness?

PubMed Central

Bullimore, Sharon R.; Siddiqui, Sana; Donovan, Graham M.; Martin, James G.; Sneyd, James; Bates, Jason H. T.

2011-01-01

Airway hyperresponsiveness (AHR) is a characteristic feature of asthma. It has been proposed that an increase in the shortening velocity of airway smooth muscle (ASM) could contribute to AHR. To address this possibility, we tested whether an increase in the isotonic shortening velocity of ASM is associated with an increase in the rate and total amount of shortening when ASM is subjected to an oscillating load, as occurs during breathing. Experiments were performed in vitro using 27 rat tracheal ASM strips supramaximally stimulated with methacholine. Isotonic velocity at 20% isometric force (Fiso) was measured, and then the load on the muscle was varied sinusoidally (0.33 ± 0.25 Fiso, 1.2 Hz) for 20 min, while muscle length was measured. A large amplitude oscillation was applied every 4 min to simulate a deep breath. We found that: 1) ASM strips with a higher isotonic velocity shortened more quickly during the force oscillations, both initially (P < 0.001) and after the simulated deep breaths (P = 0.002); 2) ASM strips with a higher isotonic velocity exhibited a greater total shortening during the force oscillation protocol (P < 0.005); and 3) the effect of an increase in isotonic velocity was at least comparable in magnitude to the effect of a proportional increase in ASM force-generating capacity. A cross-bridge model showed that an increase in the total amount of shortening with increased isotonic velocity could be explained by a change in either the cycling rate of phosphorylated cross bridges or the rate of myosin light chain phosphorylation. We conclude that, if asthma involves an increase in ASM velocity, this could be an important factor in the associated AHR. PMID:20971805

PM2.5-induced airway inflammation and hyperresponsiveness in NC/Nga mice.

PubMed

Ogino, Keiki; Nagaoka, Kenjiro; Okuda, Tomoaki; Oka, Akira; Kubo, Masayuki; Eguchi, Eri; Fujikura, Yoshihisa

2017-03-01

The allergic inflammatory effects of particulate matter (PM) 2.5, collected with the cyclone system in Yokohama city in Japan, were investigated in NC/Nga mice, which are hypersensitive to mite allergens. PM2.5 with alum was injected intraperitoneally for sensitization. Five days later, 200 μg of PM2.5 in 25 μL of saline was administered to mice intranasally five times for further sensitization. On the 11th day, PM2.5 was administered as a challenge. On the 12th day, mice were examined for airway hyperresponsiveness (AHR), the bronchoalveolar lavage fluid (BALF) cell count, mRNA expression of Th 1 , Th 2 cytokines, and metallothioneins in lung tissue, and histopathology. PM2.5 increased AHR, total cell numbers including eosinophils in BALF, and mRNA levels of IL-5, IL-22, eotaxin, eotaxin 2, and metallothionein 3. In PM2.5-induced lungs, inflammation was observed around the bronchus. These results demonstrate that PM2.5 alone, collected with the cyclone system in Yokohama city in Japan, induces asthma-like airway inflammation. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1047-1054, 2017. © 2016 Wiley Periodicals, Inc.

Vitamin D deficiency causes airway hyperresponsiveness, increases airway smooth muscle mass, and reduces TGF‐β expression in the lungs of female BALB/c mice

PubMed Central

Foong, Rachel E.; Shaw, Nicole C.; Berry, Luke J.; Hart, Prue H.; Gorman, Shelley; Zosky, Graeme R.

2014-01-01

Abstract Vitamin D deficiency is associated with disease severity in asthma. We tested whether there is a causal association between vitamin D deficiency, airway smooth muscle (ASM) mass, and the development of airway hyperresponsiveness (AHR). A physiologically relevant mouse model of vitamin D deficiency was developed by raising BALB/c mice on vitamin D‐deficient or ‐replete diets. AHR was assessed by measuring lung function responses to increasing doses of inhaled methacholine. Five‐micron sections from formalin‐fixed lungs were used for ASM measurement and assessment of lung structure using stereological methods. Transforming growth factor (TGF)‐β levels were measured in bronchoalveolar lavage fluid (BALF). Lungs were dissected from embryonic day (E) 17.5 vitamin D‐deficient and ‐replete fetal mice for quantification of ASM density and relative gene expression of TGF‐β signaling pathway molecules. Eight‐week‐old adult vitamin D‐deficient female mice had significantly increased airway resistance and ASM in the large airways compared with controls. Vitamin D‐deficient female mice had a smaller lung volume, volume of parenchyma, and alveolar septa. Both vitamin D‐deficient male and female mice had reduced TGF‐β levels in BALF. Vitamin D deficiency did not have an effect on ASM density in E17.5 mice, however, expression of TGF‐β1 and TGF‐β receptor I was downregulated in vitamin D‐deficient female fetal mice. Decreased expression of TGF‐β1 and TGF‐β receptor I during early lung development in vitamin D‐deficient mice may contribute to airway remodeling and AHR in vitamin D‐deficient adult female mice. This study provides a link between vitamin D deficiency and respiratory symptoms in chronic lung disease. PMID:24760528

Targeting Phosphoinositide 3-Kinase γ in Airway Smooth Muscle Cells to Suppress Interleukin-13-Induced Mouse Airway Hyperresponsiveness

PubMed Central

Jiang, Haihong; Xie, Yan; Abel, Peter W.; Toews, Myron L.; Townley, Robert G.; Casale, Thomas B.

2012-01-01

We recently reported that phosphoinositide 3-kinase γ (PI3Kγ) directly regulates airway smooth muscle (ASM) contraction by modulating Ca2+ oscillations. Because ASM contraction plays a critical role in airway hyperresponsiveness (AHR) of asthma, the aim of the present study was to determine whether targeting PI3Kγ in ASM cells could suppress AHR in vitro and in vivo. Intranasal administration into mice of interleukin-13 (IL-13; 10 μg per mouse), a key pathophysiologic cytokine in asthma, induced AHR after 48 h, as assessed by invasive tracheostomy. Intranasal administration of a broad-spectrum PI3K inhibitor or a PI3Kγ-specific inhibitor 1 h before AHR assessment attenuated IL-13 effects. Airway responsiveness to bronchoconstrictor agonists was also examined in precision-cut mouse lung slices pretreated without or with IL-13 for 24 h. Acetylcholine and serotonin dose-response curves indicated that IL-13-treated lung slices had a 40 to 50% larger maximal airway constriction compared with controls. Furthermore, acetylcholine induced a larger initial Ca2+ transient and increased Ca2+ oscillations in IL-13-treated primary mouse ASM cells compared with control cells, correlating with increased cell contraction. As expected, PI3Kγ inhibitor treatment attenuated IL-13-augmented airway contractility of lung slices and ASM cell contraction. In both control and IL-13-treated ASM cells, small interfering RNA-mediated knockdown of PI3Kγ by 70% only reduced the initial Ca2+ transient by 20 to 30% but markedly attenuated Ca2+ oscillations and contractility of ASM cells by 50 to 60%. This report is the first to demonstrate that PI3Kγ in ASM cells is important for IL-13-induced AHR and that acute treatment with a PI3Kγ inhibitor can ameliorate AHR in a murine model of asthma. PMID:22543031

Vaccination against IL-33 Inhibits Airway Hyperresponsiveness and Inflammation in a House Dust Mite Model of Asthma

PubMed Central

Lei, Ying; Adner, Mikael; Hellman, Lars; Nilsson, Gunnar

2015-01-01

In several clinical and experimental studies IL-33 and its receptor have been found to play important roles in the development of asthma and allergic airway inflammation. We evaluated the effects of vaccination against IL-33 in a mouse model of airway inflammation induced by house dust mite (HDM) allergen. Balb/c mice received the IL-33 vaccine subcutaneously, followed by intranasal administration of HDM for up to six weeks. Vaccination against IL-33 induced high titers of specific anti-IL-33 IgG antibodies that inhibited HDM-induced airway hyperresponsiveness (AHR) in the conducting airways and tissue damping. The vaccination also attenuated the HDM-induced elevation in the numbers of eosinophils in bronchoalveolar lavage fluid (BALF) and suppressed the accumulation of inflammatory cells in the airways. Furthermore, the levels of IL-17A, IL-25, IL-33 and TSLP in lung tissue homogenates were reduced by vaccination against IL-33. These observations demonstrate that vaccination against IL-33 inhibits HDM-induced development of AHR, airway inflammation and production of inflammatory cytokines. The results also indicate an important role of IL-33 in the regulation of AHR of the distal lung compartments. Thus, administration of such a vaccine is potentially an effective therapeutic tool for treating allergic asthma. PMID:26214807

Curine inhibits eosinophil activation and airway hyper-responsiveness in a mouse model of allergic asthma

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

Ribeiro-Filho, Jaime; Laboratório de Imunofarmacologia, Departamento de Fisiologia e Patologia, UFPB, João Pessoa, Paraíba; Calheiros, Andrea Surrage

Allergic asthma is a chronic inflammatory airway disease with increasing prevalence around the world. Current asthma therapy includes drugs that usually cause significant side effects, justifying the search for new anti-asthmatic drugs. Curine is a bisbenzylisoquinoline alkaloid that modulates calcium influx in many cell types; however, its anti-allergic and putative toxic effects remain to be elucidated. Our aim was to investigate the effects of curine on eosinophil activation and airway hyper-responsiveness (AHR) and to characterize its potential toxic effects. We used a mouse model of allergic asthma induced by sensitization and challenge with ovalbumin (OVA) to evaluate the anti-allergic effectsmore » of oral treatment with curine. The oral administration of curine significantly inhibited eosinophilic inflammation, eosinophil lipid body formation and AHR in animals challenged with OVA compared with animals in the untreated group. The curine treatment also reduced eotaxin and IL-13 production triggered by OVA. Verapamil, a calcium channel antagonist, had similar anti-allergic properties, and curine pre-treatment inhibited the calcium-induced tracheal contractile response ex-vivo, suggesting that the mechanism by which curine exerts its effects is through the inhibition of a calcium-dependent response. A toxicological evaluation showed that orally administered curine did not significantly alter the biochemical, hematological, behavioral and physical parameters measured in the experimental animals compared with saline-treated animals. In conclusion, curine showed anti-allergic activity through mechanisms that involve inhibition of IL-13 and eotaxin and of Ca{sup ++} influx, without inducing evident toxicity and as such, has the potential for the development of anti-asthmatic drugs. - Highlights: • Curine is a bisbenzylisoquinoline alkaloid from Chondrodendron platyphyllum. • Curine inhibits eosinophil influx and activation and airway hyper-responsiveness. �

G Protein βγ-Subunit Signaling Mediates Airway Hyperresponsiveness and Inflammation in Allergic Asthma

PubMed Central

Grunstein, Judith S.; McDonough, Joseph; Kreiger, Portia A.; Josephson, Maureen B.; Choi, John K.; Grunstein, Michael M.

2012-01-01

Since the Gβγ subunit of Gi protein has been importantly implicated in regulating immune and inflammatory responses, this study investigated the potential role and mechanism of action of Gβγ signaling in regulating the induction of airway hyperresponsiveness (AHR) in a rabbit model of allergic asthma. Relative to non-sensitized animals, OVA-sensitized rabbits challenged with inhaled OVA exhibited AHR, lung inflammation, elevated BAL levels of IL-13, and increased airway phosphodiesterase-4 (PDE4) activity. These proasthmatic responses were suppressed by pretreatment with an inhaled membrane-permeable anti-Gβγ blocking peptide, similar to the suppressive effect of glucocorticoid pretreatment. Extended mechanistic studies demonstrated that: 1) corresponding proasthmatic changes in contractility exhibited in isolated airway smooth muscle (ASM) sensitized with serum from OVA-sensitized+challenged rabbits or IL-13 were also Gβγ-dependent and mediated by MAPK-upregulated PDE4 activity; and 2) the latter was attributed to Gβγ-induced direct stimulation of the non-receptor tyrosine kinase, c-Src, resulting in downstream activation of ERK1/2 and its consequent transcriptional upregulation of PDE4. Collectively, these data are the first to identify that a mechanism involving Gβγ-induced direct activation of c-Src, leading to ERK1/2-mediated upregulation of PDE4 activity, plays a decisive role in regulating the induction of AHR and inflammation in a rabbit model of allergic airway disease. PMID:22384144

Weight Loss Decreases Inherent and Allergic Methacholine Hyperresponsiveness in Mouse Models of Diet-Induced Obese Asthma

PubMed Central

Ather, Jennifer L.; Chung, Michael; Hoyt, Laura R.; Randall, Matthew J.; Georgsdottir, Anna; Daphtary, Nirav A.; Aliyeva, Minara I.; Suratt, Benjamin T.; Bates, Jason H. T.; Irvin, Charles G.; Russell, Sheila R.; Forgione, Patrick M.; Dixon, Anne E.

2016-01-01

Obese asthma presents with inherent hyperresponsiveness to methacholine or augmented allergen-driven allergic asthma, with an even greater magnitude of methacholine hyperresponsiveness. These physiologic parameters and accompanying obese asthma symptoms can be reduced by successful weight loss, yet the underlying mechanisms remain incompletely understood. We implemented mouse models of diet-induced obesity, dietary and surgical weight loss, and environmental allergen exposure to examine the mechanisms and mediators of inherent and allergic obese asthma. We report that the methacholine hyperresponsiveness in these models of inherent obese asthma and obese allergic asthma manifests in distinct anatomical compartments but that both are amenable to interventions that induce substantial weight loss. The inherent obese asthma phenotype, with characteristic increases in distal airspace tissue resistance and tissue elastance, is associated with elevated proinflammatory cytokines that are reduced with dietary weight loss. Surprisingly, bariatric surgery–induced weight loss further elevates these cytokines while reducing methacholine responsiveness to levels similar to those in lean mice or in formerly obese mice rendered lean through dietary intervention. In contrast, the obese allergic asthma phenotype, with characteristic increases in central airway resistance, is not associated with increased adaptive immune responses, yet diet-induced weight loss reduces methacholine hyperresponsiveness without altering immunological variables. Diet-induced weight loss is effective in models of both inherent and allergic obese asthma, and our examination of the fecal microbiome revealed that the obesogenic Firmicutes/Bacteroidetes ratio was normalized after diet-induced weight loss. Our results suggest that structural, immunological, and microbiological factors contribute to the manifold presentations of obese asthma. PMID:27064658

Length oscillation induces force potentiation in infant guinea pig airway smooth muscle.

PubMed

Wang, Lu; Chitano, Pasquale; Murphy, Thomas M

2005-12-01

Deep inspiration counteracts bronchospasm in normal subjects but triggers further bronchoconstriction in hyperresponsive airways. Although the exact mechanisms for this contrary response by normal and hyperresponsive airways are unclear, it has been suggested that the phenomenon is related to changes in force-generating ability of airway smooth muscle after mechanical oscillation. It is known that healthy immature airways of both humans and animals exhibit hyperresponsiveness. We hypothesize that the profile of active force generation after mechanical oscillation changes with maturation and that this change contributes to the expression of airway hyperresponsiveness in juveniles. We examined the effect of an acute sinusoidal length oscillation on the force-generating ability of tracheal smooth muscle from 1 wk, 3 wk, and 2- to 3-mo-old guinea pigs. We found that the length oscillation produced 15-20% initial reduction in active force equally in all age groups. This was followed by a force recovery profile that displayed striking maturation-specific features. Unique to tracheal strips from 1-wk-old animals, active force potentiated beyond the maximal force generated before oscillation. We also found that actin polymerization was required in force recovery and that prostanoids contributed to the maturation-specific force potentiation in immature airway smooth muscle. Our results suggest a potentiated mechanosensitive contractile property of hyperresponsive airway smooth muscle. This can account for further bronchoconstriction triggered by deep inspiration in hyperresponsive airways.

Multiple exposures to swine barn air induce lung inflammation and airway hyper-responsiveness

PubMed Central

Charavaryamath, Chandrashekhar; Janardhan, Kyathanahalli S; Townsend, Hugh G; Willson, Philip; Singh, Baljit

2005-01-01

Background Swine farmers repeatedly exposed to the barn air suffer from respiratory diseases. However the mechanisms of lung dysfunction following repeated exposures to the barn air are still largely unknown. Therefore, we tested a hypothesis in a rat model that multiple interrupted exposures to the barn air will cause chronic lung inflammation and decline in lung function. Methods Rats were exposed either to swine barn (8 hours/day for either one or five or 20 days) or ambient air. After the exposure periods, airway hyper-responsiveness (AHR) to methacholine (Mch) was measured and rats were euthanized to collect bronchoalveolar lavage fluid (BALF), blood and lung tissues. Barn air was sampled to determine endotoxin levels and microbial load. Results The air in the barn used in this study had a very high concentration of endotoxin (15361.75 ± 7712.16 EU/m3). Rats exposed to barn air for one and five days showed increase in AHR compared to the 20-day exposed and controls. Lungs from the exposed groups were inflamed as indicated by recruitment of neutrophils in all three exposed groups and eosinophils and an increase in numbers of airway epithelial goblet cells in 5- and 20-day exposure groups. Rats exposed to the barn air for one day or 20 days had more total leukocytes in the BALF and 20-day exposed rats had more airway epithelial goblet cells compared to the controls and those subjected to 1 and 5 exposures (P < 0.05). Bronchus-associated lymphoid tissue (BALT) in the lungs of rats exposed for 20 days contained germinal centers and mitotic cells suggesting activation. There were no differences in the airway smooth muscle cell volume or septal macrophage recruitment among the groups. Conclusion We conclude that multiple exposures to endotoxin-containing swine barn air induce AHR, increase in mucus-containing airway epithelial cells and lung inflammation. The data also show that prolonged multiple exposures may also induce adaptation in AHR response in the exposed

Airway hyperresponsiveness, peak flow variability and inflammatory markers in non-asthmatic subjects with respiratory infections.

PubMed

Björnsson, Eythór; Lúdvíksdóttir, Dóra; Hedenström, Hans; Eriksson, Britt-Marie; Högman, Marieann; Venge, Per; Janson, Christer

2007-07-01

The aim of this study was to characterise non-asthmatic subjects with asthma-like symptoms during a common cold, particularly in relation to airway hyperresponsiveness (AHR). Subjects with acute respiratory infections and a group of controls (n = 20 + 20), age 20-65 years, underwent bronchial provocations with methacholine, adenosine and cold air. All were non-smokers and had no history of asthma or heart disease. Those with infection had asthma-like symptoms (>2). Measurements of exhaled nitric oxide (eNO), serum levels of eosinophil cationic protein (ECP), eosinophil peroxidase, myeloperoxidase and human neutrophil lipocalin were made at each provocation. A 17-day symptom and peak flow diary was calculated. No differences between the two groups were found, regarding responsiveness to methacholine, adenosine or cold air challenge, as well as the inflammatory markers measured. In the infected group, the mean (standard deviation) ECP was higher in those with AHR to methacholine or cold air [15.7 (6.5) and 11.4 (4.2) microg/L, respectively; P < 0.05]; furthermore, eNO was higher in the infected group [116 (54) and 88 (52) nL/min, respectively; P = 0.055]. The infected group had, at all times, more symptoms and higher peak flow, with a decrease in the symptoms (P = 0.02) and a tendency to change in peak flow variation (P = 0.06). AHR does not seem to be the main cause of asthma-like symptoms in adults with infectious wheezing. Peak flow variation and symptom prevalence during the post-infection period may imply airway pathology different from AHR.

Chronic Low Dose Chlorine Exposure Aggravates Allergic Inflammation and Airway Hyperresponsiveness and Activates Inflammasome Pathway

PubMed Central

Kim, Sae-Hoon; Park, Da-Eun; Lee, Hyun-Seung; Kang, Hye-Ryun; Cho, Sang-Heon

2014-01-01

Background Epidemiologic clinical studies suggested that chronic exposure to chlorine products is associated with development of asthma and aggravation of asthmatic symptoms. However, its underlying mechanism was not clearly understood. Studies were undertaken to define the effects and mechanisms of chronic low-dose chlorine exposure in the pathogenesis of airway inflammation and airway hyperresponsiveness (AHR). Methods Six week-old female BALB/c mice were sensitized and challenged with OVA in the presence and absence of chronic low dose chlorine exposure of naturally vaporized gas of 5% sodium hypochlorite solution. Airway inflammation and AHR were evaluated by bronchoalveolar lavage (BAL) cell recovery and non-invasive phlethysmography, respectively. Real-time qPCR, Western blot assay, and ELISA were used to evaluate the mRNA and protein expressions of cytokines and other inflammatory mediators. Human A549 and murine epithelial (A549 and MLE12) and macrophage (AMJ2-C11) cells were used to define the responses to low dose chlorine exposure in vitro. Results Chronic low dose chlorine exposure significantly augmented airway inflammation and AHR in OVA-sensitized and challenged mice. The expression of Th2 cytokines IL-4 and IL-5 and proinflammatory cytokine IL-1β and IL-33 were significantly increased in OVA/Cl group compared with OVA group. The chlorine exposure also activates the major molecules associated with inflammasome pathway in the macrophages with increased expression of epithelial alarmins IL-33 and TSLP in vitro. Conclusion Chronic low dose exposure of chlorine aggravates allergic Th2 inflammation and AHR potentially through activation of inflammasome danger signaling pathways. PMID:25202911

Inflammation and airway hyperresponsiveness after chlorine exposure are prolonged by Nrf2 deficiency in mice.

PubMed

Ano, Satoshi; Panariti, Alice; Allard, Benoit; O'Sullivan, Michael; McGovern, Toby K; Hamamoto, Yoichiro; Ishii, Yukio; Yamamoto, Masayuki; Powell, William S; Martin, James G

2017-01-01

Chlorine gas (Cl 2 ) is a potent oxidant and trigger of irritant induced asthma. We explored NF-E2-related factor 2 (Nrf2)-dependent mechanisms in the asthmatic response to Cl 2 , using Nrf2-deficient mice, buthionine sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis and sulforaphane (SFN), a phytochemical regulator of Nrf2. Airway inflammation and airway hyperresponsiveness (AHR) were assessed 24 and 48h after a 5-min nose-only exposure to 100ppm Cl 2 of Nrf2-deficient and wild type Balb/C mice treated with BSO or SFN. Animals were anesthetized, paralyzed and mechanically ventilated (FlexiVent™) and challenged with aerosolized methacholine. Bronchoalveolar lavage (BAL) was performed and lung tissues were harvested for assessment of gene expression. Cl 2 exposure induced a robust AHR and an intense neutrophilic inflammation that, although similar in Nrf2-deficient mice and wild-type mice at 24h after Cl 2 exposure, were significantly greater at 48h post exposure in Nrf2-deficient mice. Lung GSH and mRNA for Nrf2-dependent phase II enzymes (NQO-1 and GPX2) were significantly lower in Nrf2-deficient than wild-type mice after Cl 2 exposure. BSO reduced GSH levels and promoted Cl 2 -induced airway inflammation in wild-type mice, but not in Nrf2-deficient mice, whereas SFN suppressed Cl 2 -induced airway inflammation in wild-type but not in Nrf2-deficient mice. AHR was not affected by either BSO or SFN at 48h post Cl 2 exposure. Nrf2-dependent phase II enzymes play a role in the resolution of airway inflammation and AHR after Cl 2 exposure. Moderate deficiency of GSH affects the magnitude of acute inflammation but not AHR. Copyright © 2016 Elsevier Inc. All rights reserved.

Sildenafil decreases rat tracheal hyperresponsiveness to carbachol and changes canonical transient receptor potential gene expression after antigen challenge.

PubMed

Sousa, C T; Brito, T S; Lima, F J B; Siqueira, R J B; Magalhães, P J C; Lima, A A M; Santos, A A; Havt, A

2011-06-01

Inhibition of type-5 phosphodiesterase by sildenafil decreases capacitative Ca2+ entry mediated by transient receptor potential proteins (TRPs) in the pulmonary artery. These families of channels, especially the canonical TRP (TRPC) subfamily, may be involved in the development of bronchial hyperresponsiveness, a hallmark of asthma. In the present study, we evaluated i) the effects of sildenafil on tracheal rings of rats subjected to antigen challenge, ii) whether the extent of TRPC gene expression may be modified by antigen challenge, and iii) whether inhibition of type-5 phosphodiesterase (PDE5) may alter TRPC gene expression after antigen challenge. Sildenafil (0.1 µM to 0.6 mM) fully relaxed carbachol-induced contractions in isolated tracheal rings prepared from naive male Wistar rats (250-300 g) by activating the NO-cGMP-K+ channel pathway. Rats sensitized to antigen by intraperitoneal injections of ovalbumin were subjected to antigen challenge by ovalbumin inhalation, and their tracheal rings were used to study the effects of sildenafil, which more effectively inhibited contractions induced by either carbachol (10 µM) or extracellular Ca2+ restoration after thapsigargin (1 µM) treatment. Antigen challenge increased the expression of the TRPC1 and TRPC4 genes but not the expression of the TRPC5 and TRPC6 genes. Applied before the antigen challenge, sildenafil increased the gene expression, which was evaluated by RT-PCR, of TRPC1 and TRPC6, decreased TRPC5 expression, and was inert against TRPC4. Thus, we conclude that PDE5 inhibition is involved in the development of an airway hyperresponsive phenotype in rats after antigen challenge by altering TRPC gene expression.

Do individuals with asthma experience airway hyper-responsiveness after exposure to nitrogen dioxide?

PubMed

Goodman, Julie E; Kennedy, Erin M; Seeley, Mara

2017-10-01

The current 100 ppb short-term National Ambient Air Quality Standard for NO 2 , and EPA's determination of a causal association for respiratory effects, are based in part on controlled human exposure studies evaluating airway hyper-responsiveness (AHR). A meta-analysis by Goodman et al. (2009) found increased AHR at 100 ppb NO 2 but no clear concentration-response relationship up to 600 ppb, and an overall lack of an AHR effect for studies involving exercise or exposure to allergens. Several factors have been suggested to explain why effects on AHR are observed while people are at rest, but not during exercise or after exposure to allergens. These include an exercise-induced refractory period; partial reversal of bronchospasm from use of forced expiration maneuvers; and greater airway responsiveness of participants exposed to NO 2 at rest. We reviewed the scientific evidence to determine whether there is biological support for these factors and found that none sufficiently explained the lack of an effect during exercise or after exposure to allergens. In the absence of either a consistent concentration-response or a plausible explanation for the paradoxical AHR findings, the biological significance of these findings is uncertain and provides equivocal support for NO 2 as a causal factor of AHR at these exposure levels. Copyright © 2017 Gradient. Published by Elsevier Inc. All rights reserved.

Toluene diisocyanate increases airway responsiveness to substance P and decreases airway neutral endopeptidase.

PubMed

Sheppard, D; Thompson, J E; Scypinski, L; Dusser, D; Nadel, J A; Borson, D B

1988-04-01

Substance P and related tachykinins contribute to the airway hyperresponsiveness caused by toluene diisocyanate (TDI) in guinea pigs. Neutral endopeptidase (NEP) is an important modulator of substance P-induced responses. To test the hypothesis that exposure to TDI would increase responsiveness to substance P by inhibiting activity of this enzyme, we determined the dose of substance P required to increase pulmonary resistance by 200% above baseline (PD200) before and after administration of the pharmacologic inhibitor phosphoramidon in guinea pigs studied 1 h after a 1-h exposure to air or 3 ppm TDI. TDI exposure increased responsiveness to substance P significantly. However, phosphoramidon caused a significantly greater leftward shift of the substance P dose-response curve in air-exposed animals than it did in TDI-exposed animals, so that after phosphoramidon, mean values of PD200 in animals exposed to air or TDI did not differ. Tracheal NEP activity was significantly less after exposure to TDI than after exposure to air, whereas activity in the esophagus was the same in both groups. These results suggest that TDI exposure increases the bronchoconstrictor responsiveness of guinea pigs to substance P, in large part through inhibition of airway NEP.

Toluene diisocyanate increases airway responsiveness to substance P and decreases airway neutral endopeptidase.

PubMed Central

Sheppard, D; Thompson, J E; Scypinski, L; Dusser, D; Nadel, J A; Borson, D B

1988-01-01

Substance P and related tachykinins contribute to the airway hyperresponsiveness caused by toluene diisocyanate (TDI) in guinea pigs. Neutral endopeptidase (NEP) is an important modulator of substance P-induced responses. To test the hypothesis that exposure to TDI would increase responsiveness to substance P by inhibiting activity of this enzyme, we determined the dose of substance P required to increase pulmonary resistance by 200% above baseline (PD200) before and after administration of the pharmacologic inhibitor phosphoramidon in guinea pigs studied 1 h after a 1-h exposure to air or 3 ppm TDI. TDI exposure increased responsiveness to substance P significantly. However, phosphoramidon caused a significantly greater leftward shift of the substance P dose-response curve in air-exposed animals than it did in TDI-exposed animals, so that after phosphoramidon, mean values of PD200 in animals exposed to air or TDI did not differ. Tracheal NEP activity was significantly less after exposure to TDI than after exposure to air, whereas activity in the esophagus was the same in both groups. These results suggest that TDI exposure increases the bronchoconstrictor responsiveness of guinea pigs to substance P, in large part through inhibition of airway NEP. PMID:2450892

An essential role of mast cells in the development of airway hyperresponsiveness in a murine asthma model.

PubMed

Kobayashi, T; Miura, T; Haba, T; Sato, M; Serizawa, I; Nagai, H; Ishizaka, K

2000-04-01

Immunization of BALB/c mice with alum-adsorbed OVA, followed by three bronchoprovocations with aerosolized OVA, resulted in the development of airway hyperresponsiveness (AHR) and allergic inflammation in the lung accompanied by severe infiltration of eosinophils into airways. In this murine asthma model, administration of monoclonal anti-IL-5 Ab before each Ag challenge markedly inhibited airway eosinophilia, but the treatment did not affect the development of AHR. Immunization and aerosol challenges with OVA following the same protocol failed to induce AHR in the mast cell-deficient W/Wv mice, but induced AHR in their congenic littermates, i.e., WBB6F1 (+/+) mice. No significant difference was found between the W/Wv mice and +/+ mice with respect to the IgE and IgG1 anti-OVA Ab responses and to the airway eosinophilia after Ag provocations. It was also found that reconstitution of W/Wv mice with bone marrow-derived mast cells cultured from normal littermates restored the capacity of developing Ag-induced AHR, indicating that lack of mast cells was responsible for the failure of W/Wv mice to develop Ag-induced AHR under the experimental conditions. However, the OVA-immunized W/Wv mice developed AHR by increasing the frequency and Ag dose of bronchoprovocations. The results suggested that AHR could be developed by two distinct cellular mechanisms. One would go through mast cell activation and the other is IgE/mast cell independent but an eosinophil/IL-5-dependent mechanism.

The novel compound Sul-121 inhibits airway inflammation and hyperresponsiveness in experimental models of chronic obstructive pulmonary disease

PubMed Central

Han, Bing; Poppinga, Wilfred J.; Zuo, Haoxiao; Zuidhof, Annet B.; Bos, I. Sophie T.; Smit, Marieke; Vogelaar, Pieter; Krenning, Guido; Henning, Robert H.; Maarsingh, Harm; Halayko, Andrew J.; van Vliet, Bernard; Stienstra, Stef; Graaf, Adrianus Cornelis van der; Meurs, Herman; Schmidt, Martina

2016-01-01

COPD is characterized by persistent airflow limitation, neutrophilia and oxidative stress from endogenous and exogenous insults. Current COPD therapy involving anticholinergics, β2-adrenoceptor agonists and/or corticosteroids, do not specifically target oxidative stress, nor do they reduce chronic pulmonary inflammation and disease progression in all patients. Here, we explore the effects of Sul-121, a novel compound with anti-oxidative capacity, on hyperresponsiveness (AHR) and inflammation in experimental models of COPD. Using a guinea pig model of lipopolysaccharide (LPS)-induced neutrophilia, we demonstrated that Sul-121 inhalation dose-dependently prevented LPS-induced airway neutrophilia (up to ~60%) and AHR (up to ~90%). Non-cartilaginous airways neutrophilia was inversely correlated with blood H2S, and LPS-induced attenuation of blood H2S (~60%) was prevented by Sul-121. Concomitantly, Sul-121 prevented LPS-induced production of the oxidative stress marker, malondialdehyde by ~80%. In immortalized human airway smooth muscle (ASM) cells, Sul-121 dose-dependently prevented cigarette smoke extract-induced IL-8 release parallel with inhibition of nuclear translocation of the NF-κB subunit, p65 (each ~90%). Sul-121 also diminished cellular reactive oxygen species production in ASM cells, and inhibited nuclear translocation of the anti-oxidative response regulator, Nrf2. Our data show that Sul-121 effectively inhibits airway inflammation and AHR in experimental COPD models, prospectively through inhibition of oxidative stress. PMID:27229886

OVA-induced airway hyperresponsiveness alters murine heart rate variability and body temperature.

PubMed

Domnik, N J; Seaborn, G; Vincent, S G; Akl, S G; Redfearn, D P; Fisher, J T

2012-01-01

Altered autonomic (ANS) tone in chronic respiratory disease is implicated as a factor in cardiovascular co-morbidities, yet no studies address its impact on cardiovascular function in the presence of murine allergic airway (AW) hyperresponsiveness (AHR). Since antigen (Ag)-induced AHR is used to model allergic asthma (in which ANS alterations have been reported), we performed a pilot study to assess measurement feasibility of, as well as the impact of allergic sensitization to ovalbumin (OVA) on, heart rate variability (HRV) in a murine model. Heart rate (HR), body temperature (T(B)), and time- and frequency-domain HRV analyses, a reflection of ANS control, were obtained in chronically instrumented mice (telemetry) before, during and for 22 h after OVA or saline aerosolization in sensitized (OVA) or Alum adjuvant control exposed animals. OVA mice diverged significantly from Alum mice with respect to change in HR during aerosol challenge (P < 0.001, Two-Way ANOVA; HR max change Ctrl = +80 ± 10 bpm vs. OVA = +1 ± 23 bpm, mean ± SEM), and displayed elevated HR during the subsequent dark cycle (P = 0.006). Sensitization decreased the T(B) during aerosol challenge (P < 0.001). Sensitized mice had decreased HRV prior to challenge (SDNN: P = 0.038; Low frequency (LF) power: P = 0.021; Low/high Frequency (HF) power: P = 0.042), and increased HRV during Ag challenge (RMSSD: P = 0.047; pNN6: P = 0.039). Sensitized mice displayed decreased HRV subsequent to OVA challenge, primarily in the dark cycle (RMSSD: P = 0.018; pNN6: P ≤ 0.001; LF: P ≤ 0.001; HF: P = 0.040; LF/HF: P ≤ 0.001). We conclude that implanted telemetry technology is an effective method to assess the ANS impact of allergic sensitization. Preliminary results show mild sensitization is associated with reduced HRV and a suppression of the acute T(B)-response to OVA challenge. This approach to assess altered ANS control in the acute OVA model may also be beneficial in chronic AHR models.

Nociceptin/orphanin FQ (N/OFQ) modulates immunopathology and airway hyperresponsiveness representing a novel target for the treatment of asthma.

PubMed

Singh, Shailendra R; Sullo, Nikol; Matteis, Maria; Spaziano, Giuseppe; McDonald, John; Saunders, Ruth; Woodman, Lucy; Urbanek, Konrad; De Angelis, Antonella; De Palma, Raffaele; Berair, Rachid; Pancholi, Mitesh; Mistry, Vijay; Rossi, Francesco; Guerrini, Remo; Calò, Girolamo; D'Agostino, Bruno; Brightling, Christopher E; Lambert, David G

2016-04-01

There is evidence supporting a role for the nociceptin/orphanin FQ (N/OFQ; NOP) receptor and its endogenous ligand N/OFQ in the modulation of neurogenic inflammation, airway tone and calibre. We hypothesized that NOP receptor activation has beneficial effects upon asthma immunopathology and airway hyperresponsiveness. Therefore, the expression and function of N/OFQ and the NOP receptor were examined in healthy and asthmatic human airway tissues. The concept was further addressed in an animal model of allergic asthma. NOP receptor expression was investigated by quantitative real-time PCR. Sputum N/OFQ was determined by RIA. N/OFQ function was tested using several assays including proliferation, migration, collagen gel contraction and wound healing. The effects of N/OFQ administration in vivo were studied in ovalbumin (OVA)-sensitized and challenged mice. NOP receptors were expressed on a wide range of human and mouse immune and airway cells. Eosinophils expressed N/OFQ-precursor mRNA and their number correlated with N/OFQ concentration. N/OFQ was found in human sputum and increased in asthma. Additionally, in asthmatic human lungs N/OFQ immunoreactivity was elevated. NOP receptor activation inhibited migration of immunocytes and increased wound healing in airway structural cells. Furthermore, N/OFQ relaxed spasmogen-stimulated gel contraction. Remarkably, these findings were mirrored in OVA-mice where N/OFQ treatment before or during sensitization substantially reduced airway constriction and immunocyte trafficking to the lung, in particular eosinophils. N/OFQ also reduced inflammatory mediators and mucin production. We demonstrated a novel dual airway immunomodulator/bronchodilator role for N/OFQ and suggest targeting this system as an innovative treatment for asthma. © 2016 The British Pharmacological Society.

T helper 1 background protects against airway hyperresponsiveness and inflammation in guinea pigs with persistent respiratory syncytial virus infection.

PubMed

Sutton, Troy C; Tayyari, Farnoosh; Khan, M Aatif; Manson, Heather E; Hegele, Richard G

2007-05-01

A family history of allergy has been implicated in children who develop post-bronchiolitis wheezing and asthma. In a guinea pig model of respiratory syncytial virus (RSV) lung infection, we evaluated the role of host Th1 background (either genetic or induced) on the development of a persistent infection, nonspecific airway hyperresponsiveness (AHR) and airway inflammation. Allergy resistant/T helper 1 (Th1)-skewed strain 2 guinea pigs (STR2) and cytosine phosphate guanine oligodeoxynucleotides (CpG-ODN) (Th1 stimuli) pretreated Cam Hartley guinea pigs (CH) were inoculated with RSV and compared with virus-inoculated allergy-susceptible/Th2-skewed CHs and to sham-inoculated STR2 and CH, 60 d post-inoculation. We measured titers of intrapulmonary RSV, lung interferon (IFN)-gamma and interleukin (IL)-5 mRNA expression, AHR and airway T cells and eosinophils. All virus-inoculated groups of animals showed evidence of persistent RSV lung infection; however, Th2-skewed guinea pigs had virus-associated AHR and significantly greater levels of airway T cells and eosinophils. In conclusion, RSV can establish persistent infection of the guinea pig lung regardless of host Th1/Th2 background; however; a host Th1 background limits the extent of virus-associated AHR and airway inflammation. Heterogeneity in virus-host interactions may be relevant to understanding why some children hospitalized for RSV bronchiolitis go on to develop recurrent wheezing/asthma symptoms.

Group-2 innate lymphoid cells mediate ozone induced airway inflammation and hyperresponsiveness in mice

PubMed Central

Yang, Qi; Ge, Moyar Q.; Kokalari, Blerina; Redai, Imre G.; Wang, Xinxin; Kemeny, David M.; Bhandoola, Avinash; Haczku, Angela

2015-01-01

Background Patients with asthma are highly susceptible to air pollution and in particular, to the effects of ozone (O3) inhalation, but the underlying mechanisms remain unclear. Objective Using mouse models of O3-induced airway inflammation and hyperresponsiveness (AHR), we sought to investigate the role of the recently discovered group 2 innate lymphoid cells (ILC2). Methods C57BL/6 and Balb/c mice were exposed to Aspergillus fumigatus and/or O3 (2ppm, 2h). ILC2 were isolated by FACS sorting and studied for IL-5 and IL-13 mRNA expression. ILC2 were depleted with anti-Thy1.2 mAb and replaced by intratracheal transfer of ex vivo expanded Thy1.1 ILC2. Cytokines (ELISA, qPCR), inflammatory cell profile and AHR (FlexiVent) were assessed in the mice. Results In addition to neutrophil influx, O3 inhalation elicited the appearance of eosinophils and IL-5 in the airways of Balb/c but not C57BL/6 mice. Although O3 induced expression of IL-33, a known activator of ILC2 in the lung was similar between these strains, isolated pulmonary ILC2 from O3 exposed Balb/c mice had significantly greater IL-5 and IL-13 mRNA expression than those of C57BL/6 mice. This suggested that an altered ILC2 function in Balb/c mice may mediate the increased O3 responsiveness. Indeed, anti-Thy1.2 treatment abolished, whereas ILC2 add-back dramatically enhanced O3-induced AHR. Conclusions O3-induced activation of pulmonary ILC2 was necessary and sufficient to mediate asthma-like changes in Balb/c mice. This previously unrecognized role of ILC2 may help explain the heightened susceptibility of human asthmatic airways to O3 exposure. PMID:26282284

A maturational model for the study of airway smooth muscle adaptation to mechanical oscillation.

PubMed

Wang, Lu; Chitano, Pasquale; Murphy, Thomas M

2005-10-01

It has been shown that mechanical stretches imposed on airway smooth muscle (ASM) by deep inspiration reduce the subsequent contractile response of the ASM. This passive maneuver of lengthening and retraction of the muscle is beneficial in normal subjects to counteract bronchospasm. However, it is detrimental to hyperresponsive airways because it triggers further bronchoconstriction. Although the exact mechanisms for this contrary response by normal and hyperresponsive airways are unclear, it has been suggested that the phenomenon is related to changes in ASM adaptability to mechanical oscillation. Healthy immature airways of both human and animal exhibit hyperresponsiveness, but whether the adaptative properties of hyperresponsive airway differ from normal is still unknown. In this article, we review the phenomenon of ASM adaptation to mechanical oscillation and its relevance and implication to airway hyperresponsiveness. We demonstrate that the age-specific expression of ASM adaptation is prominent using an established maturational animal model developed in our laboratory. Our data on immature ASM showed potentiated contractile force shortly after a length oscillation compared with the maximum force generated before oscillation. Several potential mechanisms such as myogenic response, changes in actin polymerization, or changes in the quantity of the cytoskeletal regulatory proteins plectin and vimentin, which may underlie this age-specific force potentiation, are discussed. We suggest a working model of the structure of smooth muscle associated with force transmission, which may help to elucidate the mechanisms responsible for the age-specific expression of smooth muscle adaptation. It is important to study the maturational profile of ASM adaptation as it could contribute to juvenile hyperresponsiveness.

Trefoil factor-2 reverses airway remodeling changes in allergic airways disease.

PubMed

Royce, Simon G; Lim, Clarice; Muljadi, Ruth C; Samuel, Chrishan S; Ververis, Katherine; Karagiannis, Tom C; Giraud, Andrew S; Tang, Mimi L K

2013-01-01

Trefoil factor 2 (TFF2) is a small peptide with an important role in mucosal repair. TFF2 is up-regulated in asthma, suggesting a role in asthma pathogenesis. Given its known biological role in promoting epithelial repair, TFF2 might be expected to exert a protective function in limiting the progression of airway remodeling in asthma. The contribution of TFF2 to airway remodeling in asthma was investigated by examining the expression of TFF2 in the airway and lung, and evaluating the effects of recombinant TFF2 treatment on established airway remodeling in a murine model of chronic allergic airways disease (AAD). BALB/c mice were sensitized and challenged with ovalbumin (OVA) or saline for 9 weeks, whereas mice with established OVA-induced AAD were treated with TFF2 or vehicle control (intranasally for 14 d). Effects on airway remodeling, airway inflammation, and airway hyperresponsiveness were then assessed, whereas TFF2 expression was determined by immunohistochemistry. TFF2 expression was significantly increased in the airways of mice with AAD, compared with expression levels in control mice. TFF2 treatment resulted in reduced epithelial thickening, subepithelial collagen deposition, goblet-cell metaplasia, bronchial epithelium apoptosis, and airway hyperresponsiveness (all P < 0.05, versus vehicle control), but TFF2 treatment did not influence airway inflammation. The increased expression of endogenous TFF2 in response to chronic allergic inflammation is insufficient to prevent the progression of airway inflammation and remodeling in a murine model of chronic AAD. However, exogenous TFF2 treatment is effective in reversing aspects of established airway remodeling. TFF2 has potential as a novel treatment for airway remodeling in asthma.

Airway responsiveness to mannitol in asthma is associated with chymase-positive mast cells and eosinophilic airway inflammation.

PubMed

Sverrild, A; Bergqvist, A; Baines, K J; Porsbjerg, C; Andersson, C K; Thomsen, S F; Hoffmann, H J; Gibson, P; Erjefält, J S; Backer, V

2016-02-01

Airway hyperresponsiveness (AHR) to inhaled mannitol is associated with indirect markers of mast cell activation and eosinophilic airway inflammation. It is unknown how AHR to mannitol relates to mast cell phenotype, mast cell function and measures of eosinophilic inflammation in airway tissue. We compared the number and phenotype of mast cells, mRNA expression of mast cell-associated genes and number of eosinophils in airway tissue of subjects with asthma and healthy controls in relation to AHR to mannitol. Airway hyperresponsiveness to inhaled mannitol was measured in 23 non-smoking, corticosteroid-free asthmatic individuals and 10 healthy controls. Mast cells and eosinophils were identified in mucosal biopsies from all participants. Mast cells were divided into phenotypes based on the presence of chymase. mRNA expression of mast cell-associated genes was measured by real-time PCR. The proportion of submucosal MCTC was higher in asthmatic individuals with AHR to mannitol compared with asthmatic individuals without AHR (median: 40.3% vs. 18.7%, P = 0.03). Increased submucosal MCTC numbers were associated with increased levels of mRNA for thymic stromal lymphopoietin (TSLP) and CPA3 in asthmatics. Reactivity to mannitol correlated significantly with eosinophils in submucosa (r(s): 0.56, P = 0.01). Airway hyperresponsiveness to inhaled mannitol is associated with an altered submucosal mast cell profile in asthmatic individuals. This mast cell profile is associated with increased levels of TSLP and CPA3. The degree of AHR to mannitol is correlated with the degree of eosinophilic inflammation in the airway submucosa. © 2015 John Wiley & Sons Ltd.

IκBNS induces Muc5ac expression in epithelial cells and causes airway hyper-responsiveness in murine asthma models.

PubMed

Yokota, M; Tamachi, T; Yokoyama, Y; Maezawa, Y; Takatori, H; Suto, A; Suzuki, K; Hirose, K; Takeda, K; Nakajima, H

2017-07-01

In allergic asthma, environmental allergens including house dust mite (HDM) trigger pattern recognition receptors and activate downstream signaling pathways including NF-κB pathways not only in immune cells but also in airway epithelial cells. Recent studies have shown that NF-κB activation is regulated positively or negatively depending on the cellular context by IκBNS (encoded by the gene Nfkbid), one of atypical IκB proteins, in the nucleus. Therefore, we hypothesized that IκBNS expressed in immune cells or epithelial cells is involved in the regulation of asthmatic responses. To determine the roles of IκBNS in HDM-induced asthmatic responses. Roles of IκBNS in HDM-induced airway inflammation and airway hyper-responsiveness (AHR) were examined by using IκBNS-deficient (Nfkbid -/- ) mice. Roles of IκBNS expressed in hematopoietic cells and nonhematopoietic cells were separately evaluated by bone marrow chimeric mice. Roles of IκBNS expressed in murine tracheal epithelial cells (mTECs) were examined by air-liquid interface culture. House dust mite-induced airway inflammation and AHR were exacerbated in mice lacking IκBNS in hematopoietic cells. In contrast, HDM-induced airway inflammation was exacerbated, but AHR was attenuated in mice lacking IκBNS in nonhematopoietic cells. The induction of Muc5ac, a representative mucin in asthmatic airways, was reduced in Nfkbid -/- mTEC, whereas the induction of Spdef, a master regulator of goblet cell metaplasia, was not impaired in Nfkbid -/- mTEC. Moreover, IκBNS bound to and activated the MUC5AC distal promoter in epithelial cells. IκBNS is involved in inducing Muc5ac expression in lung epithelial cells and causing AHR in HDM-induced asthma models. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

dNP2-ctCTLA-4 inhibits German cockroach extract-induced allergic airway inflammation and hyper-responsiveness via inhibition of Th2 responses

PubMed Central

Lim, Sangho; Ho Sohn, Jung; Koo, Ja-Hyun; Park, Jung-Won; Choi, Je-Min

2017-01-01

German cockroaches are major household allergens that can trigger allergic airway inflammatory diseases with sensitive T-cell responses. Although the use of immune modulatory biologics, such as antibodies, to mediate allergic responses has recently been examined, only systemic administration is available because of the size limitations on intranasal administration. Here we utilized a cell-permeable peptide, dNP2, to deliver the cytoplasmic domain of cytotoxic T-lymphocyte antigen-4 (ctCTLA-4) through the airway epithelium to modulate Th2 responses in a German cockroach extract (GCE)-induced allergic airway inflammation model. The intranasal delivery efficiency of the dNP2-dTomato protein to the lungs was higher in GCE-induced asthmatic lung parenchymal cells compared to the sham cells. Intranasal administration of the dNP2-ctCTLA-4 protein inhibited airway hyper-responsiveness and reduced airway inflammation and remodeling, including goblet cell metaplasia and collagen deposition around the bronchi. The number of infiltrated cells, including eosinophils, and the levels of IL-4, IL-5, IL-13 and IFN-γ in the lungs were significantly reduced, presumably owing to inhibition of Th2 differentiation. However, intranasal administration of CTLA4-Ig did not inhibit airway inflammation. These results collectively suggest that dNP2-ctCTLA-4 is an efficient intranasally applicable candidate biologic for treating allergic asthma. PMID:28775364

dNP2-ctCTLA-4 inhibits German cockroach extract-induced allergic airway inflammation and hyper-responsiveness via inhibition of Th2 responses.

PubMed

Lim, Sangho; Ho Sohn, Jung; Koo, Ja-Hyun; Park, Jung-Won; Choi, Je-Min

2017-08-04

German cockroaches are major household allergens that can trigger allergic airway inflammatory diseases with sensitive T-cell responses. Although the use of immune modulatory biologics, such as antibodies, to mediate allergic responses has recently been examined, only systemic administration is available because of the size limitations on intranasal administration. Here we utilized a cell-permeable peptide, dNP2, to deliver the cytoplasmic domain of cytotoxic T-lymphocyte antigen-4 (ctCTLA-4) through the airway epithelium to modulate Th2 responses in a German cockroach extract (GCE)-induced allergic airway inflammation model. The intranasal delivery efficiency of the dNP2-dTomato protein to the lungs was higher in GCE-induced asthmatic lung parenchymal cells compared to the sham cells. Intranasal administration of the dNP2-ctCTLA-4 protein inhibited airway hyper-responsiveness and reduced airway inflammation and remodeling, including goblet cell metaplasia and collagen deposition around the bronchi. The number of infiltrated cells, including eosinophils, and the levels of IL-4, IL-5, IL-13 and IFN-γ in the lungs were significantly reduced, presumably owing to inhibition of Th2 differentiation. However, intranasal administration of CTLA4-Ig did not inhibit airway inflammation. These results collectively suggest that dNP2-ctCTLA-4 is an efficient intranasally applicable candidate biologic for treating allergic asthma.

Strain-dependent airway hyperresponsiveness and a chromosome 7 locus of elevated lymphocyte numbers in cystic fibrosis transmembrane conductance regulator-deficient mice.

PubMed

Bazett, Mark; Stefanov, Anguel N; Paun, Alexandra; Paradis, Josee; Haston, Christina K

2012-03-01

We previously observed the lungs of naive BALB/cJ Cftr(tm1UNC) mice to have greater numbers of lymphocytes, by immunohistochemical staining, than did BALB wild type littermates or C57BL/6J Cftr(tm1UNC) mice. In the present study, we initially investigated whether this mutation in Cftr alters the adaptive immunity phenotype by measuring the lymphocyte populations in the lungs and spleens by FACS and by evaluating CD3-stimulated cytokine secretion, proliferation, and apoptosis responses. Next, we assessed a potential influence of this lymphocyte phenotype on lung function through airway resistance measures. Finally, we mapped the phenotype of pulmonary lymphocyte counts in BALB × C57BL/6J F2 Cftr(tm1UNC) mice and reviewed positional candidate genes. By FACS analysis, both the lungs and spleens of BALB Cftr(tm1UNC) mice had more CD3(+) (both CD4(+) and CD8(+)) cells than did littermates or C57BL/6J Cftr(tm1UNC) mice. Cftr(tm1UNC) and littermate mice of either strain did not differ in anti-CD3-stimulated apoptosis or proliferation levels. Lymphocytes from BALB Cftr(tm1UNC) mice produced more IL-4 and IL-5 and reduced levels of IFN-γ than did littermates, whereas lymphocytes from C57BL/6J Cftr(tm1UNC) mice demonstrated increased Il-17 secretion. BALB Cftr(tm1UNC) mice presented an enhanced airway hyperresponsiveness to methacholine challenge compared with littermates and C57BL/6J Cftr(tm1UNC) mice. A chromosome 7 locus was identified to be linked to lymphocyte numbers, and genetic evaluation of the interval suggests Itgal and Il4ra as candidate genes for this trait. We conclude that the pulmonary phenotype of BALB Cftr(tm1UNC) mice includes airway hyperresponsiveness and increased lymphocyte numbers, with the latter trait being influenced by a chromosome 7 locus.

IFN-γ elevates airway hyper-responsiveness via up-regulation of neurokinin A/neurokinin-2 receptor signaling in a severe asthma model.

PubMed

Kobayashi, Minoru; Ashino, Shigeru; Shiohama, Yasuo; Wakita, Daiko; Kitamura, Hidemitsu; Nishimura, Takashi

2012-02-01

The adoptive transfer of OVA-specific Th1 cells into WT mice followed by OVA inhalation induces a significant elevation of airway hyper-responsiveness (AHR) with neutrophilia but not mucus hypersecretion. Here, we demonstrate that the airway inflammation model, pathogenically characterized as severe asthma, was partly mimicked by i.n. administration of IFN-γ. The administration of IFN-γ instead of Th1 cells caused AHR elevation but not neutrophilia, and remarkably induced neurokinin-2 receptor (NK2R) expression along with neurokinin A (NKA) production in the lung. To evaluate whether NKA/NK2R was involved in airway inflammation, we first investigated the role of NKA/NK2R-signaling in airway smooth muscle cells (ASMCs) in vitro. NK2R mRNA expression was significantly augmented in tracheal tube-derived ASMCs of WT mice but not STAT-1(-/-) mice after stimulation with IFN-γ. In addition, methacholine-mediated Ca(2+) influx into the ASMCs was significantly reduced in the presence of NK2R antagonist. Moreover, the NK2R antagonist strongly inhibited IFN-γ-dependent AHR elevation in vivo. Thus, these results demonstrated that IFN-γ directly acts on ASMCs to elevate AHR via the NKA/NK2R-signaling cascade. Our present findings suggested that NK2R-mediated neuro-immuno crosstalk would be a promising target for developing novel drugs in Th1-cell-mediated airway inflammation, including severe asthma. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Effects of the phosphodiesterase type 4 inhibitor roflumilast on early and late allergic response and airway hyperresponsiveness in Aspergillus-fumigatus-sensitized mice.

PubMed

Hoymann, Heinz-Gerd; Wollin, Lutz; Muller, Meike; Korolewitz, Regina; Krug, Norbert; Braun, Armin; Beume, Rolf

2009-01-01

Inhibitory effects of roflumilast on responses characteristic of allergic asthma were investigated in a fungal asthma model in BALB/c mice. Mice were sensitized with Aspergillus antigen (Afu) and exposed to Afu or vehicle, and given roflumilast 1 or 5 mg/kg. Early airway response (EAR) and late airway hyperresponsiveness (AHR) to methacholine were measured via plethysmography. Bronchoalveolar lavage (BAL) was used to assess inflammatory cell count. In Afu-exposed mice, roflumilast dose-dependently reduced the EAR [26% at 1 mg/kg (NS) and 94% at 5 mg/kg (p < 0.01)] and AHR [46% at 1 mg/kg (NS) and 128% at 5 mg/kg (p < 0.05)]. Roflumilast 5 mg/kg reduced neutrophil, eosinophil and lymphocyte counts [87% (p < 0.01), 40% (NS) and 67% (p < 0.01), respectively] in BAL fluid versus controls. In this model, roflumilast inhibited the EAR, suppressed AHR and reduced inflammatory cell infiltration. 2009 S. Karger AG, Basel.

Silibinin attenuates allergic airway inflammation in mice

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

Choi, Yun Ho; Jin, Guang Yu; Guo, Hui Shu

Highlights: Black-Right-Pointing-Pointer Silibinin diminishes ovalbumin-induced inflammatory reactions in the mouse lung. Black-Right-Pointing-Pointer Silibinin reduces the levels of various cytokines into the lung of allergic mice. Black-Right-Pointing-Pointer Silibinin prevents the development of airway hyperresponsiveness in allergic mice. Black-Right-Pointing-Pointer Silibinin suppresses NF-{kappa}B transcriptional activity. -- Abstract: Allergic asthma is a chronic inflammatory disease regulated by coordination of T-helper2 (Th2) type cytokines and inflammatory signal molecules. Silibinin is one of the main flavonoids produced by milk thistle, which is reported to inhibit the inflammatory response by suppressing the nuclear factor-kappa B (NF-{kappa}B) pathway. Because NF-{kappa}B activation plays a pivotal role in the pathogenesismore » of allergic inflammation, we have investigated the effect of silibinin on a mouse ovalbumin (OVA)-induced asthma model. Airway hyperresponsiveness, cytokines levels, and eosinophilic infiltration were analyzed in bronchoalveolar lavage fluid and lung tissue. Pretreatment of silibinin significantly inhibited airway inflammatory cell recruitment and peribronchiolar inflammation and reduced the production of various cytokines in bronchoalveolar fluid. In addition, silibinin prevented the development of airway hyperresponsiveness and attenuated the OVA challenge-induced NF-{kappa}B activation. These findings indicate that silibinin protects against OVA-induced airway inflammation, at least in part via downregulation of NF-{kappa}B activity. Our data support the utility of silibinin as a potential medicine for the treatment of asthma.« less

Nedocromil sodium reduces cigarette smoke-induced bronchoconstrictor hyperresponsiveness to substance P in the guinea-pig.

PubMed

Dusser, D J; Lacroix, H; Desmazes-Dufeu, N; Mordelet-Dambrine, M; Roisman, G L

1995-01-01

Acute exposure to cigarette smoke provokes airway hyperresponsiveness to substance P and inactivates neutral endopeptidase (NEP). To determine whether nedocromil sodium can prevent cigarette smoke-induced hyperresponsiveness to substance P, we studied two groups of anaesthetized guinea-pigs. One group of guinea-pigs was pretreated with aerosolized 0.9% NaCl solution (90 breaths), the other group was pretreated with aerosolized nedocromil sodium (10(-4) M, 90 breaths). In each animal, pretreatment was followed by either exposure to the smoke of one cigarette or exposure to air. After acute exposure to cigarette smoke or to air, we measured the change in total pulmonary resistance (RL) induced by increasing concentrations of aerosolized substance P. In the absence of nedocromil sodium, the bronchoconstrictor responses to substance P were greater in cigarette smoke-exposed guinea-pigs than in air-exposed animals. Aerosolized nedocromil sodium had no effect on the response to substance P in air-exposed animals, but it reduced cigarette smoke-induced hyperresponsiveness to substance P. The preventive effect on cigarette smoke-induced hyperresponsiveness to substance P was observed at concentrations of aerosolized nedocromil sodium of 3 x 10(-5), 10(-4), and 3 x 10(-4) M. In vitro, cigarette smoke solution inhibited NEP activity from lung membrane preparations, but this inhibitory effect was not modified by nedocromil sodium (10(-4) M). We conclude that aerosolized nedocromil sodium reduces cigarette smoke-induced airway hyperresponsiveness to substance P in vivo. This action of nedocromil sodium is not due to a protective effect on cigarette smoke-induced inactivation of NEP in vitro.

NEUROTROPHIN MEDIATION OF ALLERGIC AIRWAYS RESPONSES TO INHALED DIESEL PARTICLES IN MICE

EPA Science Inventory

Neurotrophins, including nerve growth factor (NGF) partially mediate many features of allergic airways disease including airway hyper-responsiveness. Diesel exhaust particulates (DEP) associated with the combustion of diesel fuel exacerbate many of these allergic airways respons...

Allergic Sensitization through the Airway Primes Th17-dependent Neutrophilia and Airway Hyperresponsiveness

PubMed Central

Wilson, Rhonda H.; Whitehead, Gregory S.; Nakano, Hideki; Free, Meghan E.; Kolls, Jay K.; Cook, Donald N.

2009-01-01

Rationale: In humans, immune responses to inhaled aeroallergens develop in the lung and draining lymph nodes. Many animal models of asthma bypass this route and instead use intraperitoneal injections of allergen using aluminum hydroxide as an adjuvant. Objectives: We investigated whether allergic sensitization through the airway elicits immune responses qualitatively different than those arising in the peritoneum. Methods: Mice were sensitized to allergen through the airway using low-dose LPS as an adjuvant, or through the peritoneum using aluminum hydroxide as an adjuvant. After a single allergen challenge, ELISA and flow cytometry were used to measure cytokines and leukocyte subsets. Invasive measurements of airway resistance were used to measure allergen-induced airway hyperreactivity (AHR). Measurements and Main Results: Sensitization through the peritoneum primed strong Th2 responses and eosinophilia, but not AHR, after a single allergen challenge. By contrast, allergic sensitization through the airway primed only modest Th2 responses, but strong Th17 responses. Th17 cells homed to the lung and released IL-17 into the airway on subsequent encounter with inhaled allergen. As a result, these mice developed IL-17–dependent airway neutrophilia and AHR. This AHR was neutrophil-dependent because it was abrogated in CXCR2-deficient mice and also in wild-type mice receiving a neutrophil-depleting antibody. Individually, neither IL-17 nor ongoing Th2 responses were sufficient to confer AHR, but together they acted synergistically to promote neutrophil recruitment, eosinophil recruitment and AHR. Conclusions: Allergic sensitization through the airway primes modest Th2 responses but strong Th17 responses that promote airway neutrophilia and acute AHR. These findings support a causal role for neutrophils in severe asthma. PMID:19661246

Effect of thromboxane antagonists on ozone-induced airway responses in dogs

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

Jones, G.L.; Lane, C.G.; O'Byrne, P.M.

1990-09-01

Airway hyperresponsiveness after inhaled ozone in dogs may occur as a result of thromboxane release in the airway. In this study, two thromboxane receptor antagonists, L-655,240 and L-670,596, were used in doses that inhibit the response to an inhaled thromboxane mimetic, U-46619, to determine further the role of thromboxane in ozone-induced airway hyperresponsiveness. Dogs were studied on 2 days separated by 1 wk. On each day, the dogs inhaled ozone (3 ppm) for 30 min. On one randomly assigned day, 10 dogs received an infusion of L-655,240 (5 mg.kg-1.h-1) and 5 dogs received an infusion of L-670,596 (1 mg.kg-1.h-1); onmore » the other day dogs received a control infusion. Airway responses to doubling doses of acetylcholine were measured before and after inhalation of ozone and were expressed as the concentration of acetylcholine giving a rise in resistance of 5 cmH2O.l-1.s from baseline (acetylcholine provocation concentration). The development of airway hyperresponsiveness after ozone was not inhibited by the thromboxane antagonists. The mean log difference in the acetylcholine provocative concentration before and after ozone on the L-655,240 treatment day was 0.62 +/- 0.12 (SE) and on the control day was 0.71 +/- 0.12 (P = 0.48); on the L-670,596 treatment day the mean log difference was 0.68 +/- 0.15 (SE) and on the control day it was 0.75 +/- 0.19 (P = 0.45). These results do not support an important role for thromboxane in causing ozone-induced airway hyperresponsiveness.« less

A 4-Week Model of House Dust Mite (HDM) Induced Allergic Airways Inflammation with Airway Remodeling.

PubMed

Woo, L N; Guo, W Y; Wang, X; Young, A; Salehi, S; Hin, A; Zhang, Y; Scott, J A; Chow, C W

2018-05-02

Animal models of allergic airways inflammation are useful tools in studying the pathogenesis of asthma and potential therapeutic interventions. The different allergic airways inflammation models available to date employ varying doses, frequency, duration and types of allergen, which lead to the development of different features of asthma; showing varying degrees of airways inflammation and hyper-responsiveness (AHR) and airways remodeling. Models that also exhibit airway remodeling, a key feature of asthma, in addition to AHR and airway inflammation typically require 5-12 weeks to develop. In this report, we describe a 4-week mouse model of house dust mite (HDM)-induced allergic airways inflammation, and compare the phenotypic features of two different doses of HDM exposures (10 µg and 25 µg) for 5 days/week with a well-characterized 8-week chronic HDM model. We found that 4 weeks of intranasal HDM (25 µg in 35 µl saline; 5 days/week) resulted in AHR, airway inflammation and airway remodeling that were comparable to the 8-week model. We conclude that this new 4-week HDM model is another useful tool in studies of human asthma that offers advantages of shorter duration for development and decreased costs when compared to other models that require longer durations of exposure (5-12 weeks) to develop.

Effect of a chemical chaperone, tauroursodeoxycholic acid, on HDM-induced allergic airway disease

PubMed Central

Siddesha, Jalahalli M.; Nakada, Emily M.; Mihavics, Bethany R.; Hoffman, Sidra M.; Rattu, Gurkiranjit K.; Chamberlain, Nicolas; Cahoon, Jonathon M.; Lahue, Karolyn G.; Daphtary, Nirav; Aliyeva, Minara; Chapman, David G.; Desai, Dhimant H.; Poynter, Matthew E.

2016-01-01

Endoplasmic reticulum (ER) stress-induced unfolded protein response plays a critical role in inflammatory diseases, including allergic airway disease. However, the benefits of inhibiting ER stress in the treatment of allergic airway disease are not well known. Herein, we tested the therapeutic potential of a chemical chaperone, tauroursodeoxycholic acid (TUDCA), in combating allergic asthma, using a mouse model of house dust mite (HDM)-induced allergic airway disease. TUDCA was administered during the HDM-challenge phase (preventive regimen), after the HDM-challenge phase (therapeutic regimen), or therapeutically during a subsequent HDM rechallenge (rechallenge regimen). In the preventive regimen, TUDCA significantly decreased HDM-induced inflammation, markers of ER stress, airway hyperresponsiveness (AHR), and fibrosis. Similarly, in the therapeutic regimen, TUDCA administration efficiently decreased HDM-induced airway inflammation, mucus metaplasia, ER stress markers, and AHR, but not airway remodeling. Interestingly, TUDCA administered therapeutically in the HDM rechallenge regimen markedly attenuated HDM-induced airway inflammation, mucus metaplasia, ER stress markers, methacholine-induced AHR, and airway fibrotic remodeling. These results indicate that the inhibition of ER stress in the lungs through the administration of chemical chaperones could be a valuable strategy in the treatment of allergic airway diseases. PMID:27154200

Neurokinin-1 receptor mediates stress-exacerbated allergic airway inflammation and airway hyperresponsiveness in mice.

PubMed

Joachim, Ricarda A; Sagach, Viktoriya; Quarcoo, David; Dinh, Q Thai; Arck, Petra C; Klapp, Burghard F

2004-01-01

A wealth of clinical observation has suggested that stress and asthma morbidity are associated. We have previously established a mouse model of stress-exacerbated allergic airway inflammation, which reflects major clinical findings. The aim of the current study was to investigate the role of the neurokinin- (NK-)1 receptor in the mediation of stress effects in allergic airway inflammation. BALB/c mice were systemically sensitized with ovalbumin (OVA) on assay days 1, 14, and 21 and repeatedly challenged with OVA aerosol on days 26 and 27. Sound stress was applied to the animals for 24 hours, starting with the first airway challenge. Additionally, one group of stressed and one group of nonstressed mice received the highly specific NK-1 receptor antagonist RP 67580. Bronchoalveolar lavage fluid was obtained, and cell numbers and differentiation were determined. Airway hyperreactivity was measured in vitro by electrical field stimulation of tracheal smooth-muscle elements. Application of stress in sensitized and challenged animals resulted in a significant increase in leukocyte number in the bronchoalveolar lavage fluid. Furthermore, stressed animals showed enhanced airway reactivity. The increase of inflammatory cells and airway reactivity was blocked by treatment of animals with the NK-1 receptor antagonist. These data indicate that the NK-1 receptor plays an important role in mediating stress effects in allergen-induced airway inflammation.

Sulfuric acid induces airway hyperresponsiveness to substance P in the guinea pig.

PubMed

Stengel, P W; Bendele, A M; Cockerham, S L; Silbaugh, S A

1993-01-01

We investigated whether sulfuric acid inhalation would cause hyperresponsiveness to substance P. Guinea pigs became dyspneic during a 1 h sulfuric acid exposure, but recovered by 24 h when they were challenged with substance P or histamine aerosols. Eight minutes after the start of challenge, animals were killed and excised lung gas volumes measured. Sulfuric acid slightly increased histamine responsiveness compared to controls. However, sulfuric acid caused a much more pronounced leftward shift in the dose response to substance P. Coadministration of the neutral endopeptidase (NEP) inhibitor, thiorphan, did not reduce sulfuric acid-related hyperresponsiveness to substance P. By 72 h, sensitization to substance P was absent. Histological evaluation of sulfuric acid-treated lungs revealed mild alveolitis at 24 h, but not at 72 h. We conclude that sulfuric acid produces a marked sensitization to substance P. Inactivation of NEP does not appear to account for this effect.

Association of IL-13 gene polymorphisms with airway hyperresponsiveness in a Japanese adult asthmatic population.

PubMed

Utsumi, Yu; Sasaki, Nobuhito; Nagashima, Hiromi; Suzuki, Naomi; Nakamura, Yutaka; Yamashita, Masahiro; Kobayashi, Hitoshi; Yamauchi, Kohei

2013-09-01

A single nucleotide polymorphism (SNP; rs20541) in the IL-13 gene has been recognized as a risk factor for asthma. This SNP causes Arg to Gln (Q) substitution at position 110 in the mature IL-13 protein. We have recently showed that FEV1 in asthmatics with the Q110 variant of IL-13 declined faster, and progressive airway remodeling was observed in these subjects (Wynn, 2003 [1]). However, the effects of the IL-13 variant on airway hyperresponsiveness (AHR) remain to be elucidated. We analyzed the relationship between SNP rs20541 in IL-13 and AHR in asthmatics. We recruited 182 asthmatics who visited the asthma outpatient clinic at Iwate Medical University Hospital from 2006 to 2011. Subjects were genotyped for rs20541. Asthma severity, atopic status, age of asthma onset, serum IgE concentration, AHR, and pulmonary function were studied in these subjects. AHR was measured using the continuous methacholine inhalation method (Astograph; Chest; Tokyo, Japan). Genotyping of rs20541 revealed 26 A/A, 77 A/G, and 79 G/G patient genotypes. The D min (U) of the 3 genotypes was 1.17±0.300 in A/A, 1.99±0.35 in A/G, and 2.85±0.39 in G/G. The D min in the 3 genotypes was significantly different. Spirometric data revealed that % FEV1 and % FEF75 were significantly different among the 3 groups of IL-13 genotypes, whereas no significant differences were observed in therapeutic steps, atopic status, house dust mite sensitization, or serum IgE concentration. The SNP rs20541 in IL-13 was associated with AHR in Japanese adult asthmatics. Copyright © 2013 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

Determinants of lung function and airway hyperresponsiveness in asthmatic children.

PubMed

Bisgaard, H; Pedersen, S; Anhøj, J; Agertoft, L; Hedlin, G; Gulsvik, A; Bjermer, L; Carlsen, K H; Nordvall, L; Lundbäck, B; Wennergren, G; Werner, S; Bønnelykke, K; Weiss, S T

2007-07-01

Asthma patients exhibit an increased rate of loss of lung function. Determinants to such decline are largely unknown and the modifying effect of steroid therapy is disputed. This cross-sectional study aimed to elucidate factors contributing to such decline and the possible modifying effect of steroid treatment. We analyzed determinants of lung function and airway hyperresponsiveness (AHR) in a Scandinavian study of 2390 subjects from 550 families. Families were selected for the presence of two or more asthmatic children as part of a genetic study, Scandinavian Asthma Genetic Study (SAGA). The primary analysis studied the association between the lung function and delay of inhaled corticosteroids (ICS) after asthma diagnosis among asthmatic children and young adults with a history of regular ICS treatment (N=919). FEV(1) percent predicted (FEV(1)% pred) was 0.25% lower per year of delay from diagnosis until treatment (p=0.039). This association was significantly greater in allergy skin prick test negative children. There was no significant influence of gender, age at asthma onset, or smoking. In the secondary analysis of the whole population of 2390 asthmatics and non-asthmatics, FEV(1)% pred was inversely related to having asthmatic siblings (-7.9%; p<0.0001), asthma diagnosis (-2.7%; p=0.0007), smoking (-3.5%; p=0.0027), and positive allergy skin prick test (-0.47% per test; p=0.012), while positively related to being of female gender (1.8%; p=0.0029). Risk of AHR was higher by having asthmatic siblings (OR 2.7; p<0.0001), being of female gender (OR 2.0; p<0.0001), and having asthma (OR 2.0; p<0.0001). These data suggest that lung function is lower in asthmatics with delayed introduction of ICS therapy, smoking, and positive allergy skin prick test. Lung function is lower and AHR higher in female asthmatics and subjects with asthmatic siblings or established asthma.

Pulmonary Stress Induced by Hyperthermia: Role of Airway Sensory Nerves

DTIC Science & Technology

2012-10-01

conclusions: 1) Airway hyperresponsiveness developed in Ova-sensitized mice was less pronounced in TRPV1 -null mice, indicating an important role of TRPV1 ...expression of the transient receptor potential vanilloid type 1 ( TRPV1 ) channel is up-regulated in the airway mucosa of patients with mild asthma... TRPV1 channel in triggering the bronchoconstriction caused by airway hyperthermia, and to determine whether this acute bronchoconstrictive effect was

Transient receptor potential melastatin 8 gene polymorphism is associated with cold-induced airway hyperresponsiveness in bronchial asthma.

PubMed

Naumov, Denis E; Perelman, Juliy M; Kolosov, Victor P; Potapova, Tatyana A; Maksimov, Vladimir N; Zhou, Xiangdong

2015-11-01

Cold-induced airway hyperresponsiveness (CAH) is common in bronchial asthma (BA) patients and represents a problem for those living in cold climate. Transient receptor potential melastatin 8 (TRPM8) channel is the main cold temperature sensor in humans that could mediate cold response in asthmatics with CAH. No associations between TRPM8 gene polymorphisms and CAH have been reported. The present study involved 123 BA patients. CAH was assessed by 3-min isocapnic (5% CO2 ) cold air (-20°C) hyperventilation challenge. The c.750G > C (rs11562975), c.1256G > A (rs7593557), c.3048C > T (rs11563208) and c.3174C > G (rs11563071) polymorphisms of TRPM8 gene were genotyped by allele-specific polymerase chain reaction (PCR) and PCR with subsequent restriction fragment length polymorphism analysis. GC genotype and C allele carriers of the c.750G > C (rs11562975) polymorphism were more frequently observed to exhibit CAH. The estimated odds ratio for the GC genotype was 3.73 95%CI (1.48; 9.37), P = 0.005. Furthermore, GC heterozygotes had a prominent decrease in forced expiratory volume in 1 s after the challenge as compared to GG homozygotes (-12% (-16; -8.1) vs -6.45% (-11; -2.1), P < 0.001). GC carriers also had a marked reduction in other spirometric parameters. The GC variant of the TRPM8:c.750G > C (rs11562975) polymorphism is associated with CAH in patients with BA, which suggests a potential role of TRPM8 in CAH development. © 2015 Asian Pacific Society of Respirology.

Airway hyper-responsiveness to mannitol provides a good evaluation of atopy in childhood asthma.

PubMed

Attanasi, M; Rapino, D; Marcovecchio, M L; Consilvio, N P; Scaparrotta, A; Cingolani, A; Di Pillo, S; Chiarelli, F

2015-07-01

The relationship between airway hyper-responsiveness (AHR) and atopy has been previously investigated, but there are still some issues to be clarified. The aim of this study was to assess the link between AHR and mannitol and atopy in asthmatic children. We evaluated 44 children with asthma, aged 6-16 years of age, using skin prick tests (SPTs), serum total and specific immunoglobulin E (IgE) levels and the mannitol challenge test (MCT). We found a good correlation between AHR to mannitol and specific IgE against Dermatophagoides pteronissinus (r = -0.66, p < 0.001) and a weak correlation with specific IgE against dog dander (r = -0.33, p = 0.01) and Aspergillus fumigatus (r = -0.23, p = 0.02). Furthermore, we found a weak correlation between AHR to mannitol and serum total IgE (r = -0.30; p = 0.03), the sum of specific IgE to aeroallergens (r = -0.37, p = 0.01) and the number of positive SPTs (r = -0.31, p = 0.02). Measuring AHR with MCT might provide an accurate evaluation of the degree of atopy in children. The patients with a higher degree of atopy were significantly more reactive to mannitol. In clinical practice, these results indicate that children with asthma who are more atopic may require more intensive treatment strategies to reduce AHR. ©2015 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

A mathematical model of airway and pulmonary arteriole smooth muscle.

PubMed

Wang, Inga; Politi, Antonio Z; Tania, Nessy; Bai, Yan; Sanderson, Michael J; Sneyd, James

2008-03-15

Airway hyperresponsiveness is a major characteristic of asthma and is believed to result from the excessive contraction of airway smooth muscle cells (SMCs). However, the identification of the mechanisms responsible for airway hyperresponsiveness is hindered by our limited understanding of how calcium (Ca2+), myosin light chain kinase (MLCK), and myosin light chain phosphatase (MLCP) interact to regulate airway SMC contraction. In this work, we present a modified Hai-Murphy cross-bridge model of SMC contraction that incorporates Ca2+ regulation of MLCK and MLCP. A comparative fit of the model simulations to experimental data predicts 1), that airway and arteriole SMC contraction is initiated by fast activation by Ca2+ of MLCK; 2), that airway SMC, but not arteriole SMC, is inhibited by a slower activation by Ca2+ of MLCP; and 3), that the presence of a contractile agonist inhibits MLCP to enhance the Ca2+ sensitivity of airway and arteriole SMCs. The implication of these findings is that murine airway SMCs exploit a Ca2+-dependent mechanism to favor a default state of relaxation. The rate of SMC relaxation is determined principally by the rate of release of the latch-bridge state, which is predicted to be faster in airway than in arteriole. In addition, the model also predicts that oscillations in calcium concentration, commonly observed during agonist-induced smooth muscle contraction, cause a significantly greater contraction than an elevated steady calcium concentration.

A Mathematical Model of Airway and Pulmonary Arteriole Smooth Muscle

PubMed Central

Wang, Inga; Politi, Antonio Z.; Tania, Nessy; Bai, Yan; Sanderson, Michael J.; Sneyd, James

2008-01-01

Airway hyperresponsiveness is a major characteristic of asthma and is believed to result from the excessive contraction of airway smooth muscle cells (SMCs). However, the identification of the mechanisms responsible for airway hyperresponsiveness is hindered by our limited understanding of how calcium (Ca2+), myosin light chain kinase (MLCK), and myosin light chain phosphatase (MLCP) interact to regulate airway SMC contraction. In this work, we present a modified Hai-Murphy cross-bridge model of SMC contraction that incorporates Ca2+ regulation of MLCK and MLCP. A comparative fit of the model simulations to experimental data predicts 1), that airway and arteriole SMC contraction is initiated by fast activation by Ca2+ of MLCK; 2), that airway SMC, but not arteriole SMC, is inhibited by a slower activation by Ca2+ of MLCP; and 3), that the presence of a contractile agonist inhibits MLCP to enhance the Ca2+ sensitivity of airway and arteriole SMCs. The implication of these findings is that murine airway SMCs exploit a Ca2+-dependent mechanism to favor a default state of relaxation. The rate of SMC relaxation is determined principally by the rate of release of the latch-bridge state, which is predicted to be faster in airway than in arteriole. In addition, the model also predicts that oscillations in calcium concentration, commonly observed during agonist-induced smooth muscle contraction, cause a significantly greater contraction than an elevated steady calcium concentration. PMID:18065464

Construction of a Der p2-transgenic plant for the alleviation of airway inflammation

PubMed Central

Lee, CC; Ho, H; Lee, KT; Jeng, ST; Chiang, BL

2011-01-01

In clinical therapy, the amount of antigen administered to achieve oral tolerance for allergic diseases is large, and the cost is a major consideration. In this study, we used tobacco plants to develop a large-scale protein production system for allergen-specific immunotherapy, and we investigated the mechanisms of oral tolerance induced by a transgenic plant-derived antigen. We used plants (tobacco leaves) transgenic for the Dermatophagoides pteronyssinus 2 (Der p2) antigen to produce Der p2. Mice received total protein extract from Der p2 orally once per day over 6 days (days 0–2 and days 6–8). Mice were also sensitized and challenged with yeast-derived recombinant Der p2 (rDer p2), after which the mice were examined for airway hyper-responsiveness and airway inflammation. After sensitization and challenge with rDer p2, mice that were fed with total protein extracted from transgenic plants showed decreases in serum Der p2-specific IgE and IgG1 titers, decreased IL-5 and eotaxin levels in bronchial alveolar lavage fluid, and eosinophil infiltration in the airway. In addition, hyper-responsiveness was also decreased in mice that were fed with total protein extracted from transgenic plants, and CD4+CD25+Foxp3+ regulatory T cells were significantly increased in mediastinal and mesenteric lymph nodes. Furthermore, splenocytes isolated from transgenic plant protein-fed mice exhibited decreased proliferation and increased IL-10 secretion after stimulation with rDer p2. The data here suggest that allergen-expressing transgenic plants could be used for therapeutic purposes for allergic diseases. PMID:21602845

l-Arginine administration attenuates airway inflammation by altering l-arginine metabolism in an NC/Nga mouse model of asthma.

PubMed

Zhang, Ran; Kubo, Masayuki; Murakami, Ikuo; Setiawan, Heri; Takemoto, Kei; Inoue, Kiyomi; Fujikura, Yoshihisa; Ogino, Keiki

2015-05-01

Changes in l-arginine metabolism, including increased arginase levels and decreased nitric oxide production, are involved in the pathophysiology of asthma. In this study, using an intranasal mite-induced NC/Nga mouse model of asthma, we examined whether administration of l-arginine ameliorated airway hyperresponsiveness and inflammation by altering l-arginine metabolism. Experimental asthma was induced in NC/Nga mice via intranasal administration of mite crude extract (50 µg/day) on 5 consecutive days (days 0-4, sensitization) and on day 11 (challenge). Oral administration of l-arginine (250 mg/kg) was performed twice daily on days 5-10 for prevention or on days 11-13 for therapy. On day 14, we evaluated the inflammatory airway response (airway hyperresponsiveness, the number of cells in the bronchoalveolar lavage fluid, and the changes in pathological inflammation of the lung), arginase expression and activity, l-arginine bioavailability, and the concentration of NOx, the end products of nitric oxide. Treatment with l-arginine ameliorated the mite-induced inflammatory airway response. Furthermore, l-arginine administration attenuated the increases in arginase expression and activity and elevated the NOx levels by enhancing l-arginine bioavailability. These findings indicate that l-arginine administration may contribute to the improvement of asthmatic symptoms by altering l-arginine metabolism.

Effects of drug treatment on inflammation and hyperreactivity of airways and on immune variables in cats with experimentally induced asthma.

PubMed

Reinero, Carol R; Decile, Kendra C; Byerly, Jenni R; Berghaus, Roy D; Walby, William E; Berghaus, Londa J; Hyde, Dallas M; Schelegle, Edward S; Gershwin, Laurel J

2005-07-01

To compare the effects of an orally administered corticosteroid (prednisone), an inhaled corticosteroid (flunisolide), a leukotriene-receptor antagonist (zafirlukast), an antiserotonergic drug (cyproheptadine), and a control substance on the asthmatic phenotype in cats with experimentally induced asthma. 6 cats with asthma experimentally induced by the use of Bermuda grass allergen (BGA). A randomized, crossover design was used to assess changes in the percentage of eosinophils in bronchoalveolar lavage fluid (BALF); airway hyperresponsiveness; blood lymphocyte phenotype determined by use of flow cytometry; and serum and BALF content of BGA-specific IgE, IgG, and IgA determined by use of ELISAs. Mean +/- SE eosinophil percentages in BALF when cats were administered prednisone (5.0 +/- 2.3%) and flunisolide (2.5 +/- 1.7%) were significantly lower than for the control treatment (33.7 +/- 11.1%). We did not detect significant differences in airway hyperresponsiveness or lymphocyte surface markers among treatments. Content of BGA-specific IgE in serum was significantly lower when cats were treated with prednisone (25.5 +/- 5.4%), compared with values for the control treatment (63.6 +/- 12.9%); no other significant differences were observed in content of BGA-specific immunoglobulins among treatments. Orally administered and inhaled corticosteroids decreased eosinophilic inflammation in airways of cats with experimentally induced asthma. Only oral administration of prednisone decreased the content of BGA-specific IgE in serum; no other significant local or systemic immunologic effects were detected among treatments. Inhaled corticosteroids can be considered as an alternate method for decreasing airway inflammation in cats with asthma.

Key Role of Group V Secreted Phospholipase A2 in Th2 Cytokine and Dendritic Cell-Driven Airway Hyperresponsiveness and Remodeling

PubMed Central

Henderson Jr, William R.; Ye, Xin; Lai, Ying; Ni, Zhanglin; Bollinger, James G.; Tien, Ying-Tzang; Chi, Emil Y.; Gelb, Michael H.

2013-01-01

Background Previous work has shown that disruption of the gene for group X secreted phospholipase A2 (sPLA2-X) markedly diminishes airway hyperresponsiveness and remodeling in a mouse asthma model. With the large number of additional sPLA2s in the mammalian genome, the involvement of other sPLA2s in the asthma model is possible – in particular, the group V sPLA2 (sPLA2-V) that like sPLA2-X is highly active at hydrolyzing membranes of mammalian cells. Methodology and Principal Findings The allergen-driven asthma phenotype was significantly reduced in sPLA2-V-deficient mice but to a lesser extent than observed previously in sPLA2-X-deficient mice. The most striking difference observed between the sPLA2-V and sPLA2-X knockouts was the significant impairment of the primary immune response to the allergen ovalbumin (OVA) in the sPLA2-V−/− mice. The impairment in eicosanoid generation and dendritic cell activation in sPLA2-V−/− mice diminishes Th2 cytokine responses in the airways. Conclusions This paper illustrates the diverse roles of sPLA2s in the immunopathogenesis of the asthma phenotype and directs attention to developing specific inhibitors of sPLA2-V as a potential new therapy to treat asthma and other allergic disorders. PMID:23451035

Airway hyperresponsiveness to methacholine in 7-year-old children: sensitivity and specificity for pediatric allergist-diagnosed asthma.

PubMed

Carlsten, Chris; Dimich-Ward, Helen; Ferguson, Alexander; Becker, Allan; Dybuncio, Anne; Chan-Yeung, Moira

2011-02-01

The operating characteristics of PC(20) values used as cut-offs to define airway hyperresponsiveness, as it informs the diagnosis of asthma in children, are poorly understood. We examine data from a unique cohort to inform this concern. Determine the sensitivity and specificity of incremental PC(20) cut-offs for allergist-diagnosed asthma. Airway reactivity at age 7 was assessed in children within a birth cohort at high risk for asthma; PC(20) for methacholine was determined by standard technique including interpolation. The diagnosis of asthma was considered by the pediatric allergist without knowledge of the methacholine challenge results. Sensitivity and specificity were calculated using a cross-tabulation of asthma diagnosis with incremental PC(20) cut-off values, from 1.0 to 8.0 mg/ml, and plotted as receiver operator characteristic (ROC) curves. The "optimal" cut-off was defined as that PC(20) conferring maximal value for sensitivity plus specificity while the "balanced" cut-off was defined as that PC(20) at which sensitivity and specificity were most equal. 70/348 children (20.1%) were diagnosed with asthma. The optimal and balanced PC(20) cut-offs, both for all children and for females alone, were respectively 3 mg/ml (sensitivity 80.0%, specificity 49.1%) and 2 mg/ml (sensitivity 63.1%, specificity 64.7%). For males alone, the "optimal" and "balanced" PC(20) cut-offs were both 2 mg/ml. For this cohort of 7-year olds at high risk for asthma, methacholine challenge testing using a cut-off value of PC(20) 3 mg/ml conferred the maximal sum of specificity plus sensitivity. For contexts in which higher sensitivity or specificity is desired, other cut-offs may be preferred. Copyright © 2011 Wiley-Liss, Inc.

Assessment of inhibitory potential of Pothos scandens L. on ovalbumin-induced airway hyperresponsiveness in balb/c mice.

PubMed

Gupta, Saurabh; Basavan, Duraiswamy; Muthureddy Nataraj, Satish Kumar; Raju, K Rama Satyanarayana; Babu, U V; L M, Sharath Kumar; Gupta, Renu

2014-01-01

Pothos scandens L. was used in Indian traditional medicine as an antiasthmatic drug. The ethanolic and aqueous extracts were prepared with aerial parts of P. scandens (PSE & PSA). ESI MS/MS of PSE ethanolic extract was carried out for the determination of chemical constituents. CP1 is isolated from the PSE, structurally confirmed with NMR and LCMS/MS. PSE, PSA and CP1 are evaluated against ovalbumin (OVA) induced airway hyperresponsiveness (AHR) in balb/c mice. The test drugs are administered p.o. prior to challenge with aerosolized 2.5% w/v OVA. Total and differential leucocyte count, nitrite (NO2), nitrate (NO3), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-13 (IL-13) are estimated in bronchoalveolar lavage fluid (BALF). Similarly, myeloperoxidase (MPO), malonaldehyde (MDA) and total lung protein (TLP) are estimated in the lungs. The results reveal a significant increase in total and differential leucocyte count, NO2, NO3, TNF-α, IL-6, and IL-13 in OVA induced AHR. However, these parameters are significantly decreased in PSE and PSA tested doses (PSE 100 & 200mg/kg). While, treatment with CP1 is less effective at 5 & 10mg/kg doses. Similar observations obtain for MPO and MDA in lungs. However, the mean value indicated that the PSE at 200mg/kg showed a significant restoration in all the parameters. Pro-inflammatory mediators are known to be responsible for AHR. Histopathology revealed justifies the effectiveness. The present investigations suggest PSE are interesting molecules for further research for asthma, with an approach through pro-inflammatory inhibitory pathway. P. scandens is a potential herbal medicine for allergy induced asthma. Copyright © 2013 Elsevier B.V. All rights reserved.

S-Nitrosoglutathione Reductase Inhibition Regulates Allergen-Induced Lung Inflammation and Airway Hyperreactivity

PubMed Central

Bassett, David J. P.; Bradley, Matthews O.; Jaffar, Zeina

2013-01-01

Allergic asthma is characterized by Th2 type inflammation, leading to airway hyperresponsivenes, mucus hypersecretion and tissue remodeling. S-Nitrosoglutathione reductase (GSNOR) is an alcohol dehydrogenase involved in the regulation of intracellular levels of S-nitrosothiols. GSNOR activity has been shown to be elevated in human asthmatic lungs, resulting in diminished S-nitrosothiols and thus contributing to increased airway hyperreactivity. Using a mouse model of allergic airway inflammation, we report that intranasal administration of a new selective inhibitor of GSNOR, SPL-334, caused a marked reduction in airway hyperreactivity, allergen-specific T cells and eosinophil accumulation, and mucus production in the lungs in response to allergen inhalation. Moreover, SPL-334 treatment resulted in a significant decrease in the production of the Th2 cytokines IL-5 and IL-13 and the level of the chemokine CCL11 (eotaxin-1) in the airways. Collectively, these observations reveal that GSNOR inhibitors are effective not only in reducing airway hyperresponsiveness but also in limiting lung inflammatory responses mediated by CD4+ Th2 cells. These findings suggest that the inhibition of GSNOR may provide a novel therapeutic approach for the treatment of allergic airway inflammation. PMID:23936192

Pulmonary Stress Induced by Hyperthermia: Role of Airway Sensory Nerves

DTIC Science & Technology

2013-10-01

ABSTRACT Based upon the results obtained from these studies, we can draw the following conclusions: 1) Airway hyperresponsiveness developed in Ova ...hyperthermia in Ova -sensitized rats. The manuscript reporting the results obtained frim this study has been accepted for publication by the Journal of...to increasing airway temperature. Our results showed: 1) In Brown-Norway rats actively sensitized by ovalbumin ( Ova ), isocapnic hyperventilation with

Intranasal Administration of poly(I:C) and LPS in BALB/c Mice Induces Airway Hyperresponsiveness and Inflammation via Different Pathways

PubMed Central

Starkhammar, Magnus; Kumlien Georén, Susanna; Swedin, Linda; Dahlén, Sven-Erik; Adner, Mikael; Cardell, Lars Olaf

2012-01-01

Background Bacterial and viral infections are known to promote airway hyperresponsiveness (AHR) in asthmatic patients. The mechanism behind this reaction is poorly understood, but pattern recognizing Toll-like receptors (TLRs) have recently been suggested to play a role. Materials and Methods To explore the relation between infection-induced airway inflammation and the development of AHR, poly(I:C) activating TLR3 and LPS triggering TLR4, were chosen to represent viral and bacterial induced interactions, respectively. Female BALB/c or MyD88-deficient C57BL/6 mice were treated intranasally with either poly(I:C), LPS or PBS (vehicle for the control group), once a day, during 4 consecutive days. Results When methacholine challenge was performed on day 5, BALB/c mice responded with an increase in airway resistance. The maximal resistance was higher in the poly(I:C) and LPS treated groups than among the controls, indicating development of AHR in response to repeated TLR activation. The proportion of lymphocytes in broncheoalveolar lavage fluid (BALF) increased after poly(I:C) treatment whereas LPS enhanced the amount of neutrophils. A similar cellular pattern was seen in lung tissue. Analysis of 21 inflammatory mediators in BALF revealed that the TLR response was receptor-specific. MyD88-deficient C57BL/6 mice responded to poly (I:C) with an influx of lymphocytes, whereas LPS caused no inflammation. Conclusion In vivo activation of TLR3 and TLR4 in BALB/c mice both caused AHR in conjunction with a local inflammatory reaction. The AHR appeared to be identical regardless of which TLR that was activated, whereas the inflammation exhibited a receptor specific profile in terms of both recruited cells and inflammatory mediators. The inflammatory response caused by LPS appeared to be dependent on MyD88 pathway. Altogether the presented data indicate that the development of AHR and the induction of local inflammation might be the result of two parallel events, rather than one

Mast cell-dependent IL-33/ST2 signaling is protective against the development of airway hyperresponsiveness in a house dust mite mouse model of asthma.

PubMed

Zoltowska Nilsson, A M; Lei, Y; Adner, M; Nilsson, G P

2018-03-01

Interleukin-33 (IL-33) and its receptor ST2 have been influentially associated with the pathophysiology of asthma. Due to the divergent roles of IL-33 in regulating mast cell functions, there is a need to further characterize IL-33/ST2-dependent mast cell responses and their significance in the context of asthma. This study aimed to investigate how IL-33/ST2-dependent mast cell responses contribute to the development of airway hyperresponsiveness (AHR) and airway inflammation in a mouse model of house dust mite (HDM)-induced asthma. Mast cell-deficient C57BL/6-Kit W-sh (Wsh) mice engrafted with either wild-type (Wsh + MC-WT) or ST2-deficient bone marrow-derived mast cells (Wsh + MC-ST2KO) were exposed to HDM delivered intranasally. An exacerbated development of AHR in response to HDM was seen in Wsh + MC-ST2KO compared with Wsh + MC-WT mice. The contribution of this IL-33/ST2-dependent mast cell response to AHR seems to reside within the smaller airways in the peripheral parts of the lung, as suggested by the isolated yet marked effect on tissue resistance. Considering the absence of a parallel increase in cellular inflammation in bronchoalveolar lavage fluid (BALF) and lung, the aggravated AHR in Wsh + MC-ST2KO mice seems to be independent of cellular inflammation. We observed an association between the elevated AHR and reduced PGE 2 levels in BALF . Due to the protective properties of PGE 2 in airway responses, it is conceivable that IL-33/ST2-dependent mast cell induction of PGE 2 could be responsible for the dampening effect on AHR. In conclusion, we reveal that IL-33/ST2-dependent mast cell responses can have a protective, rather than causative role, in the development of AHR.

Matrix Metalloproteinase-1 Activation Contributes to Airway Smooth Muscle Growth and Asthma Severity

PubMed Central

Naveed, Shams-un-nisa; Clements, Debbie; Jackson, David J.; Philp, Christopher; Billington, Charlotte K.; Soomro, Irshad; Reynolds, Catherine; Harrison, Timothy W.; Johnston, Sebastian L.; Shaw, Dominick E.

2017-01-01

Rationale: Matrix metalloproteinase-1 (MMP-1) and mast cells are present in the airways of people with asthma. Objectives: To investigate whether MMP-1 could be activated by mast cells and increase asthma severity. Methods: Patients with stable asthma and healthy control subjects underwent spirometry, methacholine challenge, and bronchoscopy, and their airway smooth muscle cells were grown in culture. A second asthma group and control subjects had symptom scores, spirometry, and bronchoalveolar lavage before and after rhinovirus-induced asthma exacerbations. Extracellular matrix was prepared from decellularized airway smooth muscle cultures. MMP-1 protein and activity were assessed. Measurements and Main Results: Airway smooth muscle cells generated pro–MMP-1, which was proteolytically activated by mast cell tryptase. Airway smooth muscle treated with activated mast cell supernatants produced extracellular matrix, which enhanced subsequent airway smooth muscle growth by 1.5-fold (P < 0.05), which was dependent on MMP-1 activation. In asthma, airway pro–MMP-1 was 5.4-fold higher than control subjects (P = 0.002). Mast cell numbers were associated with airway smooth muscle proliferation and MMP-1 protein associated with bronchial hyperresponsiveness. During exacerbations, MMP-1 activity increased and was associated with fall in FEV1 and worsening asthma symptoms. Conclusions: MMP-1 is activated by mast cell tryptase resulting in a proproliferative extracellular matrix. In asthma, mast cells are associated with airway smooth muscle growth, MMP-1 levels are associated with bronchial hyperresponsiveness, and MMP-1 activation are associated with exacerbation severity. Our findings suggest that airway smooth muscle/mast cell interactions contribute to asthma severity by transiently increasing MMP activation, airway smooth muscle growth, and airway responsiveness. PMID:27967204

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

PubMed Central

2013-01-01

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

Hyperresponsive Sensory Patterns in Young Children with Autism, Developmental Delay, and Typical Development

ERIC Educational Resources Information Center

Baranek, Grace T.; Boyd, Brian A.; Poe, Michele D.; David, Fabian J.; Watson, Linda R.

2007-01-01

The nature of hyperresponsiveness to sensory stimuli in children with autism, using a new observational measure, the SPA, was examined. Three groups of young participants were assessed (autism, developmental delay, typical). Across all groups, MA was a predictor of hyperresponsiveness, such that aversion to multisensory toys decreased as MA…

[Effect of dental arch length decrease during orthodontic treatment in the upper airway development. A review].

PubMed

Haddad, Stéphanie; Kerbrat, Jean-Baptiste; Schouman, Thomas; Goudot, Patrick

2017-03-01

A possible relation between an upper airway space decrease and the development of obstructive sleep apnea syndrom explains the importance to know the effect of the modification of dental arch length on the upper airway during orthodontic treatment. The aim of this article is to expose recent knowledge about upper airway development and dental arch length decrease factors, to determine the influence of this decrease on upper airway development. A review was done to determine the upper airway normal development, to define dental arch to specify if an ideal position of dental arch on apical base exists. All of the length dental arch decrease factors during orthodontic treatment (dental extraction, dental agenesis and dental malpositions) and their upper airway resounding were searched. Some authors found a diminution of upper airway space after premolars extractions while others didn't found this diminution after extractions premolars when incisor retraction is finished. A decrease of transversal maxillary diameter and nasal cavity may be due to absence of permanent teeth. The effect of dental arch length decrease during orthodontic treatment in the upper airway development was not scientifically proved. However we had to be vigilant and adapt our orthodontic treatment case by case to avoid an upper airway modification. © EDP Sciences, SFODF, 2017.

AIRWAY HYPERRESPONSIVENESS IN MICE FOLLOWING ANTIGEN AND PARTICULATE MATTER EXPOSURE IS VAGALLY MEDIATED

EPA Science Inventory

Sensory nerves within the airways can initiate a variety of protective reflexes. We hypothesized that insults such as exposure to antigen and particulate matter (PM) might dysregulate airway sensory nerve function, thereby contributing to enhanced airway inflammation and hyperre...

Neutral endopeptidase activity and airway hyperresponsiveness to neurokinin A in asthmatic subjects in vivo.

PubMed

Cheung, D; Timmers, M C; Zwinderman, A H; den Hartigh, J; Dijkman, J H; Sterk, P J

1993-12-01

In a previous study we have shown that inhibition of the endogenous neuropeptide-degrading enzyme, neutral endopeptidase (NEP), potentiates airway narrowing to neurokinin A (NKA) in normal humans in vivo. In the present study, we tested the hypothesis that hyperresponsiveness to NKA in asthma is caused by a reduction in endogenous NEP activity. To that end, we used the NEP inhibitor, thiorphan, or placebo as inhaled pretreatment to NKA challenge in eight atopic asthmatic men, who were controlled by on-demand usage of beta 2-agonists alone. The dose of thiorphan pretreatment was obtained from pilot experiments in which 0.5 ml of a 2.5-mg/ml concentration appeared to be the maximally effective nebulized dose. Dose-response curves to inhaled NKA (1 to 125 micrograms/ml, 0.5 ml/dose) were recorded on 2 randomized days 1 wk apart, in a cross-over study. To detect any effects of thiorphan on bronchoconstriction per se, we also investigated the effect of thiorphan or placebo on the dose-response curve to inhaled methacholine in a separate set of experiments. The response was measured by FEV1 and by partial expiratory flow-volume curves (V40p). The position of the dose-response curves was expressed as the concentration causing a 20% fall in FEV1 (PC20FEV1) or a 40% fall in V40p (PC40V40p). Baseline FEV1 and V40p were not affected by either pretreatment (p > 0.06). PC20FEV1 and PC40V40p to NKA were significantly lower after thiorphan pretreatment as compared with placebo (mean difference +/- SEM: 2.3 +/- 0.6 and 1.6 +/- 0.5 doubling dose, respectively; p < 0.015).(ABSTRACT TRUNCATED AT 250 WORDS)

Histamine, carbachol, and serotonin induce hyperresponsiveness to ATP in guinea pig tracheas: involvement of COX-2 pathway.

PubMed

Montaño, Luis M; Carbajal, Verónica; Vargas, Mario H; García-Hernández, Luz M; Díaz-Hernández, Verónica; Checa, Marco; Barajas-López, Carlos

2013-08-01

Extracellular ATP promotes an indirect contraction of airway smooth muscle via the secondary release of thromboxane A2 (TXA2) from airway epithelium. Our aim was to evaluate if common contractile agonists modify this response to ATP. Tracheas from sensitized guinea pigs were used to evaluate ATP-induced contractions before and after a transient contraction produced by histamine, carbachol, or serotonin. Epithelial mRNA for COX-1 and COX-2 was measured by RT-PCR and their expression assessed by immunohistochemistry. Compared with the initial response, ATP-induced contraction was potentiated by pretreatment with histamine, carbachol, or serotonin. Either suramin (antagonist of P2X and P2Y receptors) plus RB2 (antagonist of P2Y receptors) or indomethacin (inhibitor of COX-1 and COX-2) annulled the ATP-induced contraction, suggesting that it was mediated by P2Y receptor stimulation and TXA2 production. When COX-2 was inhibited by SC-58125 or thromboxane receptors were antagonized by SQ-29548, just the potentiation was abolished, leaving the basal response intact. Airway epithelial cells showed increased COX-2 mRNA after stimulation with histamine or carbachol, but not serotonin, while COX-1 mRNA was unaffected. Immunochemistry corroborated this upregulation of COX-2. In conclusion, we showed for the first time that histamine and carbachol cause hyperresponsiveness to ATP by upregulating COX-2 in airway epithelium, which likely increases TXA2 production. Serotonin-mediated hyperresponsiveness seems to be independent of COX-2 upregulation, but nonetheless is TXA2 dependent. Because acetylcholine, histamine, and serotonin can be present during asthmatic exacerbations, their potential interactions with ATP might be relevant in its pathophysiology.

Adoptive transfer of induced-Treg cells effectively attenuates murine airway allergic inflammation.

PubMed

Xu, Wei; Lan, Qin; Chen, Maogen; Chen, Hui; Zhu, Ning; Zhou, Xiaohui; Wang, Julie; Fan, Huimin; Yan, Chun-Song; Kuang, Jiu-Long; Warburton, David; Togbe, Dieudonnée; Ryffel, Bernhard; Zheng, Song-Guo; Shi, Wei

2012-01-01

Both nature and induced regulatory T (Treg) lymphocytes are potent regulators of autoimmune and allergic disorders. Defects in endogenous Treg cells have been reported in patients with allergic asthma, suggesting that disrupted Treg cell-mediated immunological regulation may play an important role in airway allergic inflammation. In order to determine whether adoptive transfer of induced Treg cells generated in vitro can be used as an effective therapeutic approach to suppress airway allergic inflammation, exogenously induced Treg cells were infused into ovalbumin-sensitized mice prior to or during intranasal ovalbumin challenge. The results showed that adoptive transfer of induced Treg cells prior to allergen challenge markedly reduced airway hyperresponsiveness, eosinophil recruitment, mucus hyper-production, airway remodeling, and IgE levels. This effect was associated with increase of Treg cells (CD4(+)FoxP3(+)) and decrease of dendritic cells in the draining lymph nodes, and with reduction of Th1, Th2, and Th17 cell response as compared to the controls. Moreover, adoptive transfer of induced Treg cells during allergen challenge also effectively attenuate airway inflammation and improve airway function, which are comparable to those by natural Treg cell infusion. Therefore, adoptive transfer of in vitro induced Treg cells may be a promising therapeutic approach to prevent and treat severe asthma.

Adoptive Transfer of Induced-Treg Cells Effectively Attenuates Murine Airway Allergic Inflammation

PubMed Central

Chen, Maogen; Chen, Hui; Zhu, Ning; Zhou, Xiaohui; Wang, Julie; Fan, Huimin; Yan, Chun-Song; Kuang, Jiu-Long; Warburton, David; Togbe, Dieudonnée; Ryffel, Bernhard; Zheng, Song-Guo; Shi, Wei

2012-01-01

Both nature and induced regulatory T (Treg) lymphocytes are potent regulators of autoimmune and allergic disorders. Defects in endogenous Treg cells have been reported in patients with allergic asthma, suggesting that disrupted Treg cell-mediated immunological regulation may play an important role in airway allergic inflammation. In order to determine whether adoptive transfer of induced Treg cells generated in vitro can be used as an effective therapeutic approach to suppress airway allergic inflammation, exogenously induced Treg cells were infused into ovalbumin-sensitized mice prior to or during intranasal ovalbumin challenge. The results showed that adoptive transfer of induced Treg cells prior to allergen challenge markedly reduced airway hyperresponsiveness, eosinophil recruitment, mucus hyper-production, airway remodeling, and IgE levels. This effect was associated with increase of Treg cells (CD4+FoxP3+) and decrease of dendritic cells in the draining lymph nodes, and with reduction of Th1, Th2, and Th17 cell response as compared to the controls. Moreover, adoptive transfer of induced Treg cells during allergen challenge also effectively attenuate airway inflammation and improve airway function, which are comparable to those by natural Treg cell infusion. Therefore, adoptive transfer of in vitro induced Treg cells may be a promising therapeutic approach to prevent and treat severe asthma. PMID:22792275

Dysregulation of type 2 innate lymphoid cells and TH2 cells impairs pollutant-induced allergic airway responses.

PubMed

De Grove, Katrien C; Provoost, Sharen; Hendriks, Rudi W; McKenzie, Andrew N J; Seys, Leen J M; Kumar, Smitha; Maes, Tania; Brusselle, Guy G; Joos, Guy F

2017-01-01

Although the prominent role of T H 2 cells in type 2 immune responses is well established, the newly identified type 2 innate lymphoid cells (ILC2s) can also contribute to orchestration of allergic responses. Several experimental and epidemiologic studies have provided evidence that allergen-induced airway responses can be further enhanced on exposure to environmental pollutants, such as diesel exhaust particles (DEPs). However, the components and pathways responsible remain incompletely known. We sought to investigate the relative contribution of ILC2 and adaptive T H 2 cell responses in a murine model of DEP-enhanced allergic airway inflammation. Wild-type, Gata-3 +/nlslacZ (Gata-3-haploinsufficient), RAR-related orphan receptor α (RORα) fl/fl IL7R Cre (ILC2-deficient), and recombination-activating gene (Rag) 2 -/- mice were challenged with saline, DEPs, or house dust mite (HDM) or DEP+HDM. Airway hyperresponsiveness, as well as inflammation, and intracellular cytokine expression in ILC2s and T H 2 cells in the bronchoalveolar lavage fluid and lung tissue were assessed. Concomitant DEP+HDM exposure significantly enhanced allergic airway inflammation, as characterized by increased airway eosinophilia, goblet cell metaplasia, accumulation of ILC2s and T H 2 cells, type 2 cytokine production, and airway hyperresponsiveness compared with sole DEPs or HDM. Reduced Gata-3 expression decreased the number of functional ILC2s and T H 2 cells in DEP+HDM-exposed mice, resulting in an impaired DEP-enhanced allergic airway inflammation. Interestingly, although the DEP-enhanced allergic inflammation was marginally reduced in ILC2-deficient mice that received combined DEP+HDM, it was abolished in DEP+HDM-exposed Rag2 -/- mice. These data indicate that dysregulation of ILC2s and T H 2 cells attenuates DEP-enhanced allergic airway inflammation. In addition, a crucial role for the adaptive immune system was shown on concomitant DEP+HDM exposure. Copyright © 2016 American

Airway responsiveness and airway remodeling after chronic exposure to procaterol and fenoterol in guinea pigs in vivo.

PubMed

Nishimura, Hideko; Tokuyama, Kenichi; Arakawa, Hirokazu; Ohki, Yasushi; Sato, Akira; Kato, Masahiko; Mochizuki, Hiroyuki; Morikawa, Akihiro

2002-12-01

Chronic exposure to fenoterol (FEN), a beta(2)-adrenergic receptor (beta(2)-AR) agonist, was shown to induce both airway hyperresponsiveness and airway remodeling in experimental animals. We wanted to know the effects of chronic exposure to procaterol (PRO), a beta(2)-AR agonist, on airway function and structure, because this agent is widely used as a bronchodilator in Japan. For comparison, the effects of FEN were also examined. Aerosolized PRO (0.1 or 1 mg/ml), FEN (1 mg/ml) or vehicle (0.9% NaCl) was given to guinea pigs 3 times a day for 6 weeks. Sublaryngeal deposition of these agents was calculated using radioisotopes. At 72 h after the last inhalation of PRO, FEN or vehicle, the dose-response relationship between lung resistance (R(L)) and intravenously administered acetylcholine (ACh) was measured. After measuring R(L), histological changes in noncartilaginous airway dimensions were evaluated. The amount of sublaryngeal deposition of 0.1 mg/ml PRO in the present study was speculated to be 100 times larger than that of therapeutic dose. ACh concentrations causing 2-fold, 10-fold and maximal increases in R(L) were not different in 4 groups tested. In the smaller membranous airways (<0.4 mm in diameter), but not the larger ones, thickening of adventitial areas was significantly greater in animals treated with beta(2)-AR agonists than in control animals (23 and 25, and 96% higher in animals treated with 0.1 and 1 mg/ml PRO or 1 mg/ml FEN, respectively). The degree of the increase was significantly less in PRO-treated animals than in FEN-treated animals (p < 0.01). Our results did not provide any evidence that regular inhalation of PRO at the therapeutic dose might induce bronchial hyperresponsiveness. In addition, huge amounts of PRO only caused a mild thickening of the adventitial areas, suggesting that PRO may be a weak inducer of airway remodeling compared with FEN. Copyright 2002 S. Karger AG, Basel

Marijuana smoke induces severe pulmonary hyperresponsiveness, inflammation, and emphysema in a predictive mouse model not via CB1 receptor activation.

PubMed

Helyes, Z; Kemény, Á; Csekő, K; Szőke, É; Elekes, K; Mester, M; Sándor, K; Perkecz, A; Kereskai, L; Márk, L; Bona, Á; Benkő, A; Pintér, E; Szolcsányi, J; Ledent, C; Sperlágh, B; Molnár, T F

2017-08-01

Sporadic clinical reports suggested that marijuana smoking induces spontaneous pneumothorax, but no animal models were available to validate these observations and to study the underlying mechanisms. Therefore, we performed a systematic study in CD1 mice as a predictive animal model and assessed the pathophysiological alterations in response to 4-mo-long whole body marijuana smoke with integrative methodologies in comparison with tobacco smoke. Bronchial responsiveness was measured with unrestrained whole body plethysmography, cell profile in the bronchoalveolar lavage fluid with flow cytometry, myeloperoxidase activity with spectrophotometry, inflammatory cytokines with ELISA, and histopathological alterations with light microscopy. Daily marijuana inhalation evoked severe bronchial hyperreactivity after a week. Characteristic perivascular/peribronchial edema, atelectasis, apical emphysema, and neutrophil and macrophage infiltration developed after 1 mo of marijuana smoking; lymphocyte accumulation after 2 mo; macrophage-like giant cells, irregular or destroyed bronchial mucosa, goblet cell hyperplasia after 3 mo; and severe atelectasis, emphysema, obstructed or damaged bronchioles, and endothelial proliferation at 4 mo. Myeloperoxidase activity, inflammatory cell, and cytokine profile correlated with these changes. Airway hyperresponsiveness and inflammation were not altered in mice lacking the CB1 cannabinoid receptor. In comparison, tobacco smoke induced hyperresponsiveness after 2 mo and significantly later caused inflammatory cell infiltration/activation with only mild emphysema. We provide the first systematic and comparative experimental evidence that marijuana causes severe airway hyperresponsiveness, inflammation, tissue destruction, and emphysema, which are not mediated by the CB1 receptor. Copyright © 2017 the American Physiological Society.

Airway inflammation and mannitol challenge test in COPD

PubMed Central

2011-01-01

Background Eosinophilic airway inflammation has successfully been used to tailor anti-inflammatory therapy in chronic obstructive pulmonary disease (COPD). Airway hyperresponsiveness (AHR) by indirect challenges is associated with airway inflammation. We hypothesized that AHR to inhaled mannitol captures eosinophilia in induced sputum in COPD. Methods Twenty-eight patients (age 58 ± 7.8 yr, packyears 40 ± 15.5, post-bronchodilator FEV1 77 ± 14.0%predicted, no inhaled steroids ≥4 wks) with mild-moderate COPD (GOLD I-II) completed two randomized visits with hypertonic saline-induced sputum and mannitol challenge (including sputum collection). AHR to mannitol was expressed as response-dose-ratio (RDR) and related to cell counts, ECP, MPO and IL-8 levels in sputum. Results There was a positive correlation between RDR to mannitol and eosinophil numbers (r = 0.47, p = 0.03) and level of IL-8 (r = 0.46, p = 0.04) in hypertonic saline-induced sputum. Furthermore, significant correlations were found between RDR and eosinophil numbers (r = 0.71, p = 0.001), level of ECP (r = 0.72, p = 0.001), IL-8 (r = 0.57, p = 0.015) and MPO (r = 0.64, p = 0.007) in sputum collected after mannitol challenge. ROC-curves showed 60% sensitivity and 100% specificity of RDR for >2.5% eosinophils in mannitol-induced sputum. Conclusions In mild-moderate COPD mannitol hyperresponsiveness is associated with biomarkers of airway inflammation. The high specificity of mannitol challenge suggests that the test is particularly suitable to exclude eosinophilic airways inflammation, which may facilitate individualized treatment in COPD. Trial registration Netherlands Trial Register (NTR): NTR1283 PMID:21241520

Effect of ageing on pulmonary inflammation, airway hyperresponsiveness and T and B cell responses in antigen-sensitized and -challenged mice.

PubMed

Busse, Paula J; Zhang, Teng Fei; Srivastava, Kamal; Schofield, Brian; Li, Xiu-Min

2007-09-01

The effect of ageing on several pathologic features of allergic asthma (pulmonary inflammation, eosinophilia, mucus hypersecretion), and their relationship with airway hyperresponsiveness (AHR) is not well characterized. To evaluate lung inflammation, mucus metaplasia and AHR in relationship with age in murine models of allergic asthma comparing young and older mice. Young (6 weeks) and older (6, 12, 18 months) BALB/c mice were sensitized and challenged with ovalbumin (OVA). AHR and bronchoalveolar fluid (BALF), total inflammatory cell count and differential were measured. To evaluate mucus metaplasia, quantitative PCR for the major airway mucin-associated gene, MUC-5AC, from lung tissue was measured, and lung tissue sections stained with periodic acid-Schiff (PAS) for goblet-cell enumeration. Lung tissue cytokine gene expression was determined by quantitative PCR, and systemic cytokine protein levels by ELISA from spleen-cell cultures. Antigen-specific serum IgE was determined by ELISA. AHR developed in both aged and young OVA-sensitized/challenged mice (OVA mice), and was more significantly increased in young OVA mice than in aged OVA mice. However, BALF eosinophil numbers were significantly higher, and lung histology showed greater inflammation in aged OVA mice than in young OVA mice. MUC-5AC expression and numbers of PAS+ staining bronchial epithelial cells were significantly increased in the aged OVA mice. All aged OVA mice had increased IL-5 and IFN-gamma mRNA expression in the lung and IL-5 and IFN-gamma protein levels from spleen cell cultures compared with young OVA mice. OVA-IgE was elevated to a greater extent in aged OVA mice. Although pulmonary inflammation and mucus metaplasia after antigen sensitization/challenge occurred to a greater degree in older mice, the increase in AHR was significantly less compared with younger OVA mice. Antigen treatment produced a unique cytokine profile in older mice (elevated IFN-gamma and IL-5) compared with young mice

Boosting airway T-regulatory cells by gastrointestinal stimulation as a strategy for asthma control.

PubMed

Strickland, D H; Judd, S; Thomas, J A; Larcombe, A N; Sly, P D; Holt, P G

2011-01-01

The hallmark of atopic asthma is transient airways hyperresponsiveness (AHR) preceded by aeroallergen-induced Th-cell activation. This is preceded by upregulation of CD86 on resident airway dendritic cells (DCs) that normally lack competence in T-cell triggering. Moreover, AHR duration is controlled via T-regulatory (Treg) cells, which can attenuate CD86 upregulation on DC. We show that airway mucosal Treg/DC interaction represents an accessible therapeutic target for asthma control. Notably, baseline airway Treg activity in sensitized rats can be boosted by microbe-derived stimulation of the gut, resulting in enhanced capacity to control CD86 expression on airway DC triggered by aeroallergen and accelerated resolution of AHR.

Mesenchymal stem cells alleviate oxidative stress-induced mitochondrial dysfunction in the airways.

PubMed

Li, Xiang; Michaeloudes, Charalambos; Zhang, Yuelin; Wiegman, Coen H; Adcock, Ian M; Lian, Qizhou; Mak, Judith C W; Bhavsar, Pankaj K; Chung, Kian Fan

2018-05-01

Oxidative stress-induced mitochondrial dysfunction can contribute to inflammation and remodeling in patients with chronic obstructive pulmonary disease (COPD). Mesenchymal stem cells protect against lung damage in animal models of COPD. It is unknown whether these effects occur through attenuating mitochondrial dysfunction in airway cells. We sought to examine the effect of induced pluripotent stem cell-derived mesenchymal stem cells (iPSC-MSCs) on oxidative stress-induce mitochondrial dysfunction in human airway smooth muscle cells (ASMCs) in vitro and in mouse lungs in vivo. ASMCs were cocultured with iPSC-MSCs in the presence of cigarette smoke medium (CSM), and mitochondrial reactive oxygen species (ROS) levels, mitochondrial membrane potential (ΔΨm), and apoptosis were measured. Conditioned medium from iPSC-MSCs and transwell cocultures were used to detect any paracrine effects. The effect of systemic injection of iPSC-MSCs on airway inflammation and hyperresponsiveness in ozone-exposed mice was also investigated. Coculture of iPSC-MSCs with ASMCs attenuated CSM-induced mitochondrial ROS, apoptosis, and ΔΨm loss in ASMCs. iPSC-MSC-conditioned medium or transwell cocultures with iPSC-MSCs reduced CSM-induced mitochondrial ROS but not ΔΨm or apoptosis in ASMCs. Mitochondrial transfer from iPSC-MSCs to ASMCs was observed after direct coculture and was enhanced by CSM. iPSC-MSCs attenuated ozone-induced mitochondrial dysfunction, airway hyperresponsiveness, and inflammation in mouse lungs. iPSC-MSCs offered protection against oxidative stress-induced mitochondrial dysfunction in human ASMCs and in mouse lungs while reducing airway inflammation and hyperresponsiveness. These effects are, at least in part, dependent on cell-cell contact, which allows for mitochondrial transfer, and paracrine regulation. Therefore iPSC-MSCs show promise as a therapy for oxidative stress-dependent lung diseases, such as COPD. Copyright © 2017 American Academy of Allergy

Trichostatin A Abrogates Airway Constriction, but Not Inflammation, in Murine and Human Asthma Models

PubMed Central

Trivedi, Chinmay M.; Damera, Gautam; Jiang, Meiqi; Jester, William; Hoshi, Toshinori; Epstein, Jonathan A.; Panettieri, Reynold A.

2012-01-01

Histone deacetylase (HDAC) inhibitors may offer novel approaches in the treatment of asthma. We postulate that trichostatin A (TSA), a Class 1 and 2 inhibitor of HDAC, inhibits airway hyperresponsiveness in antigen-challenged mice. Mice were sensitized and challenged with Aspergillus fumigatus antigen (AF) and treated with TSA, dexamethasone, or vehicle. Lung resistance (RL) and dynamic compliance were measured, and bronchial alveolar lavage fluid (BALF) was analyzed for numbers of leukocytes and concentrations of cytokines. Human precision-cut lung slices (PCLS) were treated with TSA and their agonist-induced bronchoconstriction was measured, and TSA-treated human airway smooth muscle (ASM) cells were evaluated for the agonist-induced activation of Rho and intracellular release of Ca2+. The activity of HDAC in murine lungs was enhanced by antigen and abrogated by TSA. TSA also inhibited methacholine (Mch)-induced increases in RL and decreases in dynamic compliance in naive control mice and in AF-sensitized and -challenged mice. Total cell counts, concentrations of IL-4, and numbers of eosinophils in BALF were unchanged in mice treated with TSA or vehicle, whereas dexamethasone inhibited the numbers of eosinophils in BALF and concentrations of IL-4. TSA inhibited the carbachol-induced contraction of PCLS. Treatment with TSA inhibited the intracellular release of Ca2+ in ASM cells in response to histamine, without affecting the activation of Rho. The inhibition of HDAC abrogates airway hyperresponsiveness to Mch in both naive and antigen-challenged mice. TSA inhibits the agonist-induced contraction of PCLS and mobilization of Ca2+ in ASM cells. Thus, HDAC inhibitors demonstrate a mechanism of action distinct from that of anti-inflammatory agents such as steroids, and represent a promising therapeutic agent for airway disease. PMID:22298527

Flavonone treatment reverses airway inflammation and remodelling in an asthma murine model

PubMed Central

Toledo, AC; Sakoda, CPP; Perini, A; Pinheiro, NM; Magalhães, RM; Grecco, S; Tibério, IFLC; Câmara, NO; Martins, MA; Lago, JHG; Prado, CM

2013-01-01

Background and Purpose Asthma is an inflammatory disease that involves airway hyperresponsiveness and remodelling. Flavonoids have been associated to anti-inflammatory and antioxidant activities and may represent a potential therapeutic treatment of asthma. Our aim was to evaluate the effects of the sakuranetin treatment in several aspects of experimental asthma model in mice. Experimental Approach Male BALB/c mice received ovalbumin (i.p.) on days 0 and 14, and were challenged with aerolized ovalbumin 1% on days 24, 26 and 28. Ovalbumin-sensitized animals received vehicle (saline and dimethyl sulfoxide, DMSO), sakuranetin (20 mg kg–1 per mice) or dexamethasone (5 mg kg–1 per mice) daily beginning from 24th to 29th day. Control group received saline inhalation and nasal drop vehicle. On day 29, we determined the airway hyperresponsiveness, inflammation and remodelling as well as specific IgE antibody. RANTES, IL-5, IL-4, Eotaxin, IL-10, TNF-α, IFN-γ and GMC-SF content in lung homogenate was performed by Bioplex assay, and 8-isoprostane and NF-kB activations were visualized in inflammatory cells by immunohistochemistry. Key Results We have demonstrated that sakuranetin treatment attenuated airway hyperresponsiveness, inflammation and remodelling; and these effects could be attributed to Th2 pro-inflammatory cytokines and oxidative stress reduction as well as control of NF-kB activation. Conclusions and Implications These results highlighted the importance of counteracting oxidative stress by flavonoids in this asthma model and suggest sakuranetin as a potential candidate for studies of treatment of asthma. PMID:23170811

Decrease of Airway Allergies After Lung Transplantation Is Associated With Reduced Basophils and Eosinophils.

PubMed

Niedzwiecki, M; Yamada, Y; Inci, I; Weder, W; Jungraithmayr, W

2016-01-01

Allergies are hypersensitive reactions of the immune system on antigen exposure similar to immune reactions after transplantation (Tx). Their activity can change after Tx. The lung as a transplantable organ is challenged two-fold, by antigens from the blood and the air environment. Herein we analyzed if airway allergies change after lung Tx. We systematically reviewed patients' airway allergies before and after lung Tx between 1992 and 2014. The course of lymphocytes, thrombocytes, and leukocytes, among them neutrophils, eosinophils, and basophils, was analyzed in patients in whom airway allergies have changed and in whom they did not change. From 362 lung transplanted patients, 44 patients had suffered from allergies before Tx (12.2%). In 20 of these patients (45.5%), airway allergies disappeared completely within 1 year after lung Tx and were persistently absent thereafter. In these patients, basophils and eosinophils decreased significantly (P < .0012); in contrast, cells did not decrease in patients whose allergies did not disappear. Leukocytes overall, and in particular, neutrophils, decreased significantly in patients whose allergy disappeared (P < .014, P < .012, respectively). Airway allergies disappeared in almost half of cases after lung Tx. Along with this reduction, basophils and eosinophils decreased as potentially responsible cells for this phenomenon. These findings may stimulate intensified research on basophils and eosinophils as major drivers of airway allergies. Copyright © 2016 Elsevier Inc. All rights reserved.

World Trade Center fine particulate matter causes respiratory tract hyperresponsiveness in mice.

PubMed

Gavett, Stephen H; Haykal-Coates, Najwa; Highfill, Jerry W; Ledbetter, Allen D; Chen, Lung Chi; Cohen, Mitchell D; Harkema, Jack R; Wagner, James G; Costa, Daniel L

2003-06-01

Pollutants originating from the destruction of the World Trade Center (WTC) in New York City on 11 September 2001 have been reported to cause adverse respiratory responses in rescue workers and nearby residents. We examined whether WTC-derived fine particulate matter [particulate matter with a mass median aerodynamic diameter < 2.5 microm (PM2.5)] has detrimental respiratory effects in mice to contribute to the risk assessment of WTC-derived pollutants. Samples of WTC PM2.5 were derived from settled dust collected at several locations around Ground Zero on 12 and 13 September 2001. Aspirated samples of WTC PM2.5 induced mild to moderate degrees of pulmonary inflammation 1 day after exposure but only at a relatively high dose (100 microg). This response was not as great as that caused by 100 microg PM2.5 derived from residual oil fly ash (ROFA) or Washington, DC, ambient air PM [National Institute of Standards and Technology, Standard Reference Material (SRM) 1649a]. However, this same dose of WTC PM2.5 caused airway hyperresponsiveness to methacholine aerosol comparable to that from SRM 1649a and to a greater degree than that from ROFA. Mice exposed to lower doses by aspiration or inhalation exposure did not develop significant inflammation or hyperresponsiveness. These results show that exposure to high levels of WTC PM2.5 can promote mechanisms of airflow obstruction in mice. Airborne concentrations of WTC PM2.5 that would cause comparable doses in people are high (approximately 425 microg/m3 for 8 hr) but conceivable in the aftermath of the collapse of the towers when rescue and salvage efforts were in effect. We conclude that a high-level exposure to WTC PM2.5 could cause pulmonary inflammation and airway hyperresponsiveness in people. The effects of chronic exposures to lower levels of WTC PM2.5, the persistence of any respiratory effects, and the effects of coarser WTC PM are unknown and were not examined in these studies. Degree of exposure and respiratory

Exercise-induced airway obstruction in young asthmatics measured by impulse oscillometry.

PubMed

Lee, J H; Lee, Y W; Shin, Y S; Jung, Y H; Hong, C S; Park, J W

2010-01-01

Impulse oscillometry (IOS) is a good method for measuring airway resistance. It does not require special breathing skills and it can reflect different aspects of airway obstruction to those revealed by spirometry, which is an effort-dependent maneuver. To evaluate the characteristics of airway obstruction in young asthmatics after an exercise bronchial provocation test (EBPT) using IOS. Forty-seven young adults were enrolled in the study. All the participants underwent a methacholine bronchial provocation test (MBPT) and an EBPT for the evaluation of their asthma. IOS and spirometric parameters were collected at baseline and at 0, 5, 10, 20, and 30 minutes post-EBPT.The participants were divided into 2 groups according to MBPT positivity: an airway hyperresponsiveness (AHR) group and a no-AHR group. There were differences in the percent decrease in forced expiratory volume in the first second (FEV1) between the 2 groups at 5, 10, and 20 minutes after exercise. Resistance at 5 Hz (R5) increased in the AHR group but not in the no-AHR group at 5 and 10 minutes after exercise. Integration of reactance from 5 Hz to resonance frequency (area of reactance, AX) was also increased in the AHR group at only 5 and 10 minutes post-EBPT. Delta R5 and delta AX at 5 and 10 minutes post-exercise were well correlated with the percent decrease in FEV1. IOS parameters, especially delta R5 and delta AX, may be useful for performing objective evaluations and improving our understanding of exercise-induced airway obstruction in young asthmatics.

Airway compliance and dynamics explain the apparent discrepancy in length adaptation between intact airways and smooth muscle strips.

PubMed

Dowie, Jackson; Ansell, Thomas K; Noble, Peter B; Donovan, Graham M

2016-01-01

Length adaptation is a phenomenon observed in airway smooth muscle (ASM) wherein over time there is a shift in the length-tension curve. There is potential for length adaptation to play an important role in airway constriction and airway hyper-responsiveness in asthma. Recent results by Ansell et al., 2015 (JAP 2014 10.1152/japplphysiol.00724.2014) have cast doubt on this role by testing for length adaptation using an intact airway preparation, rather than strips of ASM. Using this technique they found no evidence for length adaptation in intact airways. Here we attempt to resolve this apparent discrepancy by constructing a minimal mathematical model of the intact airway, including ASM which follows the classic length-tension curve and undergoes length adaptation. This allows us to show that (1) no evidence of length adaptation should be expected in large, cartilaginous, intact airways; (2) even in highly compliant peripheral airways, or at more compliant regions of the pressure-volume curve of large airways, the effect of length adaptation would be modest and at best marginally detectable in intact airways; (3) the key parameters which control the appearance of length adaptation in intact airways are airway compliance and the relaxation timescale. The results of this mathematical simulation suggest that length adaptation observed at the level of the isolated ASM may not clearly manifest in the normal intact airway. Copyright © 2015 Elsevier B.V. All rights reserved.

Innate lymphoid cells contribute to allergic airway disease exacerbation by obesity.

PubMed

Everaere, Laetitia; Ait-Yahia, Saliha; Molendi-Coste, Olivier; Vorng, Han; Quemener, Sandrine; LeVu, Pauline; Fleury, Sebastien; Bouchaert, Emmanuel; Fan, Ying; Duez, Catherine; de Nadai, Patricia; Staels, Bart; Dombrowicz, David; Tsicopoulos, Anne

2016-11-01

Epidemiologic and clinical observations identify obesity as an important risk factor for asthma exacerbation, but the underlying mechanisms remain poorly understood. Type 2 innate lymphoid cells (ILC2s) and type 3 innate lymphoid cells (ILC3s) have been implicated, respectively, in asthma and adipose tissue homeostasis and in obesity-associated airway hyperresponsiveness (AHR). We sought to determine the potential involvement of innate lymphoid cells (ILCs) in allergic airway disease exacerbation caused by high-fat diet (HFD)-induced obesity. Obesity was induced by means of HFD feeding, and allergic airway inflammation was subsequently induced by means of intranasal administration of house dust mite (HDM) extract. AHR, lung and visceral adipose tissue inflammation, humoral response, cytokines, and innate and adaptive lymphoid populations were analyzed in the presence or absence of ILCs. HFD feeding exacerbated allergic airway disease features, including humoral response, airway and tissue eosinophilia, AHR, and T H 2 and T H 17 pulmonary profiles. Notably, nonsensitized obese mice already exhibited increased lung ILC counts and tissue eosinophil infiltration compared with values in lean mice in the absence of AHR. The numbers of total and cytokine-expressing lung ILC2s and ILC3s further increased in HDM-challenged obese mice compared with those in HDM-challenged lean mice, and this was accompanied by high IL-33 and IL-1β levels and decreased ILC markers in visceral adipose tissue. Furthermore, depletion of ILCs with an anti-CD90 antibody, followed by T-cell reconstitution, led to a profound decrease in allergic airway inflammatory features in obese mice, including T H 2 and T H 17 infiltration. These results indicate that HFD-induced obesity might exacerbate allergic airway inflammation through mechanisms involving ILC2s and ILC3s. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Prevention of airway inflammation with topical cream containing imiquimod and small interfering RNA for natriuretic peptide receptor

PubMed Central

Wang, Xiaoqin; Xu, Weidong; Mohapatra, Subhra; Kong, Xiaoyuan; Li, Xu; Lockey, Richard F; Mohapatra, Shyam S

2008-01-01

Background Asthma is a complex disease, characterized by reversible airway obstruction, hyperresponsiveness and chronic inflammation. Principle pharmacologic treatments for asthma include bronchodilating beta2-agonists and anti-inflammatory glucocorticosteroids; but these agents do not target the main cause of the disease, the generation of pathogenic Th2 cells. We previously reported reduction in allergic inflammation in mice deficient in the ANP receptor NPRA. Here we determined whether siRNA for natriuretic peptide receptor A (siNPRA) protected against asthma when administered transdermally. Methods Imiquimod cream mixed with chitosan nanoparticles containing either siRNA green indicator (siGLO) or siNPRA was applied to the skin of mice. Delivery of siGLO was confirmed by fluorescence microscopy. The anti-inflammatory activity of transdermal siNPRA was tested in OVA-sensitized mice by measuring airway hyperresponsiveness, eosinophilia, lung histopathology and pro-inflammatory cytokines. Results SiGLO appearing in the lung proved the feasibility of transdermal delivery. In a mouse asthma model, BALB/c mice treated with imiquimod cream containing siNPRA chitosan nanoparticles showed significantly reduced airway hyperresponsiveness, eosinophilia, lung histopathology and pro-inflammatory cytokines IL-4 and IL-5 in lung homogenates compared to controls. Conclusion These results demonstrate that topical cream containing imiquimod and siNPRA nanoparticles exerts an anti-inflammatory effect and may provide a new and simple therapy for asthma. PMID:18279512

Phosphoinositide 3-kinase gamma regulates airway smooth muscle contraction by modulating calcium oscillations.

PubMed

Jiang, Haihong; Abel, Peter W; Toews, Myron L; Deng, Caishu; Casale, Thomas B; Xie, Yan; Tu, Yaping

2010-09-01

Phosphoinositide 3-kinase gamma (PI3Kgamma) has been implicated in the pathogenesis of asthma, but its mechanism has been considered indirect, through release of inflammatory cell mediators. Because airway smooth muscle (ASM) contractile hyper-responsiveness plays a critical role in asthma, the aim of the present study was to determine whether PI3Kgamma can directly regulate contractility of ASM. Immunohistochemistry staining indicated expression of PI3Kgamma protein in ASM cells of mouse trachea and lung, which was confirmed by Western blot analysis in isolated mouse tracheal ASM cells. PI3Kgamma inhibitor II inhibited acetylcholine (ACh)-stimulated airway contraction of cultured precision-cut mouse lung slices in a dose-dependent manner with 75% inhibition at 10 muM. In contrast, inhibitors of PI3Kalpha, PI3Kbeta, or PI3Kdelta, at concentrations 40-fold higher than their reported IC(50) values for their primary targets, had no effect. It is noteworthy that airways in lung slices pretreated with PI3Kgamma inhibitor II still exhibited an ACh-induced initial contraction, but the sustained contraction was significantly reduced. Furthermore, the PI3Kgamma-selective inhibitor had a small inhibitory effect on the ACh-stimulated initial Ca(2+) transient in ASM cells of mouse lung slices or isolated mouse ASM cells but significantly attenuated the sustained Ca(2+) oscillations that are critical for sustained airway contraction. This report is the first to show that PI3Kgamma directly controls contractility of airways through regulation of Ca(2+) oscillations in ASM cells. Thus, in addition to effects on airway inflammation, PI3Kgamma inhibitors may also exert direct effects on the airway contraction that contribute to pathologic airway hyper-responsiveness.

Phosphoinositide 3-Kinase γ Regulates Airway Smooth Muscle Contraction by Modulating Calcium Oscillations

PubMed Central

Jiang, Haihong; Abel, Peter W.; Toews, Myron L.; Deng, Caishu; Casale, Thomas B.; Xie, Yan

2010-01-01

Phosphoinositide 3-kinase γ (PI3Kγ) has been implicated in the pathogenesis of asthma, but its mechanism has been considered indirect, through release of inflammatory cell mediators. Because airway smooth muscle (ASM) contractile hyper-responsiveness plays a critical role in asthma, the aim of the present study was to determine whether PI3Kγ can directly regulate contractility of ASM. Immunohistochemistry staining indicated expression of PI3Kγ protein in ASM cells of mouse trachea and lung, which was confirmed by Western blot analysis in isolated mouse tracheal ASM cells. PI3Kγ inhibitor II inhibited acetylcholine (ACh)-stimulated airway contraction of cultured precision-cut mouse lung slices in a dose-dependent manner with 75% inhibition at 10 μM. In contrast, inhibitors of PI3Kα, PI3Kβ, or PI3Kδ, at concentrations 40-fold higher than their reported IC50 values for their primary targets, had no effect. It is noteworthy that airways in lung slices pretreated with PI3Kγ inhibitor II still exhibited an ACh-induced initial contraction, but the sustained contraction was significantly reduced. Furthermore, the PI3Kγ-selective inhibitor had a small inhibitory effect on the ACh-stimulated initial Ca2+ transient in ASM cells of mouse lung slices or isolated mouse ASM cells but significantly attenuated the sustained Ca2+ oscillations that are critical for sustained airway contraction. This report is the first to show that PI3Kγ directly controls contractility of airways through regulation of Ca2+ oscillations in ASM cells. Thus, in addition to effects on airway inflammation, PI3Kγ inhibitors may also exert direct effects on the airway contraction that contribute to pathologic airway hyper-responsiveness. PMID:20501633

Systemic and airway oxidative stress in competitive swimmers.

PubMed

Škrgat, Sabina; Marčun, Robert; Kern, Izidor; Šilar, Mira; Šelb, Julij; Fležar, Matjaž; Korošec, Peter

2018-04-01

The environment in swimming pools, which contain chlorine, might interact with the airway epithelium, resulting in oxidative stress and/or inflammation during high intensity training periods. We evaluated pulmonary functional (metacholine challenge test, FEV1 and VC), cellular (eosinophils and neutrophils), inflammatory (FeNo, IL-5, IL-6, IL-8 and TNF-α), oxidative (8-isoprostanes) and angiogenesis factors (VEGF) in induced sputum and peripheral blood of 41 healthy non-asthmatic elite swimmers (median 16 years) during the period of high intensity training before a national championship. The second paired sampling was performed seven months later after training had been stopped for one month. There was a ten-fold increase (median 82-924 pg/ml; P < 0.001) in 8-isoprostanes in induced sputum and five-fold increase (median 82-924 pg/ml; P < 0.001) in sera during training in comparison to the period of rest. However, there was no difference in FEV1 (113 vs 116%), VC (119 vs 118%), FeNo (median 34 vs 38 ppb), eosinophils (2.7 vs 2.9% in sputum; 180 vs 165 cells/μl in blood), neutrophils, different cytokines or VEGF in induced sputum or sera. The only exception was TNF-α, which was moderately increased in sera (median 23 vs 40 pg/ml; P = 0.02) during the peak training period. Almost half (18 of 41) of swimmers showed bronchial hyperresponsiveness during the peak training period (PC20 cutoff was 4 mg/ml). There was no correlation between hyperresponsiveness and the markers of oxidative stress or inflammation. High intensity training in healthy, non-asthmatic competitive swimmers results in marked oxidative stress at the airway and systemic levels, but does not lead to airway inflammation. However, we could not confirm that oxidative stress is associated with bronchial hyperresponsiveness (AHR), which is often observed during the peak exercise training period. Copyright © 2018. Published by Elsevier Ltd.

EFFECTS OF TITANIUM DIOXIDE NANOPARTICLE EXPOSURE ON NEUROIMMUNE RESPONSES IN RAT AIRWAYS

PubMed Central

Scuri, Mario; Chen, Bean T.; Castranova, Vincent; Reynolds, Jeffrey S.; Johnson, Victor J.; Samsell, Lennie; Walton, Cheryl; Piedimonte, Giovanni

2013-01-01

Exposure to ambient nanoparticles (defined as particulate matter [PM] having one dimension < 100 nm) is associated with increased risk of childhood and adult asthma. Nanomaterials feature a smaller aerodynamic diameter and a higher surface area per unit mass ratio compared to fine or coarse-sized particles, resulting in greater lung deposition efficiency and an increased potential for biological interaction. The neurotrophins nerve growth factor and brain-derived neurotrophic factor are key regulatory elements of neuronal development and responsiveness of airway sensory neurons. Changes in their expression are associated with bronchoconstriction, airway hyperresponsiveness, and airway inflammation. The neurogenic-mediated control of airway responses is a key pathophysiological mechanism of childhood asthma. However, the effects of nanoparticle exposure on neurotrophin-driven airway responses and their potential role as a predisposing factor for developing asthma have not been clearly elucidated. In this study, in vivo inhalation exposure to titanium dioxide nanoparticles (12 mg/m13; 5.6 h/d for 3 d) produced upregulation of lung neurotrophins in weanling (2-wk-old) and newborn (2-d-old) rats but not in adult (12-wk-old) animals compared to controls. This effect was associated with increased airway responsiveness and upregulation of growth-related oncogene/keratine-derived chemokine (GRO/KC; CXCL1, rat equivalent of human interleukin [IL]-8) in bronchoalveolar lavage fluid. These data show for the first time that exposure to nanoparticulate upregulates the expression of lung neurotrophins in an age-dependent fashion and that this effect is associated with airway hyperresponsiveness and inflammation. These results suggest the presence of a critical window of vulnerability in earlier stages of lung development, which may lead to a higher risk of developing asthma. PMID:20818535

Baicalein Reduces Airway Injury in Allergen and IL-13 Induced Airway Inflammation

PubMed Central

Mabalirajan, Ulaganathan; Ahmad, Tanveer; Rehman, Rakhshinda; Leishangthem, Geeta Devi; Dinda, Amit Kumar; Agrawal, Anurag; Ghosh, Balaram; Sharma, Surendra Kumar

2013-01-01

Background Baicalein, a bioflavone present in the dry roots of Scutellaria baicalensis Georgi, is known to reduce eotaxin production in human fibroblasts. However, there are no reports of its anti-asthma activity or its effect on airway injury. Methodology/Principal Findings In a standard experimental asthma model, male Balb/c mice that were sensitized with ovalbumin (OVA), treated with baicalein (10 mg/kg, ip) or a vehicle control, either during (preventive use) or after OVA challenge (therapeutic use). In an alternate model, baicalein was administered to male Balb/c mice which were given either IL-4 or IL-13 intranasally. Features of asthma were determined by estimating airway hyperresponsiveness (AHR), histopathological changes and biochemical assays of key inflammatory molecules. Airway injury was determined with apoptotic assays, transmission electron microscopy and assessing key mitochondrial functions. Baicalein treatment reduced AHR and inflammation in both experimental models. TGF-β1, sub-epithelial fibrosis and goblet cell metaplasia, were also reduced. Furthermore, baicalein treatment significantly reduced 12/15-LOX activity, features of mitochondrial dysfunctions, and apoptosis of bronchial epithelia. Conclusion/Significance Our findings demonstrate that baicalein can attenuate important features of asthma, possibly through the reduction of airway injury and restoration of mitochondrial function. PMID:23646158

Structural and functional localization of airway effects from episodic exposure of infant monkeys to allergen and/or ozone

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

Joad, Jesse P.; Kott, Kayleen S.; Bric, John M.

2006-08-01

Both allergen and ozone exposure increase asthma symptoms and airway responsiveness in children. Little is known about how these inhalants may differentially modify airway responsiveness in large proximal as compared to small distal airways. We evaluated whether bronchi and respiratory bronchioles from infant monkeys exposed episodically to allergen and/or ozone differentially develop intrinsic hyperresponsiveness to methacholine and whether eosinophils and/or pulmonary neuroendocrine cells play a role. Infant monkeys were exposed episodically for 5 months to: (1) filtered air, (2) aerosolized house dust mite allergen, (3) ozone 0.5 ppm, or (4) house dust mite allergen + ozone. Studying the function/structure relationshipmore » of the same lung slices, we evaluated methacholine airway responsiveness and histology of bronchi and respiratory bronchioles. In bronchi, intrinsic responsiveness was increased by allergen exposure, an effect reduced by bombesin antagonist. In respiratory bronchioles, intrinsic airway responsiveness was increased by allergen + ozone exposure. Eosinophils were increased by allergen and allergen + ozone exposure in bronchi and by allergen exposure in respiratory bronchioles. In both airways, exposure to allergen + ozone resulted in fewer tissue eosinophils than did allergen exposure alone. In bronchi, but not in respiratory bronchioles, the number of eosinophils and neuroendocrine cells correlated with airway responsiveness. We conclude that episodically exposing infant monkeys to house dust mite allergen with or without ozone increased intrinsic airway responsiveness to methacholine in bronchi differently than in respiratory bronchioles. In bronchi, eosinophils and neuroendocrine cells may play a role in the development of airway hyperresponsiveness.« less

Airway hyperresponsiveness and body mass index: the Child Health and Environment Cohort Study in Hesse, Germany.

PubMed

Eneli, I U; Karmaus, W K; Davis, S; Kuehr, J

2006-06-01

Increased body mass index has been linked to wheezing, a diagnosis of asthma, and morbidity. We investigated the association between body mass index (BMI), breastfeeding, and airway hyperresponsiveness (AHR) in 536 German schoolchildren. We analyzed consecutive surveys in 1994-1995 and 1997, conducted as part of the Child Health and Environment Cohort Study in Hesse, Germany. The questionnaire included questions adapted from the German version of the International Study of Asthma and Allergy in Childhood (ISAAC). A bronchial challenge test using 4.5% hypertonic saline was conducted during the 1997 survey. AHR was defined as a fall in forced expiratory volume in 1 sec (FEV(1)) of > or = 15%. Of 536 children who participated in the 1997 survey (median age, 10.3 years), 82 (15%) tested positive for AHR. In a multivariate analysis, there was no association between AHR determined at age 10 years and the highest quintile of BMI compared to the lowest quintile at age 4 years (odds ratio (OR), 1.4; 95% confidence interval (CI), 0.5-3.6), 7-8 years (OR, 0.6; 95% CI, 0.1-2.5), or 10 years (OR, 1.1; 95% CI, 0.2-4.3). Breastfeeding for 12 weeks or longer protected against AHR (OR, 0.4; 95% CI, 0.2-0.9). However, when children in the highest quintile of BMI at age 4 years had been breastfed for 8 weeks or less, the prevalence of AHR at age 10 years was significantly increased (27.7%, P = 0.01). In conclusion, our results demonstrate a protective effect of breastfeeding against AHR, and reinforce the need to encourage breastfeeding. Although there was no association between BMI and AHR, our finding of an interactive effect of high BMI and short breastfeeding on AHR suggests a complex etiological pathway that needs to be further explored. Copyright 2006 Wiley-Liss, Inc.

Ayanin, a non-selective phosphodiesterase 1-4 inhibitor, effectively suppresses ovalbumin-induced airway hyperresponsiveness without affecting xylazine/ketamine-induced anesthesia.

PubMed

Lee, Fei-Peng; Shih, Chwen-Ming; Shen, Hsin-Yi; Chen, Chien-Ming; Chen, Chi-Ming; Ko, Wun-Chang

2010-06-10

In recent in vitro reports, the IC(50) value of ayanin (quercetin-3,7,4'-O-trimethylether) was 2.2microM for inhibiting interleukin (IL)-4 production from purified basophils, and its therapeutic ratio was >19. Therefore, we were interested in investigating the effects on ovalbumin induced airway hyperresponsiveness in vivo, and to clarify its potential for treating asthma. Ayanin (30-100micromol/kg, orally (p.o.)) dose-dependently and significantly attenuated the enhanced pause (P(enh)) value induced by methacholine in sensitized and challenged mice. It also significantly suppressed the increases in total inflammatory cells, macrophages, lymphocytes, neutrophils, and eosinophils, and levels of cytokines, including IL-2, IL-4, IL-5, and tumor necrosis factor (TNF)-alpha in bronchoalveolar lavage fluid of these mice. However, at 100micromol/kg, it significantly enhanced the level of interferon (IFN)-gamma. In addition, ayanin (30-100micromol/kg, p.o.) dose-dependently and significantly suppressed total and OVA-specific immunoglobulin (Ig)E levels in the serum and bronchoalveolar lavage fluid, and enhanced the IgG(2a) level in serum of these mice. In the present results, ayanin did not affect xylazine/ketamine-induced anesthesia, suggesting that ayanin has few or no adverse effects, such as nausea, vomiting, and gastric hypersecretion. In conclusion, the above results suggest that ayanin may have the potential for use in treating allergic asthma.

Characterization of airway and vascular responses in murine lungs

PubMed Central

Held, Heinz-Dieter; Martin, Christian; Uhlig, Stefan

1999-01-01

We characterized the responses of murine airways and pulmonary vessels to a variety of endogenous mediators in the isolated perfused and ventilated mouse lung (IPL) and compared them with those in precision-cut lung slices. Airways: The EC50 (μM) for contractions of airways in IPL/slices was methacholine (Mch), 6.1/1.5>serotonin, 0.7/2.0>U46619 (TP-receptor agonist), 0.1/0.06>endothelin-1, 0.1/0.05. In the IPL, maximum increase in airway resistance (RL) was 0.6, 0.4, 0.8 and 11 cmH2O s ml−1, respectively. Adenosine (⩽1 mM), bombesin (⩽100 μM), histamine (⩽10 mM), LTC4 (⩽1 μM), PAF (0.25 μM) and substance P (⩽100 μM) had only weak effects (<5% of Mch) on RL. Vessels: The EC50 (μM) for vasoconstriction in the IPL was LTC4, 0.06>U46619, 0.05Hyperresponsiveness: In both the IPL and slices, U46619 in subthreshold concentrations (10 nM) reduced the EC50 to 0.6 μM. In the IPL, U46619 raised the maximum airway response to Mch 5 fold and the maximum PAF-induced vasoconstriction 4 fold. Conclusion: Murine precision-cut lung slices maintain important characteristics of the whole organ. The maximum reagibility of murine airways to endogenous mediators is serotoninairway and vessel hyperreactivity induced by U46619 raises the possibility that thromboxane contributes directly to airway hyperresponsiveness in various experimental and clinical settings. PMID:10205008

KIT Inhibition by Imatinib in Patients with Severe Refractory Asthma

PubMed Central

Cahill, Katherine N.; Katz, Howard R.; Cui, Jing; Lai, Juying; Kazani, Shamsah; Crosby-Thompson, Allison; Garofalo, Denise; Castro, Mario; Jarjour, Nizar; DiMango, Emily; Erzurum, Serpil; Trevor, Jennifer L.; Shenoy, Kartik; Chinchilli, Vernon M.; Wechsler, Michael E.; Laidlaw, Tanya M.; Boyce, Joshua A.; Israel, Elliot

2017-01-01

BACKGROUND Mast cells are present in the airways of patients who have severe asthma despite glucocorticoid treatment; these cells are associated with disease characteristics including poor quality of life and inadequate asthma control. Stem cell factor and its receptor, KIT, are central to mast-cell homeostasis. We conducted a proof-of-principle trial to evaluate the effect of imatinib, a KIT inhibitor, on airway hyper-responsiveness, a physiological marker of severe asthma, as well as on airway mast-cell numbers and activation in patients with severe asthma. METHODS We conducted a randomized, double-blind, placebo-controlled, 24-week trial of imatinib in patients with poorly controlled severe asthma who had airway hyperresponsiveness despite receiving maximal medical therapy. The primary end point was the change in airway hyperresponsiveness, measured as the concentration of methacholine required to decrease the forced expiratory volume in 1 second by 20% (PC20). Patients also underwent bronchoscopy. RESULTS Among the 62 patients who underwent randomization, imatinib treatment reduced airway hyperresponsiveness to a greater extent than did placebo. At 6 months, the methacholine PC20 increased by a mean (±SD) of 1.73±0.60 doubling doses in the imatinib group, as compared with 1.07±0.60 doubling doses in the placebo group (P = 0.048). Imatinib also reduced levels of serum tryptase, a marker of mast-cell activation, to a greater extent than did placebo (decrease of 2.02±2.32 vs. 0.56±1.39 ng per milliliter, P = 0.02). Airway mast-cell counts declined in both groups. Muscle cramps and hypophosphatemia were more common in the imatinib group than in the placebo group. CONCLUSIONS In patients with severe asthma, imatinib decreased airway hyperresponsiveness, mast-cell counts, and tryptase release. These results suggest that KIT-dependent processes and mast cells contribute to the pathobiologic basis of severe asthma. (Funded by the National Institutes of Health and

Hyperoside attenuates OVA-induced allergic airway inflammation by activating Nrf2.

PubMed

Ye, Peng; Yang, Xi-Liang; Chen, Xing; Shi, Cai

2017-03-01

Allergic airways disease (AAD) is one of the most common medical illnesses that is associated with an increased allergic airway inflammation. Hyperoside, an active compound isolated from Rhododendron brachycarpum G. Don, has been reported to have anti-inflammatory effect. The aim of this study was to analyze the protective effect of hyperoside on OVA-induced allergic airway inflammation in mice. In the present study, the mouse asthma model was induced by given OVA and hyperoside was administrated 1h before OVA challenge. The levels of IL-4, IL-5, IL-13, and IgE were detected by ELISA. H&E staining was used to assess lung histopathological changes. The expression of NF-κB p65, IκB, HO-1, and Nf-E2 related factor 2 (Nrf2) were measured by western blot analysis. The results showed that hyperoside significantly reduced the inflammatory cells infiltration and the levels of IL-4, IL-5, IL-13, and IgE. Hyperoside significantly inhibited OVA-induced oxidative stress as demonstrated by decreased MDA, and increased GSH and SOD levels. Treatment of hyperoside also inhibited OVA-induced airway hyperresponsiveness (AHR). Furthermore, the results showed that treatment of hyperoside significantly inhibited LPS-induced NF-κB activation. In addition, hyperoside was found to activate Nrf2/HO-1 signaling pathway. In conclusion, these results suggest that hyperoside ameliorates OVA-induced allergic airway inflammation by activating Nrf2 signaling pathway. Copyright © 2017 Elsevier B.V. All rights reserved.

Inhibition of neutral endopeptidase increases airway responsiveness to ACh in nonsensitized normal rats.

PubMed

Chiba, Y; Misawa, M

1995-02-01

The effects of sensory neuropeptides on the airway responsiveness to acetylcholine (ACh) were investigated in normal nonsensitized rats. The airway responsiveness to inhaled ACh was significantly increased after treatment with neurokinin A (NKA; 0.001%) or substance P (SP; 0.01%) aerosol in the presence of the neutral endopeptidase (NEP) inhibitor. NKA had a more potent effect than SP. Interestingly, the intravenous treatment with NEP inhibitor alone also induced airway hyperresponsiveness (AHR) to inhaled ACh. This AHR was significantly attenuated by pretreatment with a nonselective NK-receptor antagonist, [D-Pro2,D-Trp7,9]SP, systemic capsaicin, or bilateral cervical vagotomy, indicating that decreased NEP activity results in accumulation of endogenous sensory neuropeptide(s) and enhancement of vagal reflex to cause AHR. The airway responsiveness to ACh of isolated left main bronchus was also increased after treatment with 10(-6) M NKA, but not SP, together with 10(-6) M phosphoramidon. This in vitro AHR to ACh induced by phosphoramidon plus NKA was significantly attenuated by pretreatment with 10(-6) M tetrodotoxin. These findings suggest that overaccumulated sensory neuropeptides, especially NKA, may enhance the probability of transmitter release, probably via NK2 receptors, and that the enhanced transmitter release might be involved in AHR in rats.

L-2-Oxothiazolidine-4-Carboxylic Acid or α-Lipoic Acid Attenuates Airway Remodeling: Involvement of Nuclear Factor-κB (NF-κB), Nuclear Factor Erythroid 2p45-Related Factor-2 (Nrf2), and Hypoxia-Inducible Factor (HIF)

PubMed Central

Park, Seoung Ju; Lee, Kyung Sun; Lee, Su Jeong; Kim, So Ri; Park, Seung Yong; Jeon, Myoung Shin; Lee, Heung Bum; Lee, Yong Chul

2012-01-01

Reactive oxygen species (ROS) play a crucial role in the pathogenesis of acute and chronic respiratory diseases. Antioxidants have been found to ameliorate airway inflammation and hyperresponsiveness in animal models employing short-term exposure to allergen. However, little data are available on the effect of antioxidants on airway remodeling and signaling pathways in chronic asthma. In the present study, we used a long-term exposure murine model of allergic airway disease to evaluate the effects of an antioxidant, L-2-oxothiazolidine-4-carboxylic acid (OTC) or α-lipoic acid (LA) on airway remodeling, focusing on the ROS-related hypoxia-inducible signaling. Long-term challenge of ovalbumin (OVA) increased ROS production, airway inflammation, and airway hyperresponsiveness, and developed features of airway remodeling such as excessive mucus secretion, subepithelial fibrosis, and thickening of the peribronchial smooth muscle layer. Administration of OTC or LA reduced these features of asthma, including airway remodeling, which was accompanied by suppression of transforming growth factor-β1, vascular endothelial growth factor, and T-helper 2 cytokines. In addition, OVA-induced activation of nuclear factor-κB (NF-κB), nuclear factor erythroid 2p45-related factor-2 (Nrf2), hypoxia-inducible factor (HIF)-1α, and HIF-2α was reduced by OTC or LA. Our results also showed that OTC or LA down-regulated phosphoinositide 3-kinase activity and decreased phosphorylation of p38 mitogen-activated protein kinase but not extracellular signal-regulated kinase 1/2 or c-Jun N-terminal kinase. These findings demonstrate that OTC and LA can inhibit activation of NF-κB, Nrf2, and HIF, leading to attenuate allergen-induced airway remodeling. PMID:22942681

Preventive Intra Oral Treatment of Sea Cucumber Ameliorate OVA-Induced Allergic Airway Inflammation.

PubMed

Lee, Da-In; Park, Mi-Kyung; Kang, Shin Ae; Choi, Jun-Ho; Kang, Seok-Jung; Lee, Jeong-Yeol; Yu, Hak Sun

2016-01-01

Sea cucumber extracts have potent biological effects, including anti-viral, anti-cancer, antibacterial, anti-oxidant, and anti-inflammation effects. To understand their anti-asthma effects, we induced allergic airway inflammation in mice after 7 oral administrations of the extract. The hyper-responsiveness value in mice with ovalbumin (OVA)-alum-induced asthma after oral injection of sea cucumber extracts was significantly lower than that in the OVA-alum-induced asthma group. In addition, the number of eosinophils in the lungs of asthma-induced mice pre-treated with sea cucumber extract was significantly decreased compared to that of PBS pre-treated mice. Additionally, CD4[Formula: see text]CD25[Formula: see text]Foxp3[Formula: see text]T (regulatory T; Treg) cells significantly increased in mesenteric lymph nodes after 7 administrations of the extract. These results suggest that sea cucumber extract can ameliorate allergic airway inflammation via Treg cell activation and recruitment to the lung.

Orosomucoid-like 3 (ORMDL3) upregulates airway smooth muscle proliferation, contraction, and Ca2+ oscillations in asthma.

PubMed

Chen, Jun; Miller, Marina; Unno, Hirotoshi; Rosenthal, Peter; Sanderson, Michael J; Broide, David H

2017-09-07

Airway hyperresponsiveness is a major feature of asthma attributed predominantly to an extrinsic immune/inflammatory response increasing airway smooth muscle (ASM) contractility. We investigated whether increased ASM expression of orosomucoid-like 3 (ORMDL3), a gene on chromosome 17q21 highly linked to asthma, induced increased ASM proliferation and contractility in vitro and influenced airway contractility and calcium flux in ASM in precision-cut lung slices (PCLSs) from wild-type and hORMDL3 Zp3-Cre mice (which express increased levels of human ORMDL3 [hORMDL3]). Levels of ASM proliferation and contraction were assessed in ASM cells transfected with ORMDL3 in vitro. In addition, airway contractility and calcium oscillations were quantitated in ASM cells in PCLSs derived from naive wild-type and naive hORMDL3 Zp3-Cre mice, which do not have a blood supply. Increased ASM expression of ORMDL3 in vitro resulted in increased ASM proliferation and contractility. PCLSs derived from naive hORMDL3 Zp3-Cre mice, which do not have airway inflammation, exhibit increased airway contractility with increased calcium oscillations in ASM cells. Increased ASM ORMDL3 expression increases levels of ASM sarcoplasmic reticulum Ca 2+ ATPase 2b (SERCA2b), which increases ASM proliferation and contractility. Overall, these studies provide evidence that an intrinsic increase in ORMDL3 expression in ASM can induce increased ASM proliferation and contractility, which might contribute to increased airway hyperresponsiveness in the absence of airway inflammation in asthmatic patients. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Respiratory health of elite athletes - preventing airway injury: a critical review.

PubMed

Kippelen, Pascale; Fitch, Kenneth D; Anderson, Sandra Doreen; Bougault, Valerie; Boulet, Louis-Philippe; Rundell, Kenneth William; Sue-Chu, Malcolm; McKenzie, Donald C

2012-06-01

Elite athletes, particularly those engaged in endurance sports and those exposed chronically to airborne pollutants/irritants or allergens, are at increased risk for upper and lower airway dysfunction. Airway epithelial injury may be caused by dehydration and physical stress applied to the airways during severe exercise hyperpnoea and/or by inhalation of noxious agents. This is thought to initiate an inflammatory cascade/repair process that, ultimately, could lead to airway hyperresponsiveness (AHR) and asthma in susceptible athletes. The authors review the evidence relating to prevention or reduction of the risk of AHR/asthma development. Appropriate measures should be implemented when athletes exercise strenuously in an attempt to attenuate the dehydration stress and reduce the exposure to noxious airborne agents. Environmental interventions are the most important. Non-pharmacological strategies can assist, but currently, pharmacological measures have not been demonstrated to be effective. Whether early prevention of airway injury in elite athletes can prevent or reduce progression to AHR/asthma remains to be established.

The relationship between bronchial hyperresponsiveness to methacholine and airway smooth muscle structure and reactivity.

PubMed

Armour, C L; Black, J L; Berend, N; Woolcock, A J

1984-11-01

The airway responsiveness of a group of 25 patients scheduled for lung resection was studied. 10 of 25 patients had a greater than or equal to 20% fall in FEV1 in response to inhaled methacholine (responders), with PD20 FEV1 values ranging from 0.6 to 7.3 mumol. Methacholine did not induce a 20% fall in FEV1 in 15 patients (non-responders). The sensitivity to carbachol and histamine of the bronchial smooth muscle resected from these patients was similar in tissue from responders and non-responders. There was no correlation between in vivo responsiveness to methacholine and in vitro sensitivity to carbachol or histamine. The volume of smooth muscle in some of these airway preparations was quantitated. There was a significant correlation between the maximum tension change in response to histamine and the volume of smooth muscle in each airway. There was no similar correlation for carbachol. The in vivo responsiveness to methacholine and in vitro sensitivity to histamine or carbachol was not related to the degree of inflammation in the airways studied. It is concluded that in vivo responsiveness cannot be explained in terms of smooth muscle sensitivity and that there may be differences between histamine and carbachol in the mechanism of contraction of airway smooth muscle.

Airway epithelial SPDEF integrates goblet cell differentiation and pulmonary Th2 inflammation

PubMed Central

Rajavelu, Priya; Chen, Gang; Xu, Yan; Kitzmiller, Joseph A.; Korfhagen, Thomas R.; Whitsett, Jeffrey A.

2015-01-01

Epithelial cells that line the conducting airways provide the initial barrier and innate immune responses to the abundant particles, microbes, and allergens that are inhaled throughout life. The transcription factors SPDEF and FOXA3 are both selectively expressed in epithelial cells lining the conducting airways, where they regulate goblet cell differentiation and mucus production. Moreover, these transcription factors are upregulated in chronic lung disorders, including asthma. Here, we show that expression of SPDEF or FOXA3 in airway epithelial cells in neonatal mice caused goblet cell differentiation, spontaneous eosinophilic inflammation, and airway hyperresponsiveness to methacholine. SPDEF expression promoted DC recruitment and activation in association with induction of Il33, Csf2, thymic stromal lymphopoietin (Tslp), and Ccl20 transcripts. Increased Il4, Il13, Ccl17, and Il25 expression was accompanied by recruitment of Th2 lymphocytes, group 2 innate lymphoid cells, and eosinophils to the lung. SPDEF was required for goblet cell differentiation and pulmonary Th2 inflammation in response to house dust mite (HDM) extract, as both were decreased in neonatal and adult Spdef–/– mice compared with control animals. Together, our results indicate that SPDEF causes goblet cell differentiation and Th2 inflammation during postnatal development and is required for goblet cell metaplasia and normal Th2 inflammatory responses to HDM aeroallergen. PMID:25866971

Exercise training attenuated chronic cigarette smoking-induced up-regulation of FIZZ1/RELMα in lung of rats.

PubMed

Ma, Wan-li; Cai, Peng-cheng; Xiong, Xian-zhi; Ye, Hong

2013-02-01

FIZZ/RELM is a new gene family named "found in inflammatory zone" (FIZZ) or "resistin-like molecule" (RELM). FIZZ1/RELMα is specifically expressed in lung tissue and associated with pulmonary inflammation. Chronic cigarette smoking up-regulates FIZZ1/RELMα expression in rat lung tissues, the mechanism of which is related to cigarette smoking-induced airway hyperresponsiveness. To investigate the effect of exercise training on chronic cigarette smoking-induced airway hyperresponsiveness and up-regulation of FIZZ1/RELMα, rat chronic cigarette smoking model was established. The rats were treated with regular exercise training and their airway responsiveness was measured. Hematoxylin and eosin (HE) staining, immunohistochemistry and in situ hybridization of lung tissues were performed to detect the expression of FIZZ1/RELMα. Results revealed that proper exercise training decreased airway hyperresponsiveness and pulmonary inflammation in rat chronic cigarette smoking model. Cigarette smoking increased the mRNA and protein levels of FIZZ1/RELMα, which were reversed by the proper exercise. It is concluded that proper exercise training prevents up-regulation of FIZZ1/RELMα induced by cigarette smoking, which may be involved in the mechanism of proper exercise training modulating airway hyperresponsiveness.

Dimethylthiourea protects against chlorine induced changes in airway function in a murine model of irritant induced asthma.

PubMed

McGovern, Toby K; Powell, William S; Day, Brian J; White, Carl W; Govindaraju, Karuthapillai; Karmouty-Quintana, Harry; Lavoie, Normand; Tan, Ju Jing; Martin, James G

2010-10-06

Exposure to chlorine (Cl2) causes airway injury, characterized by oxidative damage, an influx of inflammatory cells and airway hyperresponsiveness. We hypothesized that Cl2-induced airway injury may be attenuated by antioxidant treatment, even after the initial injury. Balb/C mice were exposed to Cl2 gas (100 ppm) for 5 mins, an exposure that was established to alter airway function with minimal histological disruption of the epithelium. Twenty-four hours after exposure to Cl2, airway responsiveness to aerosolized methacholine (MCh) was measured. Bronchoalveolar lavage (BAL) was performed to determine inflammatory cell profiles, total protein, and glutathione levels. Dimethylthiourea (DMTU;100 mg/kg) was administered one hour before or one hour following Cl2 exposure. Mice exposed to Cl2 had airway hyperresponsiveness to MCh compared to control animals pre-treated and post-treated with DMTU. Total cell counts in BAL fluid were elevated by Cl2 exposure and were not affected by DMTU treatment. However, DMTU-treated mice had lower protein levels in the BAL than the Cl2-only treated animals. 4-Hydroxynonenal analysis showed that DMTU given pre- or post-Cl2 prevented lipid peroxidation in the lung. Following Cl2 exposure glutathione (GSH) was elevated immediately following exposure both in BAL cells and in fluid and this change was prevented by DMTU. GSSG was depleted in Cl2 exposed mice at later time points. However, the GSH/GSSG ratio remained high in chlorine exposed mice, an effect attenuated by DMTU. Our data show that the anti-oxidant DMTU is effective in attenuating Cl2 induced increase in airway responsiveness, inflammation and biomarkers of oxidative stress.

Fisetin, a bioactive flavonol, attenuates allergic airway inflammation through negative regulation of NF-κB.

PubMed

Goh, Fera Y; Upton, Nadine; Guan, Shouping; Cheng, Chang; Shanmugam, Muthu K; Sethi, Gautam; Leung, Bernard P; Wong, W S Fred

2012-03-15

Persistent activation of nuclear factor-κB (NF-κB) has been associated with the development of asthma. Fisetin (3,7,3',4'-tetrahydroxyflavone), a naturally occurring bioactive flavonol, has been shown to inhibit NF-κB activity. We hypothesized that fisetin may attenuate allergic asthma via negative regulation of the NF-κB activity. Female BALB/c mice sensitized and challenged with ovalbumin developed airway inflammation. Bronchoalveolar lavage fluid was assessed for total and differential cell counts, and cytokine and chemokine levels. Lung tissues were examined for cell infiltration and mucus hypersecretion, and the expression of inflammatory biomarkers. Airway hyperresponsiveness was monitored by direct airway resistance analysis. Fisetin dose-dependently inhibited ovalbumin-induced increases in total cell count, eosinophil count, and IL-4, IL-5 and IL-13 levels recovered in bronchoalveolar lavage fluid. It attenuated ovalbumin-induced lung tissue eosinophilia and airway mucus production, mRNA expression of adhesion molecules, chitinase, IL-17, IL-33, Muc5ac and inducible nitric oxide synthase in lung tissues, and airway hyperresponsiveness to methacholine. Fisetin blocked NF-κB subunit p65 nuclear translocation and DNA-binding activity in the nuclear extracts from lung tissues of ovalbumin-challenged mice. In normal human bronchial epithelial cells, fisetin repressed TNF-α-induced NF-κB-dependent reporter gene expression. Our findings implicate a potential therapeutic value of fisetin in the treatment of asthma through negative regulation of NF-κB pathway. Copyright © 2012 Elsevier B.V. All rights reserved.

Respiratory health of elite athletes – preventing airway injury: a critical review

PubMed Central

Kippelen, Pascale; Fitch, Kenneth D; Anderson, Sandra Doreen; Bougault, Valerie; Boulet, Louis-Philippe; Rundell, Kenneth William; Sue-Chu, Malcolm; McKenzie, Donald C

2012-01-01

Elite athletes, particularly those engaged in endurance sports and those exposed chronically to airborne pollutants/irritants or allergens, are at increased risk for upper and lower airway dysfunction. Airway epithelial injury may be caused by dehydration and physical stress applied to the airways during severe exercise hyperpnoea and/or by inhalation of noxious agents. This is thought to initiate an inflammatory cascade/repair process that, ultimately, could lead to airway hyperresponsiveness (AHR) and asthma in susceptible athletes. The authors review the evidence relating to prevention or reduction of the risk of AHR/asthma development. Appropriate measures should be implemented when athletes exercise strenuously in an attempt to attenuate the dehydration stress and reduce the exposure to noxious airborne agents. Environmental interventions are the most important. Non-pharmacological strategies can assist, but currently, pharmacological measures have not been demonstrated to be effective. Whether early prevention of airway injury in elite athletes can prevent or reduce progression to AHR/asthma remains to be established. PMID:22522585

Effects of Ginger and Its Constituents on Airway Smooth Muscle Relaxation and Calcium Regulation

PubMed Central

Siviski, Matthew E.; Zhang, Yi; Xu, Carrie; Hoonjan, Bhupinder; Emala, Charles W.

2013-01-01

The prevalence of asthma has increased in recent years, and is characterized by airway hyperresponsiveness and inflammation. Many patients report using alternative therapies to self-treat asthma symptoms as adjuncts to short-acting and long-acting β-agonists and inhaled corticosteroids (ICS). As many as 40% of patients with asthma use herbal therapies to manage asthma symptoms, often without proven efficacy or known mechanisms of action. Therefore, investigations of both the therapeutic and possible detrimental effects of isolated components of herbal treatments on the airway are important. We hypothesized that ginger and its active components induce bronchodilation by modulating intracellular calcium ([Ca2+]i) in airway smooth muscle (ASM). In isolated human ASM, ginger caused significant and rapid relaxation. Four purified constituents of ginger were subsequently tested for ASM relaxant properties in both guinea pig and human tracheas: [6]-gingerol, [8]-gingerol, and [6]-shogaol induced rapid relaxation of precontracted ASM (100–300 μM), whereas [10]-gingerol failed to induce relaxation. In human ASM cells, exposure to [6]-gingerol, [8]-gingerol, and [6]-shogaol, but not [10]-gingerol (100 μM), blunted subsequent Ca2+ responses to bradykinin (10 μM) and S-(−)-Bay K 8644 (10 μM). In A/J mice, the nebulization of [8]-gingerol (100 μM), 15 minutes before methacholine challenge, significantly attenuated airway resistance, compared with vehicle. Taken together, these novel data show that ginger and its isolated active components, [6]-gingerol, [8]-gingerol, and [6]-shogaol, relax ASM, and [8]-gingerol attenuates airway hyperresponsiveness, in part by altering [Ca2+]i regulation. These purified compounds may provide a therapeutic option alone or in combination with accepted therapeutics, including β2-agonists, in airway diseases such as asthma. PMID:23065130

Neutrophil hyper-responsiveness in periodontitis.

PubMed

Matthews, J B; Wright, H J; Roberts, A; Ling-Mountford, N; Cooper, P R; Chapple, I L C

2007-08-01

Peripheral neutrophil hyper-responsiveness in chronic periodontitis leads to excessive reactive oxygen species (ROS) production. We aimed to determine whether neutrophil hyper-responsiveness was constitutive or reactive, and to discover the effect of non-surgical therapy. Peripheral blood neutrophils from patients (n = 19), before and 3 months after therapy, and matched control individuals were Fc gamma-receptor-stimulated with/without priming with P. gingivalis and F. nucleatum. Total and extracellular ROS were determined by luminol/isoluminol chemiluminescence. The high total ROS generation of patients' neutrophils compared with that of control individuals (P = 0.016) continued at a reduced level post-therapy (P = 0.059). Reduced activity post-therapy was also seen with priming. Unstimulated total ROS levels did not differ between patients and control individuals before or after therapy. However, the high unstimulated, extracellular ROS production by patients' neutrophils compared with control individuals (P < 0.05) continued post-therapy and was unaffected by priming. Therapy reduced Fc gamma-receptor-stimulated total ROS production, but not unstimulated extracellular radical release, suggesting that constitutive and reactive mechanisms underlie neutrophil hyper-responsiveness.

Propofol inhibits NF-κB activation to ameliorate airway inflammation in ovalbumin (OVA)-induced allergic asthma mice.

PubMed

Zhang, Qiong; Wang, Liangrong; Chen, Baihui; Zhuo, Qian; Bao, Caiying; Lin, Lina

2017-10-01

Propofol, one of the most commonly used intravenous anesthetic agents, has been reported to have anti-inflammatory property. However, the anti-allergic inflammation effect of propofol and its underlying molecular mechanisms have not been elucidated. In the present study, we aim to investigate the roles of NF-kB activation in propofol anti-asthma effect on OVA-induced allergic airway inflammation in mice. In a standard experimental asthma model, Balb/c mice were sensitized with ovalbumin, treated with propofol (50,100,150mg/kg) or a vehicle control 1h before OVA challenge. Blood samples, bronchoalveolar lavage fluid (BALF) and lung tissues were harvested after measurement of airway hyperresponsiveness. Results revealed that propofol not only significantly inhibit airway hyperresponsiveness, but also inhibited the production of Th2 cytokines, NO, Ova-specific IgE and eotaxin. Histological studies indicated that propofol significantly attenuated OVA-induced inflammatory cell infiltration in the peribronchial areas and mucus hypersecretion. Meanwhile, our results indicated that propofol was found to inhibit NF-kB activation in OVA-Induced mice. Furthermore, propofol significantly reduced the TNF-α-induced NF-kB activation in A549 cells. In conclusion, our study suggested that propofol effectively reduced allergic airway inflammation by inhibiting NF-kB activation and could thus be used as a therapy for allergic asthma. Copyright © 2017. Published by Elsevier B.V.

Emerging concepts in smooth muscle contributions to airway structure and function: implications for health and disease

PubMed Central

2016-01-01

Airway structure and function are key aspects of normal lung development, growth, and aging, as well as of lung responses to the environment and the pathophysiology of important diseases such as asthma, chronic obstructive pulmonary disease, and fibrosis. In this regard, the contributions of airway smooth muscle (ASM) are both functional, in the context of airway contractility and relaxation, as well as synthetic, involving production and modulation of extracellular components, modulation of the local immune environment, cellular contribution to airway structure, and, finally, interactions with other airway cell types such as epithelium, fibroblasts, and nerves. These ASM contributions are now found to be critical in airway hyperresponsiveness and remodeling that occur in lung diseases. This review emphasizes established and recent discoveries that underline the central role of ASM and sets the stage for future research toward understanding how ASM plays a central role by being both upstream and downstream in the many interactive processes that determine airway structure and function in health and disease. PMID:27742732

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

PubMed Central

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

2011-01-01

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

Bronchial hyperresponsiveness, word descriptors, and ethnicity: women with mild asthma.

PubMed

Hardie, Grace E; Brown, James K; Gold, Warren M

2012-02-01

Few studies have examined the ethnic differences in symptom reporting and airway hyperresponsiveness (AHR) for women with mild asthma during a methacholine (McH) challenge. The purpose of this sub-analysis was to determine: (1) whether AHR to McH varied by the ethnicity of women with mild asthma and (2) whether ethnic word descriptors (EWDs) varied by the ethnicity during induced bronchoconstriction. Specific inclusion criteria included the following: FEV(1) (forced expiratory volume in 1 second) ≥ 70% predicted normal, PC(30) ≤ 8 mg/McH, β(2) inhaler only, and self-reported ethnicity of African American (AFAM), Mexican American-Hispanic-Latino (MexAMLat), Asian-Pacific Islander (Asian PI), or white. Serial pulmonary function testing (PFT) and Borg, visual analogue scale (VAS), and EWDs were collected. A total of 44 women, mean age of 31.3 years old, with a mean baseline FEV(1) of 2.85 L comprised this sub-analysis. Ethnic-racial diversity included: 12 AFAMs, 5 MexAMLat, 13 Asian-PIs, and 14 whites. All had atopy ≥ 2 pinprick responses of 3 mm. At PC(30), Asian-PI women required a significantly (p < .05) smaller mean dose of McH 1.9 mg/mL. MexAMLat women required an McH dose of 1.6 mg/mL. At PC(30), McH dose was 2.9 mg/mL for AFAMs and 3.0 mg/mL for whites, respectively. Asian-PIs who used only upper airway EWDs at PC(30) vere itchy throat, itchy chin, and constricted throat (p < .001). AFAMs significant EWDs were itchy throat, itchy chin/face, and tight throat (p < .01). Lower airway EWD was used by both MexAMLat and whites. Significant EWD for Whites were tight chest (p < .01) and hard to inhale/lungs tight (p < .001). Asian-PI women required a significantly smaller dose (p < .05) of McH to induce a PC(30). AFAM and whites required a comparable dose of Mch at PC(30). Asian-PI and AFAM women used only upper airway EWD. Asian-PI women may be at a greater risk for acute asthma episodes that are not recognized or treated due to their upper airway symptom

Self-Assembling Nanoparticles Containing Dexamethasone as a Novel Therapy in Allergic Airways Inflammation

PubMed Central

Kenyon, Nicholas J.; Bratt, Jennifer M.; Lee, Joyce; Luo, Juntao; Franzi, Lisa M.; Zeki, Amir A.; Lam, Kit S.

2013-01-01

Nanocarriers can deliver a wide variety of drugs, target them to sites of interest, and protect them from degradation and inactivation by the body. They have the capacity to improve drug action and decrease undesirable systemic effects. We have previously developed a well-defined non-toxic PEG-dendritic block telodendrimer for successful delivery of chemotherapeutics agents and, in these studies, we apply this technology for therapeutic development in asthma. In these proof-of-concept experiments, we hypothesized that dexamethasone contained in self-assembling nanoparticles (Dex-NP) and delivered systemically would target the lung and decrease allergic lung inflammation and airways hyper-responsiveness to a greater degree than equivalent doses of dexamethasone (Dex) alone. We found that ovalbumin (Ova)-exposed mice treated with Dex-NP had significantly fewer total cells (2.78±0.44×105 (n = 18) vs. 5.98±1.3×105 (n = 13), P<0.05) and eosinophils (1.09±0.28×105 (n = 18) vs. 2.94±0.6×105 (n = 12), p<0.05) in the lung lavage than Ova-exposed mice alone. Also, lower levels of the inflammatory cytokines IL-4 (3.43±1.2 (n = 11) vs. 8.56±2.1 (n = 8) pg/ml, p<0.05) and MCP-1 (13.1±3.6 (n = 8) vs. 28.8±8.7 (n = 10) pg/ml, p<0.05) were found in lungs of the Dex-NP compared to control, and they were not lower in the Dex alone group. In addition, respiratory system resistance was lower in the Dex-NP compared to the other Ova-exposed groups suggesting a better therapeutic effect on airways hyperresponsiveness. Taken together, these findings from early-stage drug development studies suggest that the encapsulation and protection of anti-inflammatory agents such as corticosteroids in nanoparticle formulations can improve efficacy. Further development of novel drugs in nanoparticles is warranted to explore potential treatments for chronic inflammatory diseases such as asthma. PMID:24204939

Role of substance P and neurokinin A in toluene diisocyanate-induced increased airway responsiveness in rabbits.

PubMed

Marek, W; Potthast, J J; Marcynski, B; Baur, X

1996-01-01

The aim of the present study was to examine the role of neuropeptides, especially substance P (SP) and neurokinin A (NKA), in toluene diisocyanate (TDI)-induced airway hyperresponsiveness (AHR) to acetylcholine aerosols. Thirty parts per billion of TDI in air administered over 4 hours caused a significant increase in the airway constrictive response to acetylcholine (ACH) aerosols in rabbits (DeltaRI: 245 +/- 30%, p < 0.005) without altering basic values of respiratory, cardiovascular or blood gas parameters. Inhalation of the aerosolized neuropeptides SP and NKA resulted in a similar increase in airway responsiveness (AR) to ACH as exposure to 30 ppb TDI. To determine whether neuropeptides contribute to TDI-induced AHR, we studied their effects after systemic treatment with capsaicin as well as after infusion of specific synthetic antagonists for SP and NK2 (NKA) receptors. CAPS treatment performed on 4 consecutive days as well as antagonists' infusion only moderately (p > 0.05) decreased airway responses to ACH. CAPS application prevented the TDI-induced increase in AR to ACH in all rabbits. The increase in airway resistance to ACH did not significantly change after TDI exposure (98 +/- 22% of the control response before TDI, p > 0.05). Simultaneous infusion of specific synthetic SP and NK2 receptor antagonists also abolished the TDI-induced increase in airway responses to ACH in all animals investigated (p > 0.05). The results of this study demonstrate that neuropeptides, especially the tachykinins SP and NKA, are important mediators in TDI-induced AHR in rabbits.

The Pivotal Role of Airway Smooth Muscle in Asthma Pathophysiology

PubMed Central

Ozier, Annaïg; Allard, Benoit; Bara, Imane; Girodet, Pierre-Olivier; Trian, Thomas; Marthan, Roger; Berger, Patrick

2011-01-01

Asthma is characterized by the association of airway hyperresponsiveness (AHR), inflammation, and remodelling. The aim of the present article is to review the pivotal role of airway smooth muscle (ASM) in the pathophysiology of asthma. ASM is the main effector of AHR. The mechanisms of AHR in asthma may involve a larger release of contractile mediators and/or a lower release of relaxant mediators, an improved ASM cell excitation/contraction coupling, and/or an alteration in the contraction/load coupling. Beyond its contractile function, ASM is also involved in bronchial inflammation and remodelling. Whereas ASM is a target of the inflammatory process, it can also display proinflammatory and immunomodulatory functions, through its synthetic properties and the expression of a wide range of cell surface molecules. ASM remodelling represents a key feature of asthmatic bronchial remodelling. ASM also plays a role in promoting complementary airway structural alterations, in particular by its synthetic function. PMID:22220184

What evidence implicates airway smooth muscle in the cause of BHR?

PubMed

Dulin, Nickolai O; Fernandes, Darren J; Dowell, Maria; Bellam, Shashi; McConville, John; Lakser, Oren; Mitchell, Richard; Camoretti-Mercado, Blanca; Kogut, Paul; Solway, Julian

2003-02-01

Bronchial hyperresponsiveness (BHR), the occurrence of excessive bronchoconstriction in response to relatively small constrictor stimuli, is a cardinal feature of asthma. Here, we consider the role that airway smooth muscle might play in the generation of BHR. The weight of evidence suggests that smooth muscle isolated from asthmatic tissues exhibits normal sensitivity to constrictor agonists when studied during isometric contraction, but the increased muscle mass within asthmatic airways might generate more total force than the lesser amount of muscle found in normal bronchi. Another salient difference between asthmatic and normal individuals lies in the effect of deep inhalation (DI) on bronchoconstriction. DI often substantially reverses induced bronchoconstriction in normals, while it often has much less effect on spontaneous or induced bronchoconstriction in asthmatics. It has been proposed that abnormal dynamic aspects of airway smooth muscle contraction velocity of contraction or plasticity- elasticity balance might underlie the abnormal DI response in asthma. We suggest a speculative model in which abnormally long actin filaments might account for abnormally increased elasticity of contracted airway smooth muscle.

Endocrine regulation of airway contractility is overlooked.

PubMed

Bossé, Ynuk

2014-08-01

Asthma is a prevalent respiratory disorder triggered by a variety of inhaled environmental factors, such as allergens, viruses, and pollutants. Asthma is characterized by an elevated activation of the smooth muscle surrounding the airways, as well as a propensity of the airways to narrow excessively in response to a spasmogen (i.e. contractile agonist), a feature called airway hyperresponsiveness. The level of airway smooth muscle (ASM) activation is putatively controlled by mediators released in its vicinity. In asthma, many mediators that affect ASM contractility originate from inflammatory cells that are mobilized into the airways, such as eosinophils. However, mounting evidence indicates that mediators released by remote organs can also influence the level of activation of ASM, as well as its level of responsiveness to spasmogens and relaxant agonists. These remote mediators are transported through circulating blood to act either directly on ASM or indirectly via the nervous system by tuning the level of cholinergic activation of ASM. Indeed, mediators generated from diverse organs, including the adrenals, pancreas, adipose tissue, gonads, heart, intestines, and stomach, affect the contractility of ASM. Together, these results suggest that, apart from a paracrine mode of regulation, ASM is subjected to an endocrine mode of regulation. The results also imply that defects in organs other than the lungs can contribute to asthma symptoms and severity. In this review, I suggest that the endocrine mode of regulation of ASM contractility is overlooked. © 2014 Society for Endocrinology.

STAT6 inhibitory peptide given during RSV infection of neonatal mice reduces exacerbated airway responses upon adult reinfection.

PubMed

Srinivasa, Bharat T; Restori, Katherine H; Shan, Jichuan; Cyr, Louis; Xing, Li; Lee, Soojin; Ward, Brian J; Fixman, Elizabeth D

2017-02-01

Respiratory syncytial virus (RSV)-related hospitalization during infancy is strongly associated with the subsequent development of asthma. Early life RSV infection results in a Th2-biased immune response, which is also typical of asthma. Murine models of neonatal RSV infection have been developed to examine the possible contribution of RSV-driven Th2 responses to the development of airway hyper-responsiveness later in childhood. We have investigated the ability of a cell-penetrating STAT6 inhibitory peptide (STAT6-IP), when delivered selectively during neonatal RSV infection, to modify pathogenesis induced upon secondary RSV reinfection of adults 6 wk later. Neonatal STAT6-IP treatment inhibited the development of airway hyper-responsiveness (AHR) and significantly reduced lung eosinophilia and collagen deposition in adult mice following RSV reinfection. STAT6-IP-treated, RSV-infected neonates had reduced levels of both IL-4 and alternatively activated macrophages (AAMs) in the lungs. Our findings suggest that targeting STAT6 activity at the time of early-life RSV infection may effectively reduce the risk of subsequent asthma development. © Society for Leukocyte Biology.

Ionotropic and metabotropic proton-sensing receptors involved in airway inflammation in allergic asthma.

PubMed

Aoki, Haruka; Mogi, Chihiro; Okajima, Fumikazu

2014-01-01

An acidic microenvironment has been shown to evoke a variety of airway responses, including cough, bronchoconstriction, airway hyperresponsiveness (AHR), infiltration of inflammatory cells in the lung, and stimulation of mucus hyperproduction. Except for the participation of transient receptor potential vanilloid-1 (TRPV1) and acid-sensing ion channels (ASICs) in severe acidic pH (of less than 6.0)-induced cough and bronchoconstriction through sensory neurons, the molecular mechanisms underlying extracellular acidic pH-induced actions in the airways have not been fully understood. Recent studies have revealed that ovarian cancer G protein-coupled receptor 1 (OGR1)-family G protein-coupled receptors, which sense pH of more than 6.0, are expressed in structural cells, such as airway smooth muscle cells and epithelial cells, and in inflammatory and immune cells, such as eosinophils and dendritic cells. They function in a variety of airway responses related to the pathophysiology of inflammatory diseases, including allergic asthma. In the present review, we discuss the roles of ionotropic TRPV1 and ASICs and metabotropic OGR1-family G protein-coupled receptors in the airway inflammation and AHR in asthma and respiratory diseases.

Effects of the calcium ionophore A23187 on airway responsiveness to histamine and substance P in guinea pigs.

PubMed

Uno, D; Tsukagoshi, H; Hisada, T; Iwamae, S; Mori, M

1997-03-01

We evaluated the mechanism of the airway hyperresponsiveness (AHR) induced by a calcium ionophore in guinea pigs. Airway responsiveness to intravenous histamine (HS) and substance P (SP) was measured 24 h after a 1-h exposure to aerosolized A23187 (0.03 or 0.1 mg/ml) or its vehicle (10% DMSO). Changes were assessed by calculating -logPC350HS and logPC350SP. Neutral endopeptidase (NEP) activity in the airway tissues, as well as the nitrite (NO2) levels and the cell population in bronchoalveolar lavage fluid (BALF) was determined after measurement of pulmonary function. Changes in SP-induced vascular permeability 24 h after exposure to A23187 were measured by the Evans Blue dye extravasation technique. Exposure to A23187 caused a significant AHR to SP, along with a significant increase in the number of neutrophils and epithelial cells in the BALF. While there was no significant change in NEP activity in the airway tissues, the levels of nitrite in the BALF were significantly decreased in A23187-exposed animals. Significant correlations were found between the number of epithelial cells in the BALF and logPC350SP (r = 0.477, p < 0.05) and between nitrite levels in the BALF and -logPC350SP (r = 0.491, p < 0.05) A23187 exposure did not significantly change the SP-induced airway microvascular leakage. These data suggest that A23187 exposure induced AHR to SP possibly by reducing NO levels in the airway tissues. This may be due to damaged airway epithelium and/or NO breakdown by activated inflammatory cells in the airways of these guinea pigs.

MicroRNA-142 Inhibits Proliferation and Promotes Apoptosis in Airway Smooth Muscle Cells During Airway Remodeling in Asthmatic Rats via the Inhibition of TGF-β -Dependent EGFR Signaling Pathway.

PubMed

Wang, Jing; Wang, Hu-Shan; Su, Zhen-Bo

2018-06-27

Asthma is a heterogeneous disease characterized by chronic airway inflammation resulting from airway hyper-responsiveness to diverse stimuli. In this study, we investigated whether microRNA-142 (miR-142) expression affects proliferation and apoptosis in airway smooth muscle cells (ASMCs) during airway remodeling in asthmatic rats. Thirty six Wistar rats were randomly classified into a control group and an model group. miR-142 mimics and inhibitors were constructed, and ASMCs were transfected using liposomes according to the following groups: blank, negative control (NC), miR-142 mimics, miR-142 inhibitors, si-TGF-β and miR-142 inhibitors + si-TGF-β. We verified that miR-142 targets TGF-β using a dual-luciferase reporter assay. The expression levels of miR-142, TGF-β, EGFR and apoptosis signaling pathway-related genes were determined using RT-qPCR and western blotting. Changes in cell proliferation, cell cycle progression and apoptosis were analyzed using MTT assays and flow cytometry. Rats with asthma had higher expression levels of EGFR and Akt and lower miR-142 levels. miR-142 was negatively correlated with TGF-β expression. In ASMCs, the expression of TGF-β, EGFR, Akt, phosphorylated-Akt (p-Akt), Bcl-2 and Bcl-xl and the rate of early apoptosis were decreased while expression of Bax and p21 and the proliferation rate were elevated with the upregulation of miR-142. The opposite results were observed with the downregulation of miR-142. Finally, the proliferative rate was decreased while the apoptosis rate was increased and expression levels of EGFR, Akt, p-Akt, Bcl-2 and Bcl-xl were reduced while Bax and p21 were elevated in the ASMCs transfected with miR-142 inhibitors and si-TGF-β. The results of our study suggest that miR-142 inhibits proliferation and promotes apoptosis in ASMCs during airway remodeling in asthmatic rats by inhibiting TGF-β expression via a mechanism involving the EGFR signaling pathway. © 2018 The Author(s). Published by S. Karger AG

A liver-X-receptor ligand, T0901317, attenuates IgE production and airway remodeling in chronic asthma model of mice.

PubMed

Shi, Ying; Xu, Xiantao; Tan, Yan; Mao, Shan; Fang, Surong; Gu, Wei

2014-01-01

The liver-X-receptors have shown anti-inflammatory ability in several animal models of respiratory disease. Our purpose is to investigate the effect of LXR ligand in allergen-induced airway remodeling in mice. Ovalbumin-sensitized mice were chronically challenged with aerosolized ovalbumin for 8 weeks. Some mice were administered a LXR agonist, T0901317 (12.5, 25, 50 mg/kg bodyweight) before challenge. Then mice were evaluated for airway inflammation, airway hyperresponsiveness and airway remodeling. T0901317 failed to attenuate the inflammatory cells and Th2 cytokines in bronchoalveolar lavage fluid. But the application of T0901317 reduced the thickness of airway smooth muscle and the collagen deposition. Meanwhile, T0901317 treatment evidently abolished the high level of OVA-specific IgE, TGF-β1 and MMP-9 in lung. So LXRs may attenuate the progressing of airway remodeling, providing a potential treatment of asthma.

Static and dynamic stress heterogeneity in a multiscale model of the asthmatic airway wall

PubMed Central

Hiorns, J. E.

2016-01-01

Airway hyperresponsiveness (AHR) is a key characteristic of asthma that remains poorly understood. Tidal breathing and deep inspiration ordinarily cause rapid relaxation of airway smooth muscle (ASM) (as demonstrated via application of length fluctuations to tissue strips) and are therefore implicated in modulation of AHR, but in some cases (such as application of transmural pressure oscillations to isolated intact airways) this mechanism fails. Here we use a multiscale biomechanical model for intact airways that incorporates strain stiffening due to collagen recruitment and dynamic force generation by ASM cells to show that the geometry of the airway, together with interplay between dynamic active and passive forces, gives rise to large stress and compliance heterogeneities across the airway wall that are absent in tissue strips. We show further that these stress heterogeneities result in auxotonic loading conditions that are currently not replicated in tissue-strip experiments; stresses in the strip are similar to hoop stress only at the outer airway wall and are under- or overestimates of stresses at the lumen. Taken together these results suggest that a previously underappreciated factor, stress heterogeneities within the airway wall and consequent ASM cellular response to this micromechanical environment, could contribute to AHR and should be explored further both theoretically and experimentally. PMID:27197860

Evidence-based hypnotherapy for asthma: a critical review.

PubMed

Brown, Daniel

2007-04-01

Asthma is a chronic disease with intermittent acute exacerbations, characterized by obstructed airways, hyper-responsiveness, and sometimes by chronic airway inflammation. Critically reviewing evidence primarily from controlled outcome studies on hypnosis for asthma shows that hypnosis is possibly efficacious for treatment of symptom severity and illness-related behaviors and is efficacious for managing emotional states that exacerbate airway obstruction. Hypnosis is also possibly efficacious for decreasing airway obstruction and stabilizing airway hyper-responsiveness in some individuals, but there is insufficient evidence that hypnosis affects asthma's inflammatory process. Promising research needs to be replicated with larger samples and better designs with careful attention paid to the types of hypnotic suggestions given. The critical issue is not so much whether it is used but how it is used. Future outcome research must address the relative contribution of expectancies, hypnotizability, hypnotic induction, and specific suggestions.

NK cells contribute to persistent airway inflammation and AHR during the later stage of RSV infection in mice.

PubMed

Long, Xiaoru; Xie, Jun; Zhao, Keting; Li, Wei; Tang, Wei; Chen, Sisi; Zang, Na; Ren, Luo; Deng, Yu; Xie, Xiaohong; Wang, Lijia; Fu, Zhou; Liu, Enmei

2016-10-01

RSV can lead to persistent airway inflammation and AHR and is intimately associated with childhood recurrent wheezing and asthma, but the underlying mechanisms remain unclear. There are high numbers of NK cells in the lung, which not only play important roles in the acute stage of RSV infection, but also are pivotal in regulating the pathogenesis of asthma. Therefore, in this study, we assumed that NK cells might contribute to persistent airway disease during the later stage of RSV infection. Mice were killed at serial time points after RSV infection to collect samples. Leukocytes in bronchoalveolar lavage fluid (BALF) were counted, lung histopathology was examined, and airway hyperresponsiveness (AHR) was measured by whole-body plethysmography. Cytokines were detected by ELISA, and NK cells were determined by flow cytometry. Rabbit anti-mouse asialo-GM-1 antibodies and resveratrol were used to deplete or suppress NK cells. Inflammatory cells in BALF, lung tissue damage and AHR were persistent for 60 days post-RSV infection. Type 2 cytokines and NK cells were significantly increased during the later stage of infection. When NK cells were decreased by the antibodies or resveratrol, type 2 cytokines, the persistent airway inflammation and AHR were all markedly reduced. NK cells can contribute to the RSV-associated persistent airway inflammation and AHR at least partially by promoting type 2 cytokines. Therefore, therapeutic targeting of NK cells may provide a novel approach to alleviating the recurrent wheezing subsequent to RSV infection.

Adenosine Triphosphate Promotes Allergen-Induced Airway Inflammation and Th17 Cell Polarization in Neutrophilic Asthma.

PubMed

Zhang, Fang; Su, Xin; Huang, Gang; Xin, Xiao-Feng; Cao, E-Hong; Shi, Yi; Song, Yong

2017-01-01

Adenosine triphosphate (ATP) is a key mediator to alert the immune dysfunction by acting on P2 receptors. Here, we found that allergen challenge caused an increase of ATP secretion in a murine model of neutrophilic asthma, which correlated well with neutrophil counts and interleukin-17 production. When ATP signaling was blocked by intratracheal administration of the ATP receptor antagonist suramin before challenge, neutrophilic airway inflammation, airway hyperresponsiveness, and Th17-type responses were reduced significantly. Also, neutrophilic inflammation was abrogated when airway ATP levels were locally neutralized using apyrase. Furthermore, ATP promoted the Th17 polarization of splenic CD4 + T cells from DO11.10 mice in vitro. In addition, ovalbumin (OVA) challenge induced neutrophilic inflammation and Th17 polarization in DO11.10 mice, whereas administration of suramin before challenge alleviated these parameters. Thus, ATP may serve as a marker of neutrophilic asthma, and local blockade of ATP signaling might provide an alternative method to prevent Th17-mediated airway inflammation in neutrophilic asthma.

Calcium-activated chloride channel TMEM16A modulates mucin secretion and airway smooth muscle contraction.

PubMed

Huang, Fen; Zhang, Hongkang; Wu, Meng; Yang, Huanghe; Kudo, Makoto; Peters, Christian J; Woodruff, Prescott G; Solberg, Owen D; Donne, Matthew L; Huang, Xiaozhu; Sheppard, Dean; Fahy, John V; Wolters, Paul J; Hogan, Brigid L M; Finkbeiner, Walter E; Li, Min; Jan, Yuh-Nung; Jan, Lily Yeh; Rock, Jason R

2012-10-02

Mucous cell hyperplasia and airway smooth muscle (ASM) hyperresponsiveness are hallmark features of inflammatory airway diseases, including asthma. Here, we show that the recently identified calcium-activated chloride channel (CaCC) TMEM16A is expressed in the adult airway surface epithelium and ASM. The epithelial expression is increased in asthmatics, particularly in secretory cells. Based on this and the proposed functions of CaCC, we hypothesized that TMEM16A inhibitors would negatively regulate both epithelial mucin secretion and ASM contraction. We used a high-throughput screen to identify small-molecule blockers of TMEM16A-CaCC channels. We show that inhibition of TMEM16A-CaCC significantly impairs mucus secretion in primary human airway surface epithelial cells. Furthermore, inhibition of TMEM16A-CaCC significantly reduces mouse and human ASM contraction in response to cholinergic agonists. TMEM16A-CaCC blockers, including those identified here, may positively impact multiple causes of asthma symptoms.

Development and maintenance of force and stiffness in airway smooth muscle.

PubMed

Lan, Bo; Norris, Brandon A; Liu, Jeffrey C-Y; Paré, Peter D; Seow, Chun Y; Deng, Linhong

2015-03-01

Airway smooth muscle (ASM) plays a central role in the excessive narrowing of the airway that characterizes the primary functional impairment in asthma. This phenomenon is known as airway hyper-responsiveness (AHR). Emerging evidence suggests that the development and maintenance of ASM force involves dynamic reorganization of the subcellular filament network in both the cytoskeleton and the contractile apparatus. In this review, evidence is presented to support the view that regulation of ASM contraction extends beyond the classical actomyosin interaction and involves processes within the cytoskeleton and at the interfaces between the cytoskeleton, the contractile apparatus, and the extracellular matrix. These processes are initiated when the muscle is activated, and collectively they cause the cytoskeleton and the contractile apparatus to undergo structural transformation, resulting in a more connected and solid state that allows force generated by the contractile apparatus to be transmitted to the extracellular domain. Solidification of the cytoskeleton also serves to stiffen the muscle and hence the airway. Oscillatory strain from tidal breathing and deep inspiration is believed to be the counter balance that prevents hypercontraction and stiffening of ASM in vivo. Dysregulation of this balance could lead to AHR seen in asthma.

Identification of genes differentially regulated by vitamin D deficiency that alter lung pathophysiology and inflammation in allergic airways disease.

PubMed

Foong, Rachel E; Bosco, Anthony; Troy, Niamh M; Gorman, Shelley; Hart, Prue H; Kicic, Anthony; Zosky, Graeme R

2016-09-01

Vitamin D deficiency is associated with asthma risk. Vitamin D deficiency may enhance the inflammatory response, and we have previously shown that airway remodeling and airway hyperresponsiveness is increased in vitamin D-deficient mice. In this study, we hypothesize that vitamin D deficiency would exacerbate house dust mite (HDM)-induced inflammation and alterations in lung structure and function. A BALB/c mouse model of vitamin D deficiency was established by dietary manipulation. Responsiveness to methacholine, airway smooth muscle (ASM) mass, mucus cell metaplasia, lung and airway inflammation, and cytokines in bronchoalveolar lavage (BAL) fluid were assessed. Gene expression patterns in mouse lung samples were profiled by RNA-Seq. HDM exposure increased inflammation and inflammatory cytokines in BAL, baseline airway resistance, tissue elastance, and ASM mass. Vitamin D deficiency enhanced the HDM-induced influx of lymphocytes into BAL, ameliorated the HDM-induced increase in ASM mass, and protected against the HDM-induced increase in baseline airway resistance. RNA-Seq identified nine genes that were differentially regulated by vitamin D deficiency in the lungs of HDM-treated mice. Immunohistochemical staining confirmed that protein expression of midline 1 (MID1) and adrenomedullin was differentially regulated such that they promoted inflammation, while hypoxia-inducible lipid droplet-associated, which is associated with ASM remodeling, was downregulated. Protein expression studies in human bronchial epithelial cells also showed that addition of vitamin D decreased MID1 expression. Differential regulation of these genes by vitamin D deficiency could determine lung inflammation and pathophysiology and suggest that the effect of vitamin D deficiency on HDM-induced allergic airways disease is complex. Copyright © 2016 the American Physiological Society.

Effects of Angelicin on Ovalbumin (OVA)-Induced Airway Inflammation in a Mouse Model of Asthma.

PubMed

Wei, Da-Zhen; Guo, Xian-Yang; Lin, Li-Na; Lin, Meng-Xiang; Gong, Yu-Qiang; Ying, Bin-Yu; Huang, Ming-Yuan

2016-12-01

Angelicin, a furocoumarin found in Psoralea corylifolia L. fruit, has been reported to have anti-inflammatory activity. The purpose of this study was to determine the protective effects of angelicin on allergic asthma induced by ovalbumin (OVA) in mice. Mice were sensitized to OVA (on days 0 and 14) and challenged with OVA three times (on days 21 to 23). Angelicin (2.5, 5, 10 mg/kg) was given intraperitoneally 1 h before OVA treatment after the initial OVA sensitization. The production of IL-4, IL-5, and IL-13 in BALF and IgE in the serum were measured by ELISA. Lung histological changes were detected by using hematoxylin and eosin (H&E) stain. The results showed that angelicin significantly inhibited inflammatory cells infiltration into the lungs. Histological studies showed that angelicin significantly attenuated OVA-induced lung injury. Meanwhile, treatment of angelicin dose-dependently inhibited OVA-induced the production of IL-4, IL-5, and IL-13 in BALF and IgE in the serum. Furthermore, angelicin was found to inhibit airway hyperresponsiveness and NF-kB activation. In conclusion, our results suggested that angelicin inhibited allergic airway inflammation and hyperresponsiveness by inhibiting NF-kB activation.

Adam8 Limits the Development of Allergic Airway Inflammation in Mice

PubMed Central

Knolle, Martin D.; Nakajima, Takahiro; Hergrueter, Anja; Gupta, Kushagra; Polverino, Francesca; Craig, Vanessa J.; Fyfe, Susanne E.; Zahid, Muhammad; Permaul, Perdita; Cernadas, Manuela; Montano, Gilbert; Tesfaigzi, Yohannes; Sholl, Lynette; Kobzik, Lester; Israel, Elliot; Owen, Caroline A.

2013-01-01

To determine whether a disintegrin and a metalloproteinase-8 (Adam8) regulates allergic airway inflammation (AAI) and airway hyper-responsiveness (AHR), we compared AAI and AHR in wild type (WT) versus Adam8−/− mice in different genetic backgrounds sensitized and challenged with ovalbumin (OVA) or house dust mite protein extract (HDM). OVA- and HDM-treated Adam8−/− mice had higher lung leukocyte counts, more airway mucus metaplasia, greater lung levels of some TH2 cytokines, and higher methacholine-induced increases in central airway resistance than allergen-treated WT mice. Studies of OVA-treated Adam8 bone marrow chimeric mice confirmed that leukocyte-derived Adam8 predominantly mediated Adam8’s anti-inflammatory activities in murine airways. Airway eosinophils and macrophages both expressed Adam8 in WT mice with AAI. Adam8 limited AAI and AHR in mice by reducing leukocyte survival because: 1) Adam8−/− mice with AAI had fewer apoptotic eosinophils and macrophages in their airways than WT mice with AAI; and 2) Adam8−/− macrophages and eosinophils had reduced rates of apoptosis compared with WT leukocytes when the intrinsic (but not the extrinsic) apoptosis pathway was triggered in the cells in vitro. ADAM8 was robustly expressed by airway granulocytes in lung sections from human asthma patients but, surprisingly, airway macrophages had less ADAM8 staining than airway eosinophils. Thus, ADAM8 has anti-inflammatory activities during AAI in mice by activating the intrinsic apoptosis pathway in myeloid leukocytes. Strategies that increase ADAM8 levels in myeloid leukocytes may have therapeutic efficacy in asthma. PMID:23670189

D-tryptophan from probiotic bacteria influences the gut microbiome and allergic airway disease.

PubMed

Kepert, Inge; Fonseca, Juliano; Müller, Constanze; Milger, Katrin; Hochwind, Kerstin; Kostric, Matea; Fedoseeva, Maria; Ohnmacht, Caspar; Dehmel, Stefan; Nathan, Petra; Bartel, Sabine; Eickelberg, Oliver; Schloter, Michael; Hartmann, Anton; Schmitt-Kopplin, Philippe; Krauss-Etschmann, Susanne

2017-05-01

Chronic immune diseases, such as asthma, are highly prevalent. Currently available pharmaceuticals improve symptoms but cannot cure the disease. This prompted demands for alternatives to pharmaceuticals, such as probiotics, for the prevention of allergic disease. However, clinical trials have produced inconsistent results. This is at least partly explained by the highly complex crosstalk among probiotic bacteria, the host's microbiota, and immune cells. The identification of a bioactive substance from probiotic bacteria could circumvent this difficulty. We sought to identify and characterize a bioactive probiotic metabolite for potential prevention of allergic airway disease. Probiotic supernatants were screened for their ability to concordantly decrease the constitutive CCL17 secretion of a human Hodgkin lymphoma cell line and prevent upregulation of costimulatory molecules of LPS-stimulated human dendritic cells. Supernatants from 13 of 37 tested probiotic strains showed immunoactivity. Bioassay-guided chromatographic fractionation of 2 supernatants according to polarity, followed by total ion chromatography and mass spectrometry, yielded C 11 H 12 N 2 O 2 as the molecular formula of a bioactive substance. Proton nuclear magnetic resonance and enantiomeric separation identified D-tryptophan. In contrast, L-tryptophan and 11 other D-amino acids were inactive. Feeding D-tryptophan to mice before experimental asthma induction increased numbers of lung and gut regulatory T cells, decreased lung T H 2 responses, and ameliorated allergic airway inflammation and hyperresponsiveness. Allergic airway inflammation reduced gut microbial diversity, which was increased by D-tryptophan. D-tryptophan is a newly identified product from probiotic bacteria. Our findings support the concept that defined bacterial products can be exploited in novel preventative strategies for chronic immune diseases. Copyright © 2016. Published by Elsevier Inc.

Role of Rho kinase isoforms in murine allergic airway responses.

PubMed

Zhu, M; Liu, P-Y; Kasahara, D I; Williams, A S; Verbout, N G; Halayko, A J; Fedulov, A; Shoji, T; Williams, E S; Noma, K; Shore, S A; Liao, J K

2011-10-01

Inhibition of Rho-associated coiled-coil forming kinases (ROCKs) reduces allergic airway responses in mice. The purpose of this study was to determine the roles of the two ROCK isoforms, ROCK1 and ROCK2, in these responses. Wildtype (WT) mice and heterozygous ROCK1 and ROCK2 knockout mice (ROCK1(+/-) and ROCK2(+/-), respectively) were sensitised and challenged with ovalbumin. ROCK expression and activation were assessed by western blotting. Airway responsiveness was measured by forced oscillation. Bronchoalveolar lavage was performed and the lungs were fixed for histological assessment. Compared with WT mice, ROCK1 and ROCK2 expression were 50% lower in lungs of ROCK1(+/-) and ROCK2(+/-) mice, respectively, without changes in the other isoform. In WT lungs, ROCK activation increased after ovalbumin challenge and was sustained for several hours. This activation was reduced in ROCK1(+/-) and ROCK2(+/-) lungs. Airway responsiveness was comparable in WT, ROCK1(+/-), and ROCK2(+/-) mice challenged with PBS. Ovalbumin challenge caused airway hyperresponsiveness in WT, but not ROCK1(+/-) or ROCK2(+/-) mice. Lavage eosinophils and goblet cell hyperplasia were significantly reduced in ovalbumin-challenged ROCK1(+/-) and ROCK2(+/-) versus WT mice. Ovalbumin-induced changes in lavage interleukin-13, interleukin-5 and lymphocytes were also reduced in ROCK1(+/-) mice. In conclusion, both ROCK1 and ROCK2 are important in regulating allergic airway responses.

Novel Small Airway Bronchodilator Responses to Rosiglitazone in Mouse Lung Slices

PubMed Central

Bai, Yan; Donovan, Chantal; Esposito, James G.; Tan, Xiahui; Sanderson, Michael J.

2014-01-01

There is a need to identify novel agents that elicit small airway relaxation when β2-adrenoceptor agonists become ineffective in difficult-to-treat asthma. Because chronic treatment with the synthetic peroxisome proliferator activated receptor (PPAR)γ agonist rosiglitazone (RGZ) inhibits airway hyperresponsiveness in mouse models of allergic airways disease, we tested the hypothesis that RGZ causes acute airway relaxation by measuring changes in small airway size in mouse lung slices. Whereas the β-adrenoceptor agonists albuterol (ALB) and isoproterenol induced partial airway relaxation, RGZ reversed submaximal and maximal contraction to methacholine (MCh) and was similarly effective after precontraction with serotonin or endothelin-1. Concentration-dependent relaxation to RGZ was not altered by the β-adrenoceptor antagonist propranolol and was enhanced by ALB. RGZ-induced relaxation was mimicked by other synthetic PPARγ agonists but not by the putative endogenous agonist 15-deoxy-PGJ2 and was not prevented by the PPARγ antagonist GW9662. To induce airway relaxation, RGZ inhibited the amplitude and frequency of MCh-induced Ca2+ oscillations of airway smooth muscle cells (ASMCs). In addition, RGZ reduced MCh-induced Ca2+ sensitivity of the ASMCs. Collectively, these findings demonstrate that acute bronchodilator responses induced by RGZ are PPARγ independent, additive with ALB, and occur by the inhibition of ASMC Ca2+ signaling and Ca2+ sensitivity. Because RGZ continues to elicit relaxation when β-adrenoceptor agonists have a limited effect, RGZ or related compounds may have potential as bronchodilators for the treatment of difficult asthma. PMID:24188042

Detection of smoothly distributed spatial outliers, with applications to identifying the distribution of parenchymal hyperinflation following an airway challenge in asthmatics.

PubMed

Thurman, Andrew L; Choi, Jiwoong; Choi, Sanghun; Lin, Ching-Long; Hoffman, Eric A; Lee, Chang Hyun; Chan, Kung-Sik

2017-05-10

Methacholine challenge tests are used to measure changes in pulmonary function that indicate symptoms of asthma. In addition to pulmonary function tests, which measure global changes in pulmonary function, computed tomography images taken at full inspiration before and after administration of methacholine provide local air volume changes (hyper-inflation post methacholine) at individual acinar units, indicating local airway hyperresponsiveness. Some of the acini may have extreme air volume changes relative to the global average, indicating hyperresponsiveness, and those extreme values may occur in clusters. We propose a Gaussian mixture model with a spatial smoothness penalty to improve prediction of hyperresponsive locations that occur in spatial clusters. A simulation study provides evidence that the spatial smoothness penalty improves prediction under different data-generating mechanisms. We apply this method to computed tomography data from Seoul National University Hospital on five healthy and ten asthmatic subjects. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Tidal stretches do not modulate responsiveness of intact airways in vitro

PubMed Central

Szabo, Thomas L.; Suki, Béla; Lutchen, Kenneth R.

2010-01-01

Studies on isolated tracheal airway smooth muscle (ASM) strips have shown that length/force fluctuations, similar to those likely occurring during breathing, will mitigate ASM contractility. These studies conjecture that, solely by reducing length oscillations on a healthy, intact airway, one can create airway hyperresponsiveness, but this has never been explicitly tested. The intact airway has additional complexities of geometry and structure that may impact its relevance to isolated ASM strips. We examined the role of transmural pressure (Ptm) fluctuations of physiological amplitudes on the responsiveness of an intact airway. We developed an integrated system utilizing ultrasound imaging to provide real-time measurements of luminal radius and wall thickness over the full length of an intact airway (generation 10 and below) during Ptm oscillations. First, airway constriction dynamics to cumulative acetylcholine (ACh) doses (10−7 to 10−3 M) were measured during static and dynamic Ptm protocols. Regardless of the breathing pattern, the Ptm oscillation protocols were ineffective in reducing the net level of constriction for any ACh dose, compared with the static control (P = 0.225–0.793). Next, Ptm oscillations of increasing peak-to-peak amplitude were applied subsequent to constricting intact airways under static conditions (5.0-cmH2O Ptm) with a moderate ACh dose (10−5 M). Peak-to-peak Ptm oscillations ≤5.0 cmH2O resulted in no statistically significant bronchodilatory response (P = 0.429 and 0.490). Larger oscillations (10 cmH2O, peak to peak) produced modest dilation of 4.3% (P = 0.009). The lack of modulation of airway responsiveness by Ptm oscillations in intact, healthy airways suggests that ASM level mechanisms alone may not be the sole determinant of airway responsiveness. PMID:20431023

Acrolein increases airway sensitivity to substance P and decreases NEP activity in guinea pigs.

PubMed

Turner, C R; Stow, R B; Hubbs, S J; Gomes, B C; Williams, J C

1993-04-01

The effects of acrolein exposure on airway responses to intravenous substance P were determined in guinea pigs exposed to vehicle or 1.6 ppm acrolein for 7.5 h on 2 consecutive days and examined 1, 4, 8, 15, and 28 days after exposure by use of pulmonary mechanics and bronchoalveolar lavage (BAL). Lung, trachea, liver, and BAL fluid were also assayed for neutral endopeptidase (NEP) activity 1, 7, and 28 days after exposure. Pulmonary inflammation and epithelial damage were prominent 1 day after acrolein exposure. NEP activity was decreased in the lungs, trachea, and liver 1 and 7 days after acrolein. Twenty-eight days after exposure, NEP activity in the lungs and liver was not significantly different in vehicle- and acrolein-exposed guinea pigs but was still reduced in tracheal tissue. The BAL NEP activity in acrolein-exposed guinea pigs was approximately twice that of vehicle control guinea pigs at all three time points. Acrolein caused a prolonged increase in airway sensitivity to substance P. Experiments performed in the presence of thiorphan suggested that the acrolein-induced reduction in NEP may contribute to increased airway sensitivity to aerosolized substance P, but the increase in airway sensitivity to intravenous substance P may occur by additional mechanisms.

Airway lipoxin A4 generation and lipoxin A4 receptor expression are decreased in severe asthma.

PubMed

Planagumà, Anna; Kazani, Shamsah; Marigowda, Gautham; Haworth, Oliver; Mariani, Thomas J; Israel, Elliot; Bleecker, Eugene R; Curran-Everett, Douglas; Erzurum, Serpil C; Calhoun, William J; Castro, Mario; Chung, Kian Fan; Gaston, Benjamin; Jarjour, Nizar N; Busse, William W; Wenzel, Sally E; Levy, Bruce D

2008-09-15

Airway inflammation is common in severe asthma despite antiinflammatory therapy with corticosteroids. Lipoxin A(4) (LXA(4)) is an arachidonic acid-derived mediator that serves as an agonist for resolution of inflammation. Airway levels of LXA(4), as well as the expression of lipoxin biosynthetic genes and receptors, in severe asthma. Samples of bronchoalveolar lavage fluid were obtained from subjects with asthma and levels of LXA(4) and related eicosanoids were measured. Expression of lipoxin biosynthetic genes was determined in whole blood, bronchoalveolar lavage cells, and endobronchial biopsies by quantitative polymerase chain reaction, and leukocyte LXA(4) receptors were monitored by flow cytometry. Individuals with severe asthma had significantly less LXA(4) in bronchoalveolar lavage fluids (11.2 +/- 2.1 pg/ml) than did subjects with nonsevere asthma (150.1 +/- 38.5 pg/ml; P < 0.05). In contrast, levels of cysteinyl leukotrienes were increased in both asthma cohorts compared with healthy individuals. In severe asthma, 15-lipoxygenase-1 mean expression was decreased fivefold in bronchoalveolar lavage cells. In contrast, 15-lipoxgenase-1 was increased threefold in endobronchial biopsies, but expression of both 5-lipoxygenase and 15-lipoxygenase-2 in these samples was decreased. Cyclooxygenase-2 expression was decreased in all anatomic compartments sampled in severe asthma. Moreover, LXA(4) receptor gene and protein expression were significantly decreased in severe asthma peripheral blood granulocytes. Mechanisms underlying pathological airway responses in severe asthma include lipoxin underproduction with decreased expression of lipoxin biosynthetic enzymes and receptors. Together, these results indicate that severe asthma is characterized, in part, by defective lipoxin counterregulatory signaling circuits.

Induction of human airway hyperresponsiveness by tumour necrosis factor-alpha.

PubMed

Anticevich, S Z; Hughes, J M; Black, J L; Armour, C L

1995-09-15

Tumour necrosis factor-alpha (TNF alpha) is implicated in the pathogenesis of asthma; however, little is known of its direct effect on smooth muscle reactivity. We investigated the effect of TNF alpha on the responsiveness of human bronchial tissue to electrical field stimulation in vitro. Incubation of non-sensitized tissue with 1 nM, 3 nM and 10 nM TNF alpha significantly increased responsiveness to electrical field stimulation (113 +/- 8, 110 +/- 4 and 112 +/- 2% respectively) compared to control (99 +/- 2%) (P < 0.05, n = 6). Responses were not increased in sensitized tissue (101 +/- 3% versus 105 +/- 5%, n = 3, P > 0.05) nor were responses to exogenous acetylcholine (93 +/- 4% versus 73 +/- 7%, n = 3, P = 0.38). These results show that TNF alpha causes an increase in responsiveness of human bronchial tissue and that this occurs prejunctionally on the parasympathetic nerve pathway. This is the first report of a cytokine increasing human airway tissue responsiveness.

The Association of Lung Function, Bronchial Hyperresponsiveness, and Exhaled Nitric Oxide Differs Between Atopic and Non-atopic Asthma in Children

PubMed Central

Shim, Eunhee; Lee, Eun; Yang, Song-I; Jung, Young-Ho; Park, Geun Mi; Kim, Hyung Young; Seo, Ju-Hee

2015-01-01

Purpose Although many previous studies have attempted to identify differences between atopic asthma (AA) and non-atopic asthma (NAA), they have mainly focused on the difference of each variable of lung function and airway inflammation. The aim of this study was to evaluate relationships between lung function, bronchial hyperresponsiveness (BHR), and the exhaled nitric oxide (eNO) levels in children with AA and NAA. Methods One hundred and thirty six asthmatic children aged 5-15 years and 40 normal controls were recruited. Asthma cases were classified as AA (n=100) or NAA (n=36) from skin prick test results. Lung function, BHR to methacholine and adenosine-5'-monophosphate (AMP), eNO, blood eosinophils, and serum total IgE were measured. Results The AA and NAA cases shared common features including a reduced small airway function and increased BHR to methacholine. However, children with AA showed higher BHR to AMP and eNO levels than those with NAA. When the relationships among these variables in the AA and NAA cases were evaluated, the AA group showed significant relationships between lung function, BHR to AMP or methacholine and eNO levels. However, the children in the NAA group showed an association between small airway function and BHR to methacholine only. Conclusions These findings suggest that the pathogenesis of NAA may differ from that of AA during childhood in terms of the relationship between lung function, airway inflammation and BHR. PMID:25749776

S-nitrosoglutathione reductase: an important regulator in human asthma.

PubMed

Que, Loretta G; Yang, Zhonghui; Stamler, Jonathan S; Lugogo, Njira L; Kraft, Monica

2009-08-01

Nitric oxide bioactivity, mediated through the formation of S-nitrosothiols (SNOs), has a significant effect on bronchomotor tone. S-Nitrosoglutathione is an endogenous bronchodilator that is decreased in children with asthmatic respiratory failure and in adults with asthma undergoing segmental airway challenge. Recently we showed that S-nitrosoglutathione reductase (GSNOR) regulates endogenous SNOs. Mice with genetic deletion of GSNOR are protected from airway hyperresponsivity in an allergic asthma model. We hypothesized that GSNOR is increased in human asthma and correlates with lung SNO content and airway reactivity. We recruited 36 subjects with mild asthma with FEV(1) 88.5 +/- 2.3% predicted and 34 healthy control subjects with FEV(1) 100.7 +/- 2.5% predicted. Bronchoalveolar lavage (BAL) was performed in all subjects. Cell counts, differentials, GSNOR activity, and SNO levels were determined in BAL. SNO content was decreased in asthmatic BAL compared with control BAL and correlated inversely with GSNOR expression in BAL cell lysates. Furthermore, GSNOR activity measured from BAL samples was significantly increased in subjects with asthma compared with control subjects and correlated inversely with the provocative concentration of methacholine causing a 20% decrease in FEV(1). These findings suggest that GSNOR is an important regulator of airway SNO content and airways hyperresponsiveness in human asthma.

Human mast cell and airway smooth muscle cell interactions: implications for asthma.

PubMed

Page, S; Ammit, A J; Black, J L; Armour, C L

2001-12-01

Asthma is characterized by inflammation, hyperresponsiveness, and remodeling of the airway. Human mast cells (HMCs) play a central role in all of these changes by releasing mediators that cause exaggerated bronchoconstriction, induce human airway smooth muscle (HASM) cell proliferation, and recruit and activate inflammatory cells. Moreover, the number of HMCs present on asthmatic HASM is increased compared with that on nonasthmatic HASM. HASM cells also have the potential to actively participate in the inflammatory process by synthesizing cytokines and chemokines and expressing surface molecules, which have the capacity to perpetuate the inflammatory mechanisms present in asthma. This review specifically examines how the mediators of HMCs have the capacity to modulate many functions of HASM; how the synthetic function of HASM, particularly through the release and expression of stem cell factor, has the potential to influence HMC number and activation in an extraordinarily potent and proinflammatory manner; and how these interactions between HMCs and HASM have potential consequences for airway structure and inflammation relevant to the disease process of asthma.

Genetic Variation in Serotonin Transporter Modulates Tactile Hyperresponsiveness in ASD

PubMed Central

Schauder, Kimberly B.; Muller, Christopher L.; Veenstra-VanderWeele, Jeremy; Cascio, Carissa J.

2014-01-01

Several lines of evidence implicate dysfunction of the serotonin (5-HT) system in autism spectrum disorder (ASD). Specifically, the serotonin transporter (5-HTT, SERT) has been scrutinized as an ASD candidate risk gene. SERT plays key roles in the development of circuits that underlie sensory function, particularly in the somatosensory system. One previous study in ASD found association of a rare, hyperfunctional SERT variant with sensory aversion, but studies of common SERT variants have never examined sensory symptoms in ASD. Using standardized caregiver assessments of sensory function in children, we evaluated patterns of sensory responsiveness in 47 children with ASD and 38 typically developing (TD) children. Study participants were genotyped for the functional SERT promoter polymorphisms, 5-HTTLPR and rs25531, to test the hypothesis that the higher expressing genotypes would be associated with hyperresponsiveness to touch, a common sensory aversion in ASD. All measures of sensory hypo- and hyperresponsiveness were increased in children with ASD, with hyporesponsive sensory patterns negatively correlated to age and hyperresponsive sensory patterns positively correlated to repetitive behavior. Strikingly, high-expressing SERT genotypes were associated with increased tactile hyperresponsiveness in the ASD group. Our findings indicate genetic variation that increases SERT function may specifically impact somatosensory processing in ASD. PMID:25558276

Sensory neuropeptides and the human lower airways: present state and future directions.

PubMed

Joos, G F; Germonpre, P R; Kips, J C; Peleman, R A; Pauwels, R A

1994-06-01

The sensory neuropeptides, substance P and neurokinin A, are present in human airway nerves, beneath and within the epithelium, around blood vessels and submucosal glands, and within the bronchial smooth muscle layer. Studies on autopsy tissue, bronchoalveolar lavage and sputum suggest that in asthma the substance P content of the airways may be increased. Neurokinin A is a more potent bronchoconstrictor than substance P. Asthmatics are hyperresponsive to neurokinin A and substance P. The neuropeptide degrading enzyme, neutral endopeptidase is present in the airways and is involved in the degradation of endogenously released and exogenously administered substance P and neurokinin A, both in normal and asthmatic subjects. As for other indirect bronchoconstrictor stimuli, the effect of neurokinin A on airway calibre in asthmatics can be inhibited by pretreatment with nedocromil sodium. Evidence is accumulating, not only from studies in animals but also from experiments on human airways, that tachykinins may also cause mucus secretion and plasma extravasation. They also have important proinflammatory effects, such as the chemoattraction of eosinophils and neutrophils, the adhesion of neutrophils, and the stimulation of lymphocytes, macrophages and mast cells. The tachykinins interact with the targets on the airways by specific tachykinin receptors. The NK1 and the NK2 receptor have been characterized in human airways, both pharmacologically and by cloning. The NK2 receptor is responsible for the in vitro contraction of normal airways, whilst the NK1 receptor is responsible for most of the other airway effects. Because of their presence in the airways and because of their ability to mimic the various pathophysiological features of asthma, substance P and neurokinin A are presently considered as possible mediators of asthma. The present development of potent and selective tachykinin antagonists will allow us to further define the role of tachykinins in the pathogenesis

COLCHICINE DECREASES AIRWAY HYPERACTIVITY AFTER PHOSGENE EXPOSURE

EPA Science Inventory

Phosgene (COCl(2)) exposure affects an influx of inflammatory cells into the lung, which can be reduced in an animal model by pretreatment with colchicine. Inflammation in the respiratory tract can be associated with an increase in airway hyperreactivity. We tested the hypotheses...

TNF is required for TLR ligand-mediated but not protease-mediated allergic airway inflammation.

PubMed

Whitehead, Gregory S; Thomas, Seddon Y; Shalaby, Karim H; Nakano, Keiko; Moran, Timothy P; Ward, James M; Flake, Gordon P; Nakano, Hideki; Cook, Donald N

2017-09-01

Asthma is associated with exposure to a wide variety of allergens and adjuvants. The extent to which overlap exists between the cellular and molecular mechanisms triggered by these various agents is poorly understood, but it might explain the differential responsiveness of patients to specific therapies. In particular, it is unclear why some, but not all, patients benefit from blockade of TNF. Here, we characterized signaling pathways triggered by distinct types of adjuvants during allergic sensitization. Mice sensitized to an innocuous protein using TLR ligands or house dust extracts as adjuvants developed mixed eosinophilic and neutrophilic airway inflammation and airway hyperresponsiveness (AHR) following allergen challenge, whereas mice sensitized using proteases as adjuvants developed predominantly eosinophilic inflammation and AHR. TLR ligands, but not proteases, induced TNF during allergic sensitization. TNF signaled through airway epithelial cells to reprogram them and promote Th2, but not Th17, development in lymph nodes. TNF was also required during the allergen challenge phase for neutrophilic and eosinophilic inflammation. In contrast, TNF was dispensable for allergic airway disease in a protease-mediated model of asthma. These findings might help to explain why TNF blockade improves lung function in only some patients with asthma.

TNF is required for TLR ligand–mediated but not protease-mediated allergic airway inflammation

PubMed Central

Whitehead, Gregory S.; Thomas, Seddon Y.; Shalaby, Karim H.; Nakano, Keiko; Moran, Timothy P.; Ward, James M.; Flake, Gordon P.; Cook, Donald N.

2017-01-01

Asthma is associated with exposure to a wide variety of allergens and adjuvants. The extent to which overlap exists between the cellular and molecular mechanisms triggered by these various agents is poorly understood, but it might explain the differential responsiveness of patients to specific therapies. In particular, it is unclear why some, but not all, patients benefit from blockade of TNF. Here, we characterized signaling pathways triggered by distinct types of adjuvants during allergic sensitization. Mice sensitized to an innocuous protein using TLR ligands or house dust extracts as adjuvants developed mixed eosinophilic and neutrophilic airway inflammation and airway hyperresponsiveness (AHR) following allergen challenge, whereas mice sensitized using proteases as adjuvants developed predominantly eosinophilic inflammation and AHR. TLR ligands, but not proteases, induced TNF during allergic sensitization. TNF signaled through airway epithelial cells to reprogram them and promote Th2, but not Th17, development in lymph nodes. TNF was also required during the allergen challenge phase for neutrophilic and eosinophilic inflammation. In contrast, TNF was dispensable for allergic airway disease in a protease-mediated model of asthma. These findings might help to explain why TNF blockade improves lung function in only some patients with asthma. PMID:28758900

Effect of choline chloride in allergen-induced mouse model of airway inflammation.

PubMed

Mehta, A K; Gaur, S N; Arora, N; Singh, B P

2007-10-01

The incidence of asthma has increased the world over, and current therapies for the disease suffer from potential side-effects. This has created an opportunity to develop novel therapeutic approaches. Here, the anti-inflammatory activity of choline was investigated in a mouse model of allergic airway inflammation. Choline (1 mg.kg(-1)) was administered via oral gavage or intranasally before and after ovalbumin (OVA) challenge in sensitised mice. Airway hyperresponsiveness (AHR) to methacholine was measured in the mice by whole-body plethysmography. Type-2 T-helper cell cytokine and leukotriene levels were estimated in bronchoalveolar lavage fluid (BALF) and spleen culture supernatant by ELISA. Eosinophil peroxidase activity was also determined in the BALF supernatant. Choline treatment in sensitised mice before OVA challenge via oral/intranasal routes significantly inhibited eosinophilic airway inflammation and eosinophil peroxidase activity. It also reduced immunoglobulin E and G1 production and inhibited the release of type-2 T-helper cell cytokines and leukotrienes. However, the development of AHR was prevented effectively by intranasal choline treatment. Most importantly, choline treatment after OVA challenge by both routes could reverse established asthmatic conditions in mice by inhibiting AHR, eosinophilic airway inflammation and other inflammatory parameters. This study provides a new therapeutic approach for controlling as well as preventing asthma exacerbations.

Oroxylin A Inhibits Allergic Airway Inflammation in Ovalbumin (OVA)-Induced Asthma Murine Model.

PubMed

Zhou, De-Gang; Diao, Bao-Zhong; Zhou, Wen; Feng, Jia-Long

2016-04-01

Oroxylin A, a natural flavonoid isolated from the medicinal herb Scutellaria baicalensis Georgi, has been reported to have anti-inflammatory property. In this study, we aimed to investigate the protective effects and mechanism of oroxylin A on allergic inflammation in OVA-induced asthma murine model. BABL/c mice were sensitized and airway-challenged with OVA to induce asthma. Oroxylin A (15, 30, and 60 mg/kg) was administered by oral gavage 1 h before the OVA treatment on day 21 to 23. The results showed that oroxylin A attenuated OVA-induced lung histopathologic changes, airway hyperresponsiveness, and the number of inflammatory cells. Oroxylin A also inhibited the levels of IL-4, IL-5, IL-13, and OVA-specific IgE in BALF. Furthermore, oroxylin A significantly inhibited OVA-induced NF-κB activation. In conclusion, these results suggested that oroxylin A inhibited airway inflammation in OVA-induced asthma murine model by inhibiting NF-κB activation. These results suggested that oroxylin A was a potential therapeutic drug for treating allergic asthma.

TRPV1 Blocking Alleviates Airway Inflammation and Remodeling in a Chronic Asthma Murine Model.

PubMed

Choi, Joon Young; Lee, Hwa Young; Hur, Jung; Kim, Kyung Hoon; Kang, Ji Young; Rhee, Chin Kook; Lee, Sook Young

2018-05-01

Asthma is a chronic inflammatory airway disease characterized by airway hyperresponsiveness (AHR), inflammation, and remodeling. There is emerging interest in the involvement of the transient receptor potential vanilloid 1 (TRPV1) channel in the pathophysiology of asthma. This study examined whether TRPV1 antagonism alleviates asthma features in a murine model of chronic asthma. BALB/c mice were sensitized to and challenged by ovalbumin to develop chronic asthma. Capsazepine (TRPV1 antagonist) or TRPV1 small interfering RNA (siRNA) was administered in the treatment group to evaluate the effect of TPV1 antagonism on AHR, airway inflammation, and remodeling. The mice displayed increased AHR, airway inflammation, and remodeling. Treatment with capsazepine or TRPV1 siRNA reduced AHR to methacholine and airway inflammation. Type 2 T helper (Th2) cytokines (interleukin [IL]-4, IL-5, and IL-13) were reduced and epithelial cell-derived cytokines (thymic stromal lymphopoietin [TSLP], IL-33, and IL-25), which regulate Th2 cytokine-associated inflammation, were also reduced. Airway remodeling characterized by goblet cell hyperplasia, increased α-smooth muscle action, and collagen deposition was also alleviated by both treatments. Treatment directed at TRPV1 significantly alleviated AHR, airway inflammation, and remodeling in a chronic asthma murine model. The TRPV1 receptor can be a potential drug target for chronic bronchial asthma. Copyright © 2018 The Korean Academy of Asthma, Allergy and Clinical Immunology · The Korean Academy of Pediatric Allergy and Respiratory Disease.

Increase in exhaled nitric oxide is associated with bronchial hyperresponsiveness among apprentices.

PubMed

Tossa, Paul; Paris, Christophe; Zmirou-Navier, Denis; Demange, Valérie; Acouetey, Dovi-Stéphanie; Michaely, Jean-Pierre; Bohadana, Abraham

2010-09-15

Airway inflammation is a hallmark of asthma. Several studies have validated the use of the fractional concentration of exhaled nitric oxide (Fe(NO)) as a surrogate marker of airway inflammation in asthma. We examined how the change in Fe(NO) levels, since the beginning of occupational exposure, could be associated with the incidence of bronchial hyperresponsiveness (BHR) among baker, pastry maker, and hairdresser apprentices during their 2-year training. A standardized questionnaire was administered; skin prick tests for common and specific occupational allergens were done; methacholine challenge and measurement of Fe(NO) were performed 6, 12, and 15 months after the first examination. Of 441 apprentices initially included, 351 completed the study. The increase in Fe(NO), since the beginning of exposure, was associated with the incidence of BHR (odds ratio, 2.00 [95% confidence interval, 1.21-3.32] per unit increase in log parts per billion) both in atopic and nonatopic subjects. The average increase in Fe(NO) was similar in atopic and nonatopic subjects and was unrelated to past or current smoking habits, sex, or training track. Atopy in bakers/pastry makers and sensitization to alkaline persulfates in hairdressers were also independently associated with the incidence of BHR. BHR occurred sooner among bakers/pastry makers than among hairdressers, but its incidence leveled off later. Our results suggest that measurement of Fe(NO), a simple and reproducible test, could be useful in the screening of BHR in workers newly exposed to agents known to cause occupational asthma.

Parainfluenza virus type 3 induced alterations in tachykinin NK1 receptors, substance P levels and respiratory functions in guinea pig airways.

PubMed

Kudlacz, E M; Shatzer, S A; Farrell, A M; Baugh, L E

1994-08-03

We have investigated the effects of parainfluenza virus type 3 (PI-3) on sensory neuropeptide levels, tachykinin receptors and their functions in guinea pig airways during the course of respiratory viral infection. PI-3 infected guinea pigs were hyperresponsive to methacholine and substance P aerosols as determined by earlier onset of dyspnea in these animals as compared with control on post-inoculation day (PID) 7 but not 19. In addition, plasma protein extravasation produced in response to the tachykinin was increased in infected airways during the first week post inoculation. Infected guinea pig trachea did not respond any differently to methacholine when smooth muscle contraction and [3H]inositol phosphate accumulation were measured although the magnitude of substance P effects using in vitro tests was significantly greater than control on post-inoculation day 7 but not 19. Trachea from PI-3 infected animals were characterized by reductions in substance P-like immunoreactivity, tachykinin NK1 receptor number and agonist affinity during the first post-inoculation week. Substance P levels or tachykinin NK1 receptor numbers or affinity were not altered in trachea of guinea pigs 4 days after treatment with lipopolysaccharide. These data suggest substance P release occurs during critical periods of respiratory viral infection which are temporally correlated with airway hyperresponsiveness. Despite apparent down-regulation of tachykinin NK1 receptors, substance P-mediated functions remained enhanced suggesting some alterations in post-receptor mechanisms.

MAG-EPA resolves lung inflammation in an allergic model of asthma.

PubMed

Morin, C; Fortin, S; Cantin, A M; Rousseau, É

2013-09-01

Asthma is a chronic disease characterized by airways hyperresponsiveness, inflammation and airways remodelling involving reversible bronchial obstruction. Omega-3 fatty acids and their derivatives are known to reduce inflammation in several tissues including lung. The effects of eicosapentaenoic acid monoacylglyceride (MAG-EPA), a newly synthesized EPA derivative, were determined on the resolution of lung inflammation and airway hyperresponsiveness in an in vivo model of allergic asthma. Ovalbumin (OVA)-sensitized guinea-pigs were treated or not with MAG-EPA administered per os. Isometric tension measurements, histological analyses, homogenate preparation for Western blot experiments or total RNA extraction for RT-PCR were performed to assess the effect of MAG-EPA treatments. Mechanical tension measurements revealed that oral MAG-EPA treatments reduced methacholine (MCh)-induced bronchial hyperresponsiveness in OVA-sensitized guinea-pigs. Moreover, MAG-EPA treatments also decreased Ca(2+) hypersensitivity of bronchial smooth muscle. Histological analyses and leucocyte counts in bronchoalveolar lavages revealed that oral MAG-EPA treatments led to less inflammatory cell recruitment in the lung of OVA-sensitized guinea-pigs when compared with lungs from control animals. Results also revealed a reduction in mucin production and MUC5AC expression level in OVA-sensitized animals treated with MAG-EPA. Following MAG-EPA treatments, the transcript levels of pro-inflammatory markers such as IL-5, eotaxin, IL-13 and IL-4 were markedly reduced. Moreover, per os MAG-EPA administrations reduced COX2 over-expression in OVA-sensitized animals. We demonstrate that MAG-EPA reduces airway hyperresponsiveness and lung inflammation in OVA-sensitized animals, a finding consistent with a decrease in IL-4, IL-5, IL-13, COX-2 and MUC5AC expression levels in the lung. The present data suggest that MAG-EPA represents a new potential therapeutic strategy for resolving inflammation in allergic

Lipopolysaccharide does not alter small airway reactivity in mouse lung slices.

PubMed

Donovan, Chantal; Royce, Simon G; Vlahos, Ross; Bourke, Jane E

2015-01-01

The bacterial endotoxin, lipopolysaccharide (LPS) has been associated with occupational airway diseases with asthma-like symptoms and in acute exacerbations of COPD. The direct and indirect effects of LPS on small airway reactivity have not been fully elucidated. We tested the hypothesis that both in vitro and in vivo LPS treatment would increase contraction and impair relaxation of mouse small airways. Lung slices were prepared from naïve Balb/C mice and cultured in the absence or presence of LPS (10 μg/ml) for up to 48 h for measurement of TNFα levels in conditioned media. Alternatively, mice were challenged with PBS or LPS in vivo once a day for 4 days for preparation of lung slices or for harvest of lungs for Q-PCR analysis of gene expression of pro-inflammatory cytokines and receptors involved in airway contraction. Reactivity of small airways to contractile agonists, methacholine and serotonin, and bronchodilator agents, salbutamol, isoprenaline and rosiglitazone, were assessed using phase-contrast microscopy. In vitro LPS treatment of slices increased TNFα release 6-fold but did not alter contraction or relaxation to any agonists tested. In vivo LPS treatment increased lung gene expression of TNFα, IL-1β and ryanodine receptor isoform 2 more than 5-fold. However there were no changes in reactivity in lung slices from these mice, even when also incubated with LPS ex vivo. Despite evidence of LPS-induced inflammation, neither airway hyperresponsiveness or impaired dilator reactivity were evident. The increase in ryanodine receptor isoform 2, known to regulate calcium signaling in vascular smooth muscle, warrants investigation. Since LPS failed to elicit changes in small airway reactivity in mouse lung slices following in vitro or in vivo treatment, alternative approaches are required to define the potential contribution of this endotoxin to altered small airway reactivity in human lung diseases.

Lipopolysaccharide Does Not Alter Small Airway Reactivity in Mouse Lung Slices

PubMed Central

Donovan, Chantal; Royce, Simon G.; Vlahos, Ross; Bourke, Jane E.

2015-01-01

The bacterial endotoxin, lipopolysaccharide (LPS) has been associated with occupational airway diseases with asthma-like symptoms and in acute exacerbations of COPD. The direct and indirect effects of LPS on small airway reactivity have not been fully elucidated. We tested the hypothesis that both in vitro and in vivo LPS treatment would increase contraction and impair relaxation of mouse small airways. Lung slices were prepared from naïve Balb/C mice and cultured in the absence or presence of LPS (10 μg/ml) for up to 48 h for measurement of TNFα levels in conditioned media. Alternatively, mice were challenged with PBS or LPS in vivo once a day for 4 days for preparation of lung slices or for harvest of lungs for Q-PCR analysis of gene expression of pro-inflammatory cytokines and receptors involved in airway contraction. Reactivity of small airways to contractile agonists, methacholine and serotonin, and bronchodilator agents, salbutamol, isoprenaline and rosiglitazone, were assessed using phase-contrast microscopy. In vitro LPS treatment of slices increased TNFα release 6-fold but did not alter contraction or relaxation to any agonists tested. In vivo LPS treatment increased lung gene expression of TNFα, IL-1β and ryanodine receptor isoform 2 more than 5-fold. However there were no changes in reactivity in lung slices from these mice, even when also incubated with LPS ex vivo. Despite evidence of LPS-induced inflammation, neither airway hyperresponsiveness or impaired dilator reactivity were evident. The increase in ryanodine receptor isoform 2, known to regulate calcium signaling in vascular smooth muscle, warrants investigation. Since LPS failed to elicit changes in small airway reactivity in mouse lung slices following in vitro or in vivo treatment, alternative approaches are required to define the potential contribution of this endotoxin to altered small airway reactivity in human lung diseases. PMID:25822969

Mechanisms of Cigarette Smoke Effects on Human Airway Smooth Muscle.

PubMed

Wylam, Mark E; Sathish, Venkatachalem; VanOosten, Sarah Kay; Freeman, Michelle; Burkholder, David; Thompson, Michael A; Pabelick, Christina M; Prakash, Y S

2015-01-01

Cigarette smoke contributes to or exacerbates airway diseases such as asthma and COPD, where airway hyperresponsiveness and airway smooth muscle (ASM) proliferation are key features. While factors such as inflammation contribute to asthma in part by enhancing agonist-induced intracellular Ca(2+) ([Ca(2+)]i) responses of ASM, the mechanisms by which cigarette smoke affect ASM are still under investigation. In the present study, we tested the hypothesis that cigarette smoke enhances the expression and function of Ca(2+) regulatory proteins leading to increased store operated Ca(2+) entry (SOCE) and cell proliferation. Using isolated human ASM (hASM) cells, incubated in the presence and absence cigarette smoke extract (CSE) we determined ([Ca(2+)]i) responses and expression of relevant proteins as well as ASM proliferation, reactive oxidant species (ROS) and cytokine generation. CSE enhanced [Ca(2+)]i responses to agonist and SOCE: effects mediated by increased expression of TRPC3, CD38, STIM1, and/or Orai1, evident by attenuation of CSE effects when siRNAs against these proteins were used, particularly Orai1. CSE also increased hASM ROS generation and cytokine secretion. In addition, we found in the airways of patients with long-term smoking history, TRPC3 and CD38 expression were significantly increased compared to life-long never-smokers, supporting the role of these proteins in smoking effects. Finally, CSE enhanced hASM proliferation, an effect confirmed by upregulation of PCNA and Cyclin E. These results support a critical role for Ca(2+) regulatory proteins and enhanced SOCE to alter airway structure and function in smoking-related airway disease.

Molecular mechanisms underlying airway smooth muscle contraction and proliferation: implications for asthma.

PubMed

Pelaia, Girolamo; Renda, Teresa; Gallelli, Luca; Vatrella, Alessandro; Busceti, Maria Teresa; Agati, Sergio; Caputi, Mario; Cazzola, Mario; Maselli, Rosario; Marsico, Serafino A

2008-08-01

Airway smooth muscle (ASM) plays a key role in bronchomotor tone, as well as in structural remodeling of the bronchial wall. Therefore, ASM contraction and proliferation significantly participate in the development and progression of asthma. Many contractile agonists also behave as mitogenic stimuli, thus contributing to frame a hyperresponsive and hyperplastic ASM phenotype. In this review, the molecular mechanisms and signaling pathways involved in excitation-contraction coupling and ASM cell growth will be outlined. Indeed, the recent advances in understanding the basic aspects of ASM biology are disclosing important cellular targets, currently explored for the implementation of new, more effective anti-asthma therapies.

Peripheral erythrocytes decrease upon specific respiratory challenge with grass pollen allergen in sensitized mice and in human subjects.

PubMed

Jordakieva, Galateja; Wallmann, Julia; Schmutz, René; Lemell, Patrick; Wegmann, Michael; Nittke, Thomas; Mittlböck, Martina; Fehrenbach, Heinz; Godnic-Cvar, Jasminka; Zieglmayer, René; Jensen-Jarolim, Erika

2014-01-01

Specific hyper-responsiveness towards an allergen and non-specific airway hyperreactivity both impair quality of life in patients with respiratory allergic diseases. We aimed to investigate cellular responses following specific and non-specific airway challenges locally and systemically in i) sensitized BALB/c mice challenged with grass pollen allergen Phl p 5, and in ii) grass pollen sensitized allergic rhinitis subjects undergoing specific airway challenge in the Vienna Challenge Chamber (VCC). BALB/c mice (n = 20) were intraperitoneally immunized with grass pollen allergen Phl p 5 and afterwards aerosol challenged with either the specific allergen Phl p 5 (n = 10) or the non-specific antigen ovalbumin (OVA) (n = 10). A protocol for inducing allergic asthma as well as allergic rhinitis, according to the united airway concept, was used. Both groups of exposed mice showed significantly reduced physical activity after airway challenge. Specific airway challenge further resulted in goblet cell hyperplasia, enhanced mucous secretion, intrapulmonary leukocyte infiltration and lymphoid follicle formation, associated with significant expression of IL-4, IL-5 and IL-13 in splenocytes and also partially in lung tissue. Concerning circulating blood cell dynamics, we observed a significant drop of erythrocyte counts, hemoglobin and hematocrit levels in both mouse groups, challenged with allergen or OVA. A significant decrease in circulating erythrocytes and hematocrit levels after airway challenges with grass pollen allergen was also found in grass pollen sensitized human rhinitis subjects (n = 42) at the VCC. The effects on peripheral leukocyte counts in mice and humans however were opposed, possibly due to the different primary inflammation sites. Our data revealed that, besides significant leukocyte dynamics, particularly erythrocytes are involved in acute hypersensitivity reactions to respiratory allergens. A rapid recruitment of erythrocytes to the lungs to compensate

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

PubMed Central

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

2011-01-01

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

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

PubMed

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

2011-07-01

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

Comparison of Airway Responses Induced in a Mouse Model by the Gas and Particulate Fractions of Gasoline Direct Injection Engine Exhaust.

PubMed

Maikawa, Caitlin L; Zimmerman, Naomi; Ramos, Manuel; Shah, Mittal; Wallace, James S; Pollitt, Krystal J Godri

2018-03-01

Diesel exhaust has been associated with asthma, but its response to other engine emissions is not clear. The increasing prevalence of vehicles with gasoline direct injection (GDI) engines motivated this study, and the objective was to evaluate pulmonary responses induced by acute exposure to GDI engine exhaust in an allergic asthma murine model. Mice were sensitized with an allergen to induce airway hyperresponsiveness or treated with saline (non-allergic group). Animals were challenged for 2-h to exhaust from a laboratory GDI engine operated at conditions equivalent to a highway cruise. Exhaust was filtered to assess responses induced by the particulate and gas fractions. Short-term exposure to particulate matter from GDI engine exhaust induced upregulation of genes related to polycyclic aromatic hydrocarbon (PAH) metabolism ( Cyp1b1 ) and inflammation ( TNFα ) in the lungs of non-allergic mice. High molecular weight PAHs dominated the particulate fraction of the exhaust, and this response was therefore likely attributable to the presence of these PAHs. The particle fraction of GDI engine exhaust further contributed to enhanced methacholine responsiveness in the central and peripheral tissues in animals with airway hyperresponsiveness. As GDI engines gain prevalence in the vehicle fleet, understanding the health impacts of their emissions becomes increasingly important.

Comparison of Airway Responses Induced in a Mouse Model by the Gas and Particulate Fractions of Gasoline Direct Injection Engine Exhaust

PubMed Central

Maikawa, Caitlin L.; Zimmerman, Naomi; Ramos, Manuel; Wallace, James S.; Pollitt, Krystal J. Godri

2018-01-01

Diesel exhaust has been associated with asthma, but its response to other engine emissions is not clear. The increasing prevalence of vehicles with gasoline direct injection (GDI) engines motivated this study, and the objective was to evaluate pulmonary responses induced by acute exposure to GDI engine exhaust in an allergic asthma murine model. Mice were sensitized with an allergen to induce airway hyperresponsiveness or treated with saline (non-allergic group). Animals were challenged for 2-h to exhaust from a laboratory GDI engine operated at conditions equivalent to a highway cruise. Exhaust was filtered to assess responses induced by the particulate and gas fractions. Short-term exposure to particulate matter from GDI engine exhaust induced upregulation of genes related to polycyclic aromatic hydrocarbon (PAH) metabolism (Cyp1b1) and inflammation (TNFα) in the lungs of non-allergic mice. High molecular weight PAHs dominated the particulate fraction of the exhaust, and this response was therefore likely attributable to the presence of these PAHs. The particle fraction of GDI engine exhaust further contributed to enhanced methacholine responsiveness in the central and peripheral tissues in animals with airway hyperresponsiveness. As GDI engines gain prevalence in the vehicle fleet, understanding the health impacts of their emissions becomes increasingly important. PMID:29494515

Decreased expression of monocarboxylate transporter 1 and 4 in the branching airway epithelium of nitrofen-induced congenital diaphragmatic hernia.

PubMed

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

2016-06-01

Monocarboxylate transporters (MCTs) are crucial for the maintenance of intracellular pH homeostasis in developing fetal lungs. MCT1/4 is strongly expressed by epithelial airway cells throughout lung branching morphogenesis. Functional inhibition of MCT1/4 in fetal rat lung explants has been shown to result in airway defects similar to pulmonary hypoplasia (PH) in congenital diaphragmatic hernia (CDH). We hypothesized that pulmonary expression of MCT1/4 is decreased during lung branching morphogenesis in the nitrofen model of CDH-associated PH. Timed-pregnant rats received nitrofen or vehicle on gestational day 9 (D9). Fetuses were harvested on D15, D18, and D21, and divided into control and nitrofen-exposed group. Pulmonary gene expression levels of MCT1/4 were analyzed by qRT-PCR. Immunofluorescence staining for MCT1/4 was combined with E-cadherin in order to evaluate protein expression in branching airway tissue. Relative mRNA levels of MCT1/4 were significantly reduced in lungs of nitrofen-exposed fetuses on D15, D18, and D21 compared to controls. Confocal laser scanning microscopy confirmed markedly decreased immunofluorescence of MCT1/4 in distal bronchial and primitive alveolar epithelium of nitrofen-exposed fetuses on D15, D18, and D21 compared to controls. Decreased expression of MCT1/4 in distal airway epithelium may disrupt lung branching morphogenesis and thus contribute to the development of PH in the nitrofen-induced CDH model. Copyright © 2016 Elsevier Inc. All rights reserved.

Alveolar macrophages from allergic lungs are not committed to a pro-allergic response and can reduce airway hyperresponsiveness following ex vivo culture

PubMed Central

Pouliot, P.; Spahr, A.; Careau, É.; Turmel, V.; Bissonnette, E. Y.

2016-01-01

Summary Background We already demonstrated that adoptive transfer of alveolar macrophages (AMs) from non-allergic rats into AM-depleted allergic rats prevents airway hyperresponsiveness (AHR). We also showed that AMs from non-sensitized, but not from sensitized, allergy-prone rats can prevent AHR following allergen challenge in sensitized allergic animals, establishing the importance of rat immunological status on the modulation of AM functions and suggesting that an allergic lung environment alters AM functions. Objective We investigated how the activation of allergic AMs can be modulated to reinstitute them with their capacity to reduce AHR. Methods AMs from sensitized Brown Norway rats were cultured ex vivo for up to 18 h in culture media to deprogram them from the influence of the allergic lung before being reintroduced into the lung of AM-depleted sensitized recipient. AHR and cytokines in bronchoalveolar lavage (BAL) were measured following allergen challenge. AMs stimulated ex vivo with Bacillus Calmette-Guerin(BCG) were used as positive controls as BCG induces a T-helper type 1 activation in AMs. Results AMs ex vivo cultured for 4–18 h reduced AHR to normal level. Interestingly, pro-allergic functions of AMs were dampened by 18 h culture and they reduced AHR even after spending 48 h in an allergic lung microenvironment. Furthermore, transfer of cultured AMs caused an increase in the levels of IFN-γ and IL-12 in BAL when compared with their ovalbumin control. After 18 h of ex vivo culture, AMs expressed reduced levels of TNF, IL-1α, IL-6, and Arginase-2 mRNAs compared with freshly isolated AMs, suggesting that ex vivo culture exempted AMs from lung stimuli that affected their functions. Conclusions There is a significant crosstalk between lung microenvironment and AMs, affecting their functions. It is also the first report showing that sensitized AMs can be modulated ex vivo to reduce lung pro-allergic environment, opening the way to therapies targetting

SNOR and wheeze: the asthma enzyme?

PubMed

Henderson, Edward M; Gaston, Benjamin

2005-11-01

Conventionally, asthma is defined as involving both airway inflammation and airway smooth muscle hyper-responsiveness. However, Que and coworkers have recently uncoupled these concepts, showing that mice lacking an S-nitrosothiol reductase have allergen-induced airway inflammation but do not have airway hyper-responsiveness. These data are consistent with recent clinical evidence that: (i) S-nitrosothiol signaling is abnormal in human asthma, (ii) nitric oxide in exhaled air might be only a biomarker for the metabolism of more physiologically relevant nitrogen oxides and (iii) the biochemical response to airway inflammation is central to asthma pathophysiology.

Protection from experimental asthma by an endogenous bronchodilator.

PubMed

Que, Loretta G; Liu, Limin; Yan, Yun; Whitehead, Gregory S; Gavett, Stephen H; Schwartz, David A; Stamler, Jonathan S

2005-06-10

Mechanisms that protect against asthma remain poorly understood. S-nitrosoglutathione (GSNO), an endogenous bronchodilator, is depleted from asthmatic airways, suggesting a protective role. We report that, following allergen challenge, wild-type mice exhibiting airway hyperresponsivity have increased airway levels of the enzyme GSNO reductase (GSNOR) and are depleted of lung S-nitrosothiols (SNOs). In contrast, mice with genetic deletion of GSNOR exhibit increases in lung SNOs and are protected from airway hyperresponsivity. Our results indicate that endogenous SNOs, governed by GSNOR, are critical regulators of airway responsivity and may provide new therapeutic approaches to asthma.

Continuous positive airway pressure (CPAP) decreases pulmonary shunt in anaesthetized horses.

PubMed

Mosing, Martina; MacFarlane, Paul; Bardell, David; Lüthi, Laura; Cripps, Peter J; Bettschart-Wolfensberger, Regula

2016-11-01

To evaluate the effects of continuous positive airway pressure (CPAP) on intrapulmonary shunt, cardiac output and oxygen delivery in horses subjected to a 6 hour period of general anaesthesia. Randomized, experimental, crossover study. Ten healthy adult horses. Following medetomidine, diazepam and ketamine administration, orotracheal intubation was performed and horses positioned in dorsal recumbency. Anaesthesia was maintained with isoflurane carried in an oxygen and air mix (FiO 2 0.5) combined with a medetomidine infusion. Horses were anaesthetized twice and either CPAP (8 cmH 2 O) or physiologic airway pressure (NO CPAP) was applied to the lungs for 6 hours; the order of treatments was randomly assigned. Following induction of anaesthesia, cardiovascular and respiratory variables (including arterial blood gas analysis) were recorded every 30 minutes, cardiac output was measured every 60 minutes using the lithium dilution technique and oxygen delivery calculated. If PaCO 2 exceeded 100 mmHg (13.3 kPa), controlled ventilation was initiated and horses excluded from further data collection. Groups were compared using a general linear model. Data from eight horses were analysed. PaO 2 was 15-56 mmHg (2.00-7.45 kPa) higher (p < 0.001) and shunt fraction 6-14% lower (p < 0.001) in the CPAP group. No differences were seen for cardiac output and oxygen delivery. The lack of difference in oxygen delivery was attributed to lower haemoglobin levels in the CPAP group than in the NO CPAP group. CPAP of 8 cmH 2 O can be used in dorsally recumbent horses to decrease pulmonary shunt fraction without causing a decrease in cardiac output during longterm anaesthesia. © 2016 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.

Hesperetin-5,7,3'-O-triacetate suppresses airway hyperresponsiveness in ovalbumin-sensitized and challenged mice without reversing xylazine/ketamine-induced anesthesia in normal mice.

PubMed

Yang, You-Lan; Chen, Chi-Li; Chen, Chi-Ming; Ko, Wun-Chang

2017-05-30

We recently reported that hesperetin-5,7,3'-O-triacetate (HTA) dually inhibited phosphodiesterase (PDE)3/4 with a therapeutic ratio of 20.8. The application and development of PDE4 inhibitors for treating asthma or COPD are limited by their side effects, such as nausea, vomiting and gastric hypersecretion. PDE4 inhibitors were reported to reverse xylazine/ketamine-induced anesthesia in rats and triggered vomiting in ferrets. Thus the reversing effect of HTA on xylazine/ketamine-induced anesthesia in mice was studied to assess emetic effect of HTA. The aim of this study was to prove the therapeutic effect of HTA without vomiting effect at an effective dose for treating COPD. Ten female BALB/c mice in each group were sensitized by ovalbumin (OVA) on days 0 and 14. On day 21, these mice were emphasized the sensitization by Freund's complete adjuvant. Mice were challenged by 1% OVA nebulization on days 28, 29, and 30. Airway hyperresponsiveness (AHR) was assessed on day 32 in each group, using the FlexiVent system to determine airway resistance (R L ) and lung dynamic compliance (C dyn ) in anesthetized ovalbumin (OVA)-sensitized and challenged mice. Each group was orally administered HTA (10 ~ 100 μmol/kg), roflumilast (1 and 5 mg/kg) or vehicles (controls) 2 h before and 6 and 24 h after OVA provocation. For comparison, sham-treated mice were challenged with saline instead of 1% OVA. The ability to reverse xylazine/ketamine-induced anesthesia by HTA or roflumilast for 3 h was determined in normal mice. We used roflumilast, a selective PDE4 inhibitor and bronchodilator for severe COPD approved by the US Food and Drug Administration, as a reference drug. In the results, HTA (100 μmol/kg, p.o.) or roflumilast (5 mg/kg, p.o.) significantly suppressed all R L values of MCh at 0.78 ~ 25 mg/mL and enhanced C dyn values of MCh at 3.125 ~ 25 mg/mL compared to OVA-sensitized and -challenged control mice. Orally administered 1, 3 or 10 mg/kg roflumilast

IMD-4690, a novel specific inhibitor for plasminogen activator inhibitor-1, reduces allergic airway remodeling in a mouse model of chronic asthma via regulating angiogenesis and remodeling-related mediators.

PubMed

Tezuka, Toshifumi; Ogawa, Hirohisa; Azuma, Masahiko; Goto, Hisatsugu; Uehara, Hisanori; Aono, Yoshinori; Hanibuchi, Masaki; Yamaguchi, Yoichi; Fujikawa, Tomoyuki; Itai, Akiko; Nishioka, Yasuhiko

2015-01-01

Plasminogen activator inhibitor (PAI)-1 is the principal inhibitor of plasminogen activators, and is responsible for the degradation of fibrin and extracellular matrix. IMD-4690 is a newly synthesized inhibitor for PAI-1, whereas the effect on allergic airway inflammation and remodeling is still unclear. We examined the in vivo effects by using a chronic allergen exposure model of bronchial asthma in mice. The model was generated by an immune challenge for 8 weeks with house dust mite antigen, Dermatophagoides pteronyssinus (Dp). IMD-4690 was intraperitoneally administered during the challenge. Lung histopathology, hyperresponsiveness and the concentrations of mediators in lung homogenates were analyzed. The amount of active PAI-1 in the lungs was increased in mice treated with Dp. Administration with IMD-4690 reduced an active/total PAI-1 ratio. IMD-4690 also reduced the number of bronchial eosinophils in accordance with the decreased expressions of Th2 cytokines in the lung homogenates. Airway remodeling was inhibited by reducing subepithelial collagen deposition, smooth muscle hypertrophy, and angiogenesis. The effects of IMD-4690 were partly mediated by the regulation of TGF-β, HGF and matrix metalloproteinase. These results suggest that PAI-1 plays crucial roles in airway inflammation and remodeling, and IMD-4690, a specific PAI-1 inhibitor, may have therapeutic potential for patients with refractory asthma due to airway remodeling.

Bronchial inflammation induced PKCζ over-expression: involvement in mechanical properties of airway smooth muscle.

PubMed

Morin, Caroline; Fortin, Samuel; Rousseau, Eric

2012-02-01

Protein kinase C variants (PKCs) have been involved in the control of airway smooth muscle (ASM) tone, and abnormalities in PKC-dependent signaling have been associated with respiratory diseases such as asthma. In this study, the role of atypical PKCζ in airway hyperresponsiveness was investigated, using an in-vitro model of TNFα-treated human bronchi and an in vivo guinea pig model of chronic asthma. Our results demonstrated that PKCζ-specific inhibition produced a significant increase in isoproterenol sensitivity in TNFα-treated bronchi and ovalbumin (OVA)-sensitized guinea pig bronchi. The role of epoxy-eicosanoids, known to exert anti-inflammatory effects in lung, on PKCζ expression and activity in these models was evaluated. An enhanced PKCζ protein expression was delineated in TNFα-treated bronchi when compared with control (untreated) and epoxy-eicosanoid-treated bronchi. Measurements of Ca(2+) sensitivity, performed in TNFα-treated bronchi, demonstrated that treatment with myristoylated (Myr) PKCζ peptide inhibitor resulted in significant reductions of pCa-induced tension. Epoxy-eicosanoid treatments had similar effects on Ca(2+) sensitivity in TNFα-treated bronchi. In control and epoxy-eicosanoid-treated bronchi, the phosphorylated forms of p38MAPK and CPI-17 were significantly decreased compared with the TNFα-treated bronchi. An enhanced expression of PKCζ was ascertained in our in-vivo model of allergic asthma. Hence an increased Ca(2+) sensitivity could be explained by the phosphorylation of p38-MAPK, which in turn leads to phosphorylation and activation of the CPI-17 regulatory protein. This process was reversed upon treatment with the Myr-PKCζ-peptide inhibitor. The present data provide relevant evidence regarding the role of PKCζ in human and rodent models of airways inflammation.

Toxoplasma gondii tachyzoite-extract acts as a potent immunomodulator against allergic sensitization and airway inflammation.

PubMed

Drinić, Mirjana; Wagner, Angelika; Sarate, Priya; Zwicker, Christian; Korb, Elke; Loupal, Gerhard; Peschke, Roman; Joachim, Anja; Wiedermann, Ursula; Schabussova, Irma

2017-11-09

Epidemiological and experimental studies have shown an inverse relationship between infections with certain parasites and a reduced incidence of allergic diseases. We and others have shown that infection with Toxoplasma gondii prevents the development of allergy in mice. To establish whether this beneficial effect could be recapitulated by soluble products of this parasite, we tested an extract derived from T. gondii tachyzoites. Immunization of BALB/c mice with tachyzoites lysate antigen (TLA) elicited mixed Th1/Th2 responses. When TLA was applied together with the sensitizing ovalbumin (OVA), the development of allergic airway inflammation was reduced, with decreased airway hyperresponsiveness associated with reduced peribronchial and perivascular cellular infiltration, reduced production of OVA-specific Th2 cytokines in lungs and spleens and reduced levels of serum OVA-specific IgG1 as well as IgE-dependent basophil degranulation. Of note, TLA retained its immunomodulatory properties, inducing high levels of IL-6, TNFα, IL-10 and IL-12p70 in bone marrow-derived dendritic cells after heat-inactivation or proteinase K-treatment for disruption of proteins, but not after sodium metaperiodate-treatment that degrades carbohydrate structures, suggesting that carbohydrates may play a role in immunomodulatory properties of TLA. Here we show that extracts derived from parasites may replicate the benefits of parasitic infection, offering new therapies for immune-mediated disorders.

Insulin decreases expression of the pro-inflammatory receptor Proteinase-Activated Receptor-2 on human airway epithelial cells.

PubMed

Gandhi, Vivek D; Palikhe, Nami Shrestha; Hamza, Shereen M; Dyck, Jason R B; Buteau, Jean; Vliagoftis, Harissios

2018-06-08

The authors show that insulin, a hormone with anti-inflammatory properties, decreases the expression of a pro-inflammatory receptor on airway epithelial cells. This observation may explain the heightened respiratory inflammation seen in patients with metabolic syndrome. Copyright © 2018. Published by Elsevier Inc.

Ozone increases susceptibility to antigen inhalation in allergic dogs

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

Yanai, M.; Ohrui, T.; Aikawa, T.

1990-06-01

To determine whether O3 exposure increased airway responsiveness to antigen inhalation, we studied airway responsiveness to acetylcholine (ACh) and Ascaris suum antigen (AA) before and after O3 in dogs both sensitive and insensitive to AA. Airway responsiveness was assessed by determining the provocative concentration of ACh and AA aerosols that increased respiratory resistance (Rrs) to twice the base-line value. O3 (3 parts per million) increased airway responsiveness to ACh in dogs both sensitive and insensitive to AA, and it significantly decreased the ACh provocation concentration from 0.541 +/- 0.095 to 0.102 +/- 0.047 (SE) mg/ml (P less than 0.01; nmore » = 10). AA aerosols, even at the highest concentration in combination with O3, did not increase Rrs in dogs insensitive to AA. However, O3 increased airway responsiveness to AA in AA-sensitive dogs and significantly decreased log AA provocation concentration from 2.34 +/- 0.22 to 0.50 +/- 0.17 (SE) log protein nitrogen units/ml (P less than 0.01; n = 7). O3-induced hyperresponsiveness to ACh returned to the base-line level within 2 wk, but hyperresponsiveness to AA continued for greater than 2 wk. The plasma histamine concentration after AA challenge was significantly higher after than before O3 (P less than 0.01). Intravenous infusion of OKY-046 (100 micrograms.kg-1.min-1), an inhibitor of thromboxane synthesis, inhibited the O3-induced increase in responsiveness to ACh, but it had no effects on the O3-induced increase in responsiveness to AA and the increase in the plasma histamine concentration. These results suggest that O3 increases susceptibility to the antigen in sensitized dogs via a different mechanism from that of O3-induced muscarinic hyperresponsiveness.« less

Shikonin inhibits maturation of bone marrow-derived dendritic cells and suppresses allergic airway inflammation in a murine model of asthma

PubMed Central

Lee, Chen-Chen; Wang, Chien-Neng; Lai, Yu-Ting; Kang, Jaw-Jou; Liao, Jiunn-Wang; Chiang, Bor-Luen; Chen, Hui-Chen; Cheng, Yu-Wen

2010-01-01

BACKGROUND AND PURPOSE Shikonin exhibits a wide range of anti-inflammatory actions. Here, we assessed its effects on maturation of murine bone marrow-derived dendritic cells (BM-DCs) and on allergic reactions in a murine model of asthma. EXPERIMENTAL APPROACH Cultured murine BM-DCs were used to investigate the effects of shikonin on expression of cell surface markers and their stimulation of T-cell proliferation and cytokine production. The therapeutic potential of shikonin was evaluated in a model of allergic airway disease. KEY RESULTS Shikonin dose-dependently inhibited expression of major histocompatibility complex class II, CD80, CD86, CCR7 and OX40L on BM-DCs, induced by a mixture of ovalbumin (OVA; 100 µg·mL−1) and thymic stromal lymphopoietin (TSLP; 20 ng·mL−1). Shikonin-treated BM-DCs were poor stimulators of CD4+ T lymphocyte and induced lower levels of interleukin (IL)-4, IL-5, IL-13 and tumour necrosis factor (TNF)-α release by responding T-cells. After intratracheal instillation of shikonin in OVA-immunized mice, OVA challenge induced lower IL-4, IL-5, IL-13, TNF-α and eotaxin release in bronchial alveolar lavage fluid, lower IL-4 and IL-5 production in lung cells and mediastinal lymph node cells and attenuated OVA-induced lung eosinophilia and airway hyperresponsiveness. CONCLUSION AND IMPLICATIONS Shikonin effectively suppressed OVA + TSLP-induced BM-DC maturation in vitro and inhibited allergic inflammation and airway hyperresponsiveness in a murine model of asthma, showing good potential as a treatment for allergic asthma. Also, our model provides a novel platform for screening drugs for allergic diseases. PMID:20735407

Blockade of IL-23 ameliorates allergic lung inflammation via decreasing the infiltration of Tc17 cells.

PubMed

Cheng, Sheng; Chen, Huilong; Wang, Aili; Bunjhoo, Hansvin; Cao, Yong; Xie, Jungang; Xu, Yongjian; Xiong, Weining

2016-12-01

Tc17 cells are interleukin (IL)-17-producing CD8 + T cells and have been found to participate in the development of allergic asthma. Interleukin-23 is a cytokine that may be involved in modulating the IL-17 response via Th17 cells. This study aimed to investigate whether IL-23 also has immunomodulatory effects on Tc17 cells. An allergic asthmatic mouse model was induced by sensitizing and challenging with ovalbumin (OVA). Anti-IL-23 antibody was administered intratracheally before challenge to the OVA-induced asthmatic mouse model. Airway hyperresponsiveness, lung inflammation, Tc17 cell percentages and IL-17 level in the lung tissue homogenate were measured. Anti-IL-23 treatment reduced airway hyperresponsiveness (Rn 2.471 ±0.5077 vs. 4.051 ±0.2334, p < 0.05), inflammatory cell infiltration in bronchoalveolar lavage fluid (eosinophils 140.0 ±9.869 vs. 222.4 ±31.55, p < 0.05, neutrophils 75.93 ±6.745 vs. 127.4 ±19.73, p < 0.05), airway inflammation and mucus secretion. Treatment with anti-IL-23 antibody also markedly reduced IL-17 level (398.1 ±28.74 vs. 590.6 ±36.13, p < 0.01) and percentage of Th17 and Tc17 cells in lung tissue homogenate (4.200 ±0.1581 vs. 9.314 ±1.027, p < 0.01 and 2.852 ±0.2566 vs. 5.588 ±0.3631, p < 0.01, Th17 and Tc17 cells respectively). Our data suggest that the IL-23/Tc17 cell axis may be involved in the pathogenesis of asthma as the complement of IL-23/Th17 cells.

PULMONARY HYPERRESPONSIVENESS FOLLOWING DERMAL EXPOSURE TO SELECTED DIISOCYANATES

EPA Science Inventory

PULMONARY HYPERRESPONSIVENESS FOLLOWING DERMAL EXPOSURE TO SELECTED DIISOCYANATES

M.J.K. Selgrade, E.H. Boykin, N.H. Coates, D.L. Doerfler, S.H. Gavett
Experimental Toxicology Div., National Health and Environmental Research Laboratory, Office of Research and Developmen...

The effect of early-life stress on airway inflammation in adult mice.

PubMed

Vig, Rattanjeet; Gordon, John R; Thébaud, Bernard; Befus, A Dean; Vliagoftis, Harissios

2010-01-01

Neonatal stress induces permanent physiological changes that may influence the immune system. Early-life stress increases asthma disease severity in children. We investigated the effects of early-life stress on allergic airway inflammation using a murine model of asthma coupled to maternal separation as an early-life stress stimulus. Maternally separated (MS) and unseparated control (CON) mice were sensitized with ovalbumin (OVA) beginning at day 31 after birth. Challenging mice with OVA increased airway hyperresponsiveness (AHR) and the number of inflammatory cells recovered in the bronchoalveolar lavage (BAL), compared to saline-challenged mice. Challenging MS mice with OVA resulted in less total inflammatory cells, eosinophils, interferon-gamma, and interleukin-4 in BAL compared to CON mice. However, MS mice challenged with OVA exhibited AHR similar to CON mice challenged with OVA. In contrast, an enhanced stress protocol (MS+) involving removal of pups from their home cages following the removal of the dam resulted in inflammatory cell accumulation and cytokine levels in the BAL similar to CON mice and higher than MS mice. These findings indicate that the effect of early-life psychological factors on the development of airway inflammatory diseases such as asthma is very complex and depends on the quality of the psychological stress stimulus.

Iptakalim inhibits PDGF-BB-induced human airway smooth muscle cells proliferation and migration

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

Liu, Wenrui; Kong, Hui; Zeng, Xiaoning

Chronic airway diseases are characterized by airway remodeling which is attributed partly to the proliferation and migration of airway smooth muscle cells (ASMCs). ATP-sensitive potassium (K{sub ATP}) channels have been identified in ASMCs. Mount evidence has suggested that K{sub ATP} channel openers can reduce airway hyperresponsiveness and alleviate airway remodeling. Opening K{sup +} channels triggers K{sup +} efflux, which leading to membrane hyperpolarization, preventing Ca{sup 2+}entry through closing voltage-operated Ca{sup 2+} channels. Intracellular Ca{sup 2+} is the most important regulator of muscle contraction, cell proliferation and migration. K{sup +} efflux decreases Ca{sup 2+} influx, which consequently influences ASMCs proliferation andmore » migration. As a K{sub ATP} channel opener, iptakalim (Ipt) has been reported to restrain the proliferation of pulmonary arterial smooth muscle cells (PASMCs) involved in vascular remodeling, while little is known about its impact on ASMCs. The present study was designed to investigate the effects of Ipt on human ASMCs and the mechanisms underlying. Results obtained from cell counting kit-8 (CCK-8), flow cytometry and 5-ethynyl-2′-deoxyuridine (EdU) incorporation showed that Ipt significantly inhibited platelet-derived growth factor (PDGF)-BB-induced ASMCs proliferation. ASMCs migration induced by PDGF-BB was also suppressed by Ipt in transwell migration and scratch assay. Besides, the phosphorylation of Ca{sup 2+}/calmodulin-dependent kinase II (CaMKII), extracellular regulated protein kinases 1/2 (ERK1/2), protein kinase B (Akt), and cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) were as well alleviated by Ipt administration. Furthermore, we found that the inhibition of Ipt on the PDGF-BB-induced proliferation and migration in human ASMCs was blocked by glibenclamide (Gli), a selective K{sub ATP} channel antagonist. These findings provide a strong evidence to support that

Effects of gasoline engine emissions on preexisting allergic airway responses in mice.

PubMed

Day, Kimberly C; Reed, Matthew D; McDonald, Jacob D; Seilkop, Steven K; Barrett, Edward G

2008-10-01

Gasoline-powered vehicle emissions contribute significantly to ambient air pollution. We hypothesized that exposure to gasoline engine emissions (GEE) may exacerbate preexisting allergic airway responses. Male BALB/c mice were sensitized by injection with ovalbumin (OVA) and then received a 10-min aerosolized OVA challenge. Parallel groups were sham-sensitized with saline. Mice were exposed 6 h/day to air (control, C) or GEE containing particulate matter (PM) at low (L), medium (M), or high (H) concentrations, or to the H level with PM removed by filtration (high-filtered, HF). Immediately after GEE exposure mice received another 10-min aerosol OVA challenge (pre-OVA protocol). In a second (post-OVA) protocol, mice were similarly sensitized but only challenged to OVA before air or GEE exposure. Measurements of airway hyperresponsiveness (AHR), bronchoalveolar lavage (BAL), and blood collection were performed approximately 24 h after the last exposure. In both protocols, M, H, and HF GEE exposure significantly decreased BAL neutrophils from nonsensitized mice but had no significant effect on BAL cells from OVA-sensitized mice. In the pre-OVA protocol, GEE exposure increased OVA-specific IgG(1) but had no effect on BAL interleukin (IL)-2, IL-4, IL-13, or interferon (IFN)-gamma in OVA-sensitized mice. Nonsensitized GEE-exposed mice had increased OVA-specific IgG(2a), IgE, and IL-2, but decreased total IgE. In the post-OVA protocol, GEE exposure reduced BAL IL-4, IL-5, and IFN-gamma in nonsensitized mice but had no effect on sensitized mice. These results suggest acute exposure to the gas-vapor phase of GEE suppressed inflammatory cells and cytokines from nonsensitized mice but did not substantially exacerbate allergic responses.

Airway Peroxidases Catalyze Nitration of the β2-Agonist Salbutamol and Decrease Its Pharmacological Activity

PubMed Central

Sallans, Larry; Macha, Stephen; Brown, Kari; McGraw, Dennis W.; Kovacic, Melinda Butsch; Britigan, Bradley E.

2011-01-01

β2-Agonists are the most effective bronchodilators for the rapid relief of asthma symptoms, but for unclear reasons, their effectiveness may be decreased during severe exacerbations. Because peroxidase activity and nitrogen oxides are increased in the asthmatic airway, we examined whether salbutamol, a clinically important β2-agonist, is subject to potentially inactivating nitration. When salbutamol was exposed to myeloperoxidase, eosinophil peroxidase or lactoperoxidase in the presence of hydrogen peroxide (H2O2) and nitrite (NO2−), both absorption spectroscopy and mass spectrometry indicated formation of a new metabolite with features expected for the nitrated drug. The new metabolites showed an absorption maximum at 410 nm and pKa of 6.6 of the phenolic hydroxyl group. In addition to nitrosalbutamol (m/z 285.14), a salbutamol-derived nitrophenol, formed by elimination of the formaldehyde group, was detected (m/z 255.13) by mass spectrometry. It is noteworthy that the latter metabolite was detected in exhaled breath condensates of asthma patients receiving salbutamol but not in unexposed control subjects, indicating the potential for β2-agonist nitration to occur in the inflamed airway in vivo. Salbutamol nitration was inhibited in vitro by ascorbate, thiocyanate, and the pharmacological agents methimazole and dapsone. The efficacy of inhibition depended on the nitrating system, with the lactoperoxidase/H2O2/NO2− being the most affected. Functionally, nitrated salbutamol showed decreased affinity for β2-adrenergic receptors and impaired cAMP synthesis in airway smooth muscle cells compared with the native drug. These results suggest that under inflammatory conditions associated with asthma, phenolic β2-agonists may be subject to peroxidase-catalyzed nitration that could potentially diminish their therapeutic efficacy. PMID:20974700

Primary Prevention of Asthma: Age and Sex Influence Sensitivity to Allergen-Induced Airway Inflammation and Contribute to Asthma Heterogeneity in Guinea Pigs

PubMed Central

Regal, Jean F.; Regal, Ronald R.; Meehan, Jessica L.; Mohrman, Margaret E.

2010-01-01

Background Limiting allergen exposure in the sensitization phase has been proposed as a means of primary prevention of asthma, but its effectiveness is debated. Hypothesis Primary prevention of asthma is more effective in limiting asthma symptoms in young guinea pigs compared with adults, whether males or females. Methods The following experimental groups were used: young/young, sensitized and challenged before sexual maturity; young/adult, sensitized young and challenged after sexual maturity; adult/adult, sensitized and challenged after sexual maturity. Males and females were sensitized intraperitoneally with varying doses of ovalbumin (OVA) and challenged intratracheally with a constant OVA dose. Cellular infiltration into lung and lavage fluid as well as airway hyperresponsiveness to intravenous methacholine was determined 24 h later. Results In unsensitized animals, density of resident inflammatory cells as well as baseline pulmonary function differed with age and sex. Maximum OVA-induced eosinophilia in females occurred at a lower sensitizing dose of OVA than in males, and the slopes of the dose-response relationship differed significantly between sexes. Young females had more pronounced increases in eosinophils compared with some adult treatment groups. The concentrations of OVA-specific antibodies were not directly related to differences in cellular infiltration. Airway hyperresponsiveness to methacholine challenge was observed in all treatment groups. Conclusion Young animals require major reductions in allergen exposure compared with adults to effectively limit airway inflammation in primary prevention. Heterogeneity of asthma symptoms seen with age and sex suggests that primary prevention by limiting allergen exposure or treatment with anti-inflammatory or bronchodilator drugs may be more effective strategies for specific age and gender populations. PMID:16931886

Decreased Expression of Integrin Subunits α3, α6, and α8 in the Branching Airway Mesenchyme of Nitrofen-Induced Hypoplastic Lungs.

PubMed

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

2018-02-01

 Pulmonary hypoplasia (PH), characterized by smaller lung size and reduced airway branching, remains a major cause of neonatal mortality in newborns with congenital diaphragmatic hernia (CDH). Integrin-mediated cell-matrix interactions play an essential role in the fetal lung mesenchyme by stimulating branching morphogenesis. Mice lacking integrin subunits α3 (Itga3) and α6 (Itga6) exhibit severe PH. Furthermore, Itga8-knockout mice show defective airway branching, suggesting that Itga3, Itga6, and Itga8 are crucial for fetal lung development. We hypothesized that expression of Itga3, Itga6, and Itga8 is decreased in the branching airway mesenchyme of hypoplastic rat lungs in the nitrofen-induced CDH model.  Time-mated rats received nitrofen or vehicle on gestational day 9 (D9). Fetuses were sacrificed on D15, D18, and D21, and dissected lungs were divided into control and nitrofen-exposed specimens ( n  = 12 per time-point and group, respectively). Pulmonary gene expression of Itga3, Itga6, and Itga8 was analyzed by quantitative real-time polymerase chain reaction. Immunofluorescence double-staining for Itga3, Itga6, and Itga8 was combined with the mesenchymal marker Fgf10 to evaluate protein expression and localization in branching airway tissue.  Relative mRNA expression of Itga3, Itga6, and Itga8 was significantly decreased in lungs of nitrofen-exposed fetuses on D15, D18, and D21 compared with controls. Confocal laser scanning microscopy showed markedly diminished immunofluorescence of Itga3, Itga6, and Itga8 mainly in mesenchymal cells surrounding branching airways of nitrofen-exposed fetuses on D15, D18, and D21 compared with controls.  Decreased expression of Itga3, Itga6, and Itga8 in the pulmonary mesenchyme may lead to disruptions in airway branching morphogenesis, thus contributing to PH in the nitrofen-induced CDH model. Georg Thieme Verlag KG Stuttgart · New York.

Interleukin(IL)-1 Regulates Ozone-enhanced Tracheal Smooth Muscle Responsiveness by Increasing Substance P (SP) Production in Intrinsic Airway Neurons of Ferret

PubMed Central

Wu, Z.-X.; Barker, J. S.; Batchelor, T. P.; Dey, R.D.

2008-01-01

Exposure to ozone induces airway hyperresponsiveness (AHR) mediated partly by SP released from nerve terminals of intrinsic airway neurons. Our recent studies showed that IL-1, an important multifunctional proinflammatory cytokine, increases synthesis and release of SP from intrinsic airway neurons. The purpose of this study is to investigate the possible involvement of endogenous IL-1 in modulating neural responses associated with ozone-enhanced airway responsiveness. Ferrets were exposed to 2 ppm ozone or filtered air for 3 hrs. IL-1 in the bronchoalveolar lavage (BAL) fluid was significantly increased in ozone-exposed animals and responses of tracheal smooth muscle to methacholine (MCh) and electrical field stimulation (EFS) were elevated significantly. Both the SP nerve fiber density in tracheal smooth muscle and the number of SP-containing neurons in airway ganglia were significantly increased following ozone exposure. Pretreatment with IL-1 receptor antagonist (IL-1 Ra) significantly diminished ozone-enhanced airway responses to EFS as well as ozone-increased SP in the airway. To selectively investigate intrinsic airway neurons, segments of ferret trachea were maintained in culture conditions for 24 hrs to eliminate extrinsic contributions from sensory nerves. The segments were then exposed to 2 ppm ozone in vitro for 3 hrs. The changes of ozone-induced airway responses to MCh and EFS, and the SP levels in airway neurons paralleled those observed with in vivo ozone exposure. The ozone-enhanced airway responses and neuronal SP levels were inhibited by pretreatment with IL-1 Ra. These findings show that IL-1 is released during ozone exposure enhances airway responsiveness by modulating SP expression in airway neurons. PMID:18718561

Expression of T-box transcription factors 2, 4 and 5 is decreased in the branching airway mesenchyme of nitrofen-induced hypoplastic lungs.

PubMed

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

2017-02-01

Pulmonary hypoplasia (PH), characterized by smaller lung size and reduced airway branching, remains a major therapeutic challenge in newborns with congenital diaphragmatic hernia (CDH). T-box transcription factors (Tbx) have been identified as key components of the gene network that regulates fetal lung development. Tbx2, Tbx4 and Tbx5 are expressed throughout the mesenchyme of the developing lung, regulating the process of lung branching morphogenesis. Furthermore, lungs of Tbx2-, Tbx4- and Tbx5-deficient mice are hypoplastic and exhibit decreased lung branching, similar to PH in human CDH. We hypothesized that the expression of Tbx2, Tbx4 and Tbx5 is decreased in the branching airway mesenchyme of hypoplastic rat lungs with nitrofen-induced CDH. Time-mated rats received either nitrofen or vehicle on gestational day 9 (D9). Fetuses were killed on D15, D18 and D21, and dissected lungs were divided into control and nitrofen-exposed specimens. Pulmonary gene expression of Tbx2, Tbx4 and Tbx5 was investigated by quantitative real-time polymerase chain reaction. Immunofluorescence double staining for Tbx2, Tbx4 and Tbx5 was combined with the mesenchymal marker Fgf10 to assess protein expression and localization in branching airway tissue. Relative mRNA levels of Tbx2, Tbx4 and Tbx5 were significantly reduced in lungs of nitrofen-exposed fetuses on D15, D18 and D21 compared to controls. Confocal laser scanning microscopy showed markedly diminished immunofluorescence of Tbx2, Tbx4 and Tbx5 in mesenchymal cells surrounding branching airways of nitrofen-exposed fetuses on D15, D18 and D21 compared to controls. Decreased expression of Tbx2, Tbx4 and Tbx5 in the pulmonary mesenchyme during fetal lung development may lead to a decrease or arrest of airway branching, thus contributing to PH in the nitrofen-induced CDH model.

PKCλ/ι regulates Th17 differentiation and house dust mite-induced allergic airway inflammation.

PubMed

Yang, Yingying; Dong, Panpan; Zhao, Jing; Zhou, Wei; Zhou, Yonghua; Xu, Yongliang; Mei, Congjin; Guo, Fukun; Zheng, Yi; Yang, Jun-Qi

2018-03-01

Asthma is a chronic airway inflammation in which Th2 and Th17 cells play critical roles in its pathogenesis. We have reported that atypical protein kinase (PKC) λ/ι is a new regulator for Th2 differentiation and function. However, the role of PKCλ/ι for Th17 cells remains elusive. In this study, we explored the effect of PKCλ/ι on Th17 cells in the context of ex vivo cell culture systems and an in vivo murine model of allergic airway inflammation with the use of activated T cell-specific conditional PKCλ/ι-deficient mice. Our findings indicate that PKCλ/ι regulates Th17 cells. The secretion of Th17 effector cytokines, including IL-17, IL-21 and IL-22, were inhibited from PKCλ/ι-deficient T cells under non-skewing or Th17-skewing culture conditions. Moreover, the impaired Th17 differentiation and function by the PKCλ/ι-deficiency was associated with the downregulation of Stat3 and Rorγt, key Th17 transcription factors. We developed a model of Th17 and neutrophil-involved allergic airway inflammation by intratracheal inoculation of house dust mites. PKCλ/ι-deficiency significantly inhibited airway inflammations. The infiltrating cells in the lungs and bronchoalveolar lavage fluids were significantly reduced in conditional PKCλ/ι-deficient mice. Th17 effector cytokines were reduced in the bronchoalveolar lavage fluids and lungs at protein and mRNA levels. Thus, PKCλ/ι emerges as a critical regulator of Th17 differentiation and allergic airway hyperresponsiveness. Copyright © 2018 Elsevier B.V. All rights reserved.

Environmentally persistent free radicals induce airway hyperresponsiveness in neonatal rat lungs

PubMed Central

2011-01-01

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

Post-Exposure Antioxidant Treatment in Rats Decreases Airway Hyperplasia and Hyperreactivity Due to Chlorine Inhalation

PubMed Central

Bracher, Andreas; Doran, Stephen F.; Squadrito, Giuseppe L.; Fernandez, Solana; Postlethwait, Edward M.; Bowen, Larry; Matalon, Sadis

2012-01-01

We assessed the safety and efficacy of combined intravenous and aerosolized antioxidant administration to attenuate chlorine gas–induced airway alterations when administered after exposure. Adult male Sprague-Dawley rats were exposed to air or 400 parts per million (ppm) chlorine (a concentration likely to be encountered in the vicinity of industrial accidents) in environmental chambers for 30 minutes, and returned to room air, and they then received a single intravenous injection of ascorbic acid and deferoxamine or saline. At 1 hour and 15 hours after chlorine exposure, the rats were treated with aerosolized ascorbate and deferoxamine or vehicle. Lung antioxidant profiles, plasma ascorbate concentrations, airway morphology, and airway reactivity were evaluated at 24 hours and 7 days after chlorine exposure. At 24 hours after exposure, chlorine-exposed rats had significantly lower pulmonary ascorbate and reduced glutathione concentrations. Treatment with antioxidants restored depleted ascorbate in lungs and plasma. At 7 days after exposure, in chlorine-exposed, vehicle-treated rats, the thickness of the proximal airways was 60% greater than in control rats, with twice the amount of mucosubstances. Airway resistance in response to methacholine challenge was also significantly elevated. Combined treatment with intravenous and aerosolized antioxidants restored airway morphology, the amount of airway mucosubstances, and airway reactivity to control levels by 7 days after chlorine exposure. Our results demonstrate for the first time, to the best of our knowledge, that severe injury to major airways in rats exposed to chlorine, as characterized by epithelial hyperplasia, mucus accumulation, and airway hyperreactivity, can be reversed in a safe and efficacious manner by the post-exposure administration of ascorbate and deferoxamine. PMID:22162906

Tiotropium effects on airway inflammatory events in the cat as an animal model for acute cigarette smoke-induced lung inflammation.

PubMed

Kolahian, Saeed; Shahbazfar, Amir Ali; Tayefi-Nasrabadi, Hossein; Keyhanmanesh, Rana; Ansarin, Khalil; Ghasemi, Hamid; Rashidi, Amir Hossein; Gosens, Reinoud; Hanifeh, Mohsen

2014-08-01

Chronic obstructive pulmonary disease is an inflammatory lung disease mainly caused by tobacco smoke inhalation. Fifteen healthy adult male cats were categorized into 3 groups: (1) control group, (2) exposed to cigarette smoke (CS), and (3) exposed to CS treated with tiotropium. Increases in clinical signs and airway responsiveness in CS cats were found compared to control animals. The airway hyperresponsiveness and clinical signs were significantly attenuated by treatment with tiotropium. The CS-induced pulmonary release of interleukin-6, interleukin-8, monocyte chemotactic protein-1, and tumor necrosis factor alpha was reduced in the tiotropium group. Exposure to CS significantly increased total inflammatory cells number in bronchoalveolar lavage fluid, which was significantly attenuated by treatment with tiotropium. The number of macrophages, eosinophils and neutrophils and lymphocytes was increased after exposure to CS. Tiotropium significantly reduced the number of all these cells. Perivascular, peribronchiolar infiltration of inflammatory cells and Reid index increased in the CS group. Treatment with tiotropium significantly reduced these parameters to control level. Enhanced lipid peroxidation with concomitant reduction of antioxidants status was observed in the CS group. Tiotropium significantly reduced the serum, lung lavage, lung, and tracheal tissue lipid peroxides to near control levels. Tiotropium also decreased lung and tracheal protein leakage, and prevented the reduction of total antioxidant status in serum, lung lavage, lung and tracheal tissue of the CS group. Cigarette smoke increases airway responsiveness and inflammation in a cat model of CS induced lung inflammation. It can effectively be reduced by treatment with tiotropium.

Nogo-B regulates migration and contraction of airway smooth muscle cells by decreasing ARPC 2/3 and increasing MYL-9 expression.

PubMed

Xu, Wujian; Hong, Weijun; Shao, Yan; Ning, Yunye; Cai, Zailong; Li, Qiang

2011-01-21

Abnormal proliferation, apoptosis, migration and contraction of airway smooth muscle (ASM) cells in airway remodeling in asthma are basically excessive repair responses to a network of inflammatory mediators such as PDGF, but the mechanisms of such responses remain unclear. Nogo-B, a member of the reticulum family 4(RTN4), is known to play a key role in arteriogenesis and tissue repair. Further studies are needed to elucidate the role of Nogo-B in airway smooth muscle abnormalities. A mouse model of chronic asthma was established by repeated OVA inhalation and subjected to Nogo-B expression analysis using immunohistochemistry and Western Blotting. Then, primary human bronchial smooth muscle cells (HBSMCs) were cultured in vitro and a siRNA interference was performed to knockdown the expression of Nogo-B in the cells. The effects of Nogo-B inhibition on PDGF-induced HBSMCs proliferation, migration and contraction were evaluated. Finally, a proteomic analysis was conducted to unveil the underlying mechanisms responsible for the function of Nogo-B. Total Nogo-B expression was approximately 3.08-fold lower in chronic asthmatic mice compared to naïve mice, which was obvious in the smooth muscle layer of the airways. Interference of Nogo-B expression by siRNA resulted nearly 96% reduction in mRNA in cultured HBSMCs. In addition, knockdown of Nogo-B using specific siRNA significantly decreased PDGF-induced migration of HBSMCs by 2.3-fold, and increased the cellular contraction by 16% compared to negative controls, but had limited effects on PDGF-induced proliferation. Furthermore, using proteomic analysis, we demonstrate that the expression of actin related protein 2/3 complex subunit 5 (ARPC 2/3) decreased and, myosin regulatory light chain 9 isoform a (MYL-9) increased after Nogo-B knockdown. These data define a novel role for Nogo-B in airway remodeling in chronic asthma. Endogenous Nogo-B, which may exert its effects through ARPC 2/3 and MYL-9, is necessary for the

Fisetin-treatment alleviates airway inflammation through inhbition of MyD88/NF-κB signaling pathway.

PubMed

Huang, Wei; Li, Ming-Li; Xia, Ming-Yue; Shao, Jian-Ying

2018-07-01

Asthma is a common chronic airway inflammation disease and is considered as a major public health problem. Fisetin (3,3',4',7-tetrahydroxyflavone) is a naturally occurring flavonoid abundantly found in different vegetables and fruits. Fisetin has been reported to exhibit various positive biological effects, including anti-proliferative, anticancer, anti-oxidative and neuroprotective effects. We evaluated the effects of fisetin on allergic asthma regulation in mice. Mice were first sensitized, then airway-challenged with ovalbumin (OVA). Whether fisetin treatment attenuated OVA-induced airway inflammation was examined via inflammation inhibition through MyD88-related NF-κB (p65) signaling pathway. Mice were divided into the control (Con), OVA-induced asthma (Mod), 40 (FL) and 50 (FH) mg/kg fisetin-treated OVA-induced asthma groups. Our results found that OVA-induced airway inflammation in mice caused a significant inflammatory response via the activation of MyD88 and NF-κB signaling pathways, leading to release of pro-inflammatory cytokines. In contrast, fisetin-treated mice after OVA induction inhibited activation of MyD88 and NF-κB signaling pathways, resulting in downregulation of pro-inflammatory cytokine secretion. Further, fisetin significantly ameliorated the airway hyperresponsiveness (AHR) towards methacholine (Mch). In addition, fisetin reduced the number of eosinophil, monocyte, neutrophil and total white blood cell in the bronchoalveolar lavage fluid (BALF) of OVA-induced mice. The serum and BALF samples obtained from the OVA-induced mice with fisetin showed lower levels of pro-inflammatory cytokines. The results of our study illustrated that fisetin may be a new promising candidate to inhibit airway inflammation response induced by OVA.

Fisetin-treatment alleviates airway inflammation through inhbition of MyD88/NF-κB signaling pathway

PubMed Central

Huang, Wei; Li, Ming-Li; Xia, Ming-Yue; Shao, Jian-Ying

2018-01-01

Asthma is a common chronic airway inflammation disease and is considered as a major public health problem. Fisetin (3,3′,4′,7-tetrahydroxyflavone) is a naturally occurring flavonoid abundantly found in different vegetables and fruits. Fisetin has been reported to exhibit various positive biological effects, including anti-proliferative, anticancer, anti-oxidative and neuroprotective effects. We evaluated the effects of fisetin on allergic asthma regulation in mice. Mice were first sensi-tized, then airway-challenged with ovalbumin (OVA). Whether fisetin treatment attenuated OVA-induced airway inflammation was examined via inflammation inhibition through MyD88-related NF-κB (p65) signaling pathway. Mice were divided into the control (Con), OVA-induced asthma (Mod), 40 (FL) and 50 (FH) mg/kg fisetin-treated OVA-induced asthma groups. Our results found that OVA-induced airway inflammation in mice caused a significant inflammatory response via the activation of MyD88 and NF-κB signaling pathways, leading to release of pro-inflammatory cytokines. In contrast, fisetin-treated mice after OVA induction inhibited activation of MyD88 and NF-κB signaling pathways, resulting in downregulation of pro-inflammatory cytokine secretion. Further, fisetin significantly ameliorated the airway hyperresponsiveness (AHR) towards methacholine (Mch). In addition, fisetin reduced the number of eosinophil, monocyte, neutrophil and total white blood cell in the bronchoalveolar lavage fluid (BALF) of OVA-induced mice. The serum and BALF samples obtained from the OVA-induced mice with fisetin showed lower levels of pro-inflammatory cytokines. The results of our study illustrated that fisetin may be a new promising candidate to inhibit airway inflammation response induced by OVA. PMID:29568921

Airway responsiveness to methacholine, respiratory symptoms, and dust exposure levels in grain and flour mill workers in eastern France.

PubMed

Massin, N; Bohadana, A B; Wild, P; Kolopp-Sarda, M N; Toamain, J P

1995-06-01

Our goal was to assess the relation between dust exposure levels and the respiratory health status of workers in grain and flour mills in eastern France. We studied 118 male workers from 11 mills and 164 unexposed male controls. Dust concentration was measured by personal sampling methods. Outcome variables included respiratory symptoms, routine pulmonary function tests, and indices of airway responsiveness to methacholine. A great within- and between-area variability of inhalable dust concentration was found in all mills. A dose-response relationship was observed between dust exposure levels and chronic respiratory symptoms, suggesting that exposure to grain and flour dust may lead to chronic bronchitis. A significant relation was found between dust exposure and airway hyper-responsiveness; this finding is important since it has been hypothesized that the latter abnormality may lead to or be a predisposing factor in subsequent chronic, irreversible airflow obstruction.

CpG in Combination with an Inhibitor of Notch Signaling Suppresses Formalin-Inactivated Respiratory Syncytial Virus-Enhanced Airway Hyperresponsiveness and Inflammation by Inhibiting Th17 Memory Responses and Promoting Tissue-Resident Memory Cells in Lungs

PubMed Central

Zhang, Lei; Li, Hongyong; Hai, Yan; Yin, Wei; Li, Wenjian; Zheng, Boyang; Du, Xiaomin; Li, Na; Zhang, Zhengzheng; Deng, Yuqing

2017-01-01

ABSTRACT Respiratory syncytial virus (RSV) is the leading cause of childhood hospitalizations. The formalin-inactivated RSV (FI-RSV) vaccine-enhanced respiratory disease (ERD) has been an obstacle to the development of a safe and effective killed RSV vaccine. Agonists of Toll-like receptor (TLR) have been shown to regulate immune responses induced by FI-RSV. Notch signaling plays critical roles during the differentiation and effector function phases of innate and adaptive immune responses. Cross talk between TLR and Notch signaling pathways results in fine-tuning of TLR-triggered innate inflammatory responses. We evaluated the impact of TLR and Notch signaling on ERD in a murine model by administering CpG, an agonist of TLR9, in combination with L685,458, an inhibitor of Notch signaling during FI-RSV immunization. Activation with CpG or deficiency of MyD88-dependent TLR signaling did not alleviate airway inflammation in FI-RSV-immunized mice. Activation or inhibition of Notch signaling with Dll4, one of the Notch ligands, or L685,458 did not suppress FI-RSV-enhanced airway inflammation either. However, the CpG together with L685,458 markedly inhibited FI-RSV-enhanced airway hyperresponsiveness, weight loss, and lung inflammation. Interestingly, CpG plus L685,458 completely inhibited FI-RSV-associated Th17 and Th17-associated proinflammatory chemokine responses in lungs following RSV challenge but not Th1 or Th2, memory responses. In addition, FI-RSV plus CpG plus L685,458 promoted protective CD8+ lung tissue-resident memory (TRM) cells. These results indicate that activation of TLR signaling combined with inhibition of Notch signaling prevent FI-RSV ERD, and the mechanism appears to involve suppressing proinflammatory Th17 memory responses and promoting protective TRM in lungs. IMPORTANCE RSV is the most important cause of lower respiratory tract infections in infants. The FI-RSV-enhanced respiratory disease (ERD) is a major impediment to the development of a safe

CpG in Combination with an Inhibitor of Notch Signaling Suppresses Formalin-Inactivated Respiratory Syncytial Virus-Enhanced Airway Hyperresponsiveness and Inflammation by Inhibiting Th17 Memory Responses and Promoting Tissue-Resident Memory Cells in Lungs.

PubMed

Zhang, Lei; Li, Hongyong; Hai, Yan; Yin, Wei; Li, Wenjian; Zheng, Boyang; Du, Xiaomin; Li, Na; Zhang, Zhengzheng; Deng, Yuqing; Zeng, Ruihong; Wei, Lin

2017-05-15

Respiratory syncytial virus (RSV) is the leading cause of childhood hospitalizations. The formalin-inactivated RSV (FI-RSV) vaccine-enhanced respiratory disease (ERD) has been an obstacle to the development of a safe and effective killed RSV vaccine. Agonists of Toll-like receptor (TLR) have been shown to regulate immune responses induced by FI-RSV. Notch signaling plays critical roles during the differentiation and effector function phases of innate and adaptive immune responses. Cross talk between TLR and Notch signaling pathways results in fine-tuning of TLR-triggered innate inflammatory responses. We evaluated the impact of TLR and Notch signaling on ERD in a murine model by administering CpG, an agonist of TLR9, in combination with L685,458, an inhibitor of Notch signaling during FI-RSV immunization. Activation with CpG or deficiency of MyD88-dependent TLR signaling did not alleviate airway inflammation in FI-RSV-immunized mice. Activation or inhibition of Notch signaling with Dll4, one of the Notch ligands, or L685,458 did not suppress FI-RSV-enhanced airway inflammation either. However, the CpG together with L685,458 markedly inhibited FI-RSV-enhanced airway hyperresponsiveness, weight loss, and lung inflammation. Interestingly, CpG plus L685,458 completely inhibited FI-RSV-associated Th17 and Th17-associated proinflammatory chemokine responses in lungs following RSV challenge but not Th1 or Th2, memory responses. In addition, FI-RSV plus CpG plus L685,458 promoted protective CD8 + lung tissue-resident memory (TRM) cells. These results indicate that activation of TLR signaling combined with inhibition of Notch signaling prevent FI-RSV ERD, and the mechanism appears to involve suppressing proinflammatory Th17 memory responses and promoting protective TRM in lungs. IMPORTANCE RSV is the most important cause of lower respiratory tract infections in infants. The FI-RSV-enhanced respiratory disease (ERD) is a major impediment to the development of a safe and

Local small airway epithelial injury induces global smooth muscle contraction and airway constriction.

PubMed

Zhou, Jian; Alvarez-Elizondo, Martha B; Botvinick, Elliot; George, Steven C

2012-02-01

Small airway epithelial cells form a continuous sheet lining the conducting airways, which serves many functions including a physical barrier to protect the underlying tissue. In asthma, injury to epithelial cells can occur during bronchoconstriction, which may exacerbate airway hyperreactivity. To investigate the role of epithelial cell rupture in airway constriction, laser ablation was used to precisely rupture individual airway epithelial cells of small airways (<300-μm diameter) in rat lung slices (∼250-μm thick). Laser ablation of single epithelial cells using a femtosecond laser reproducibly induced airway contraction to ∼70% of the original cross-sectional area within several seconds, and the contraction lasted for up to 40 s. The airway constriction could be mimicked by mechanical rupture of a single epithelial cell using a sharp glass micropipette but not with a blunt glass pipette. These results suggest that soluble mediators released from the wounded epithelial cell induce global airway contraction. To confirm this hypothesis, the lysate of primary human small airway epithelial cells stimulated a similar airway contraction. Laser ablation of single epithelial cells triggered a single instantaneous Ca(2+) wave in the epithelium, and multiple Ca(2+) waves in smooth muscle cells, which were delayed by several seconds. Removal of extracellular Ca(2+) or decreasing intracellular Ca(2+) both blocked laser-induced airway contraction. We conclude that local epithelial cell rupture induces rapid and global airway constriction through release of soluble mediators and subsequent Ca(2+)-dependent smooth muscle shortening.

Automated airway evaluation system for multi-slice computed tomography using airway lumen diameter, airway wall thickness and broncho-arterial ratio

NASA Astrophysics Data System (ADS)

Odry, Benjamin L.; Kiraly, Atilla P.; Novak, Carol L.; Naidich, David P.; Lerallut, Jean-Francois

2006-03-01

Pulmonary diseases such as bronchiectasis, asthma, and emphysema are characterized by abnormalities in airway dimensions. Multi-slice computed tomography (MSCT) has become one of the primary means to depict these abnormalities, as the availability of high-resolution near-isotropic data makes it possible to evaluate airways at oblique angles to the scanner plane. However, currently, clinical evaluation of airways is typically limited to subjective visual inspection only: systematic evaluation of the airways to take advantage of high-resolution data has not proved practical without automation. We present an automated method to quantitatively evaluate airway lumen diameter, wall thickness and broncho-arterial ratios. In addition, our method provides 3D visualization of these values, graphically illustrating the location and extent of disease. Our algorithm begins by automatic airway segmentation to extract paths to the distal airways, and to create a map of airway diameters. Normally, airway diameters decrease as paths progress distally; failure to taper indicates abnormal dilatation. Our approach monitors airway lumen diameters along each airway path in order to detect abnormal profiles, allowing even subtle degrees of pathologic dilatation to be identified. Our method also systematically computes the broncho-arterial ratio at every terminal branch of the tree model, as a ratio above 1 indicates potentially abnormal bronchial dilatation. Finally, the airway wall thickness is computed at corresponding locations. These measurements are used to highlight abnormal branches for closer inspection, and can be summed to compute a quantitative global score for the entire airway tree, allowing reproducible longitudinal assessment of disease severity. Preliminary tests on patients diagnosed with bronchiectasis demonstrated rapid identification of lack of tapering, which also was confirmed by corresponding demonstration of elevated broncho-arterial ratios.

Artemisia argyi attenuates airway inflammation in ovalbumin-induced asthmatic animals.

PubMed

Shin, Na-Rae; Ryu, Hyung-Won; Ko, Je-Won; Park, Sung-Hyeuk; Yuk, Heung-Joo; Kim, Ha-Jung; Kim, Jong-Choon; Jeong, Seong-Hun; Shin, In-Sik

2017-09-14

Artemisia argyi is a traditional herbal medicine in Korea and commonly called as mugwort. It is traditionally used as food source and tea to control abdominal pain, dysmenorrhea, uterine hemorrhage, and inflammation. We investigated the effects of A. argyi (TOTAL) and dehydromatricarin A (DA), its active component on ovalbumin (OVA)-induced allergic asthma. The animals were sensitized on day 0 and 14 by intraperitoneal injection of OVA with aluminum hydroxide. On day 21, 22 and 23 after the initial sensitization, the animals received an airway challenge with OVA for 1h using an ultrasonic nebulizer. TOTAL (50 and 100mg/kg) or DA (10 and 20mg/kg) were administered to mice by oral gavage once daily from day 18-23. Airway hyperresponsiveness (AHR) was measured 24h after final OVA challenge. TOTAL and DA treated animals reduced inflammatory cell counts, cytokines and AHR in asthmatic animals, which was accompanied with inflammatory cell accumulation and mucus hypersecretion. Furthermore, TOTAL and DA significantly declined Erk phosphorylation and the expression of MMP-9 in asthmatic animals. In conclusion, we indicate that Total and DA suppress allergic inflammatory responses caused by OVA challenge. It was considered that A. argyi has a potential for treating allergic asthma. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Arsenic alters transcriptional responses to Pseudomonas aeruginosa infection and decreases antimicrobial defense of human airway epithelial cells.

PubMed

Goodale, Britton C; Rayack, Erica J; Stanton, Bruce A

2017-09-15

Arsenic contamination of drinking water and food threatens the health of hundreds of millions of people worldwide by increasing the risk of numerous diseases. Arsenic exposure has been associated with infectious lung disease in epidemiological studies, but it is not yet understood how ingestion of low levels of arsenic increases susceptibility to bacterial infection. Accordingly, the goal of this study was to examine the effect of arsenic on gene expression in primary human bronchial epithelial (HBE) cells and to determine if arsenic altered epithelial cell responses to Pseudomonas aeruginosa, an opportunistic pathogen. Bronchial epithelial cells line the airway surface, providing a physical barrier and serving critical roles in antimicrobial defense and signaling to professional immune cells. We used RNA-seq to define the transcriptional response of HBE cells to Pseudomonas aeruginosa, and investigated how arsenic affected HBE gene networks in the presence and absence of the bacterial challenge. Environmentally relevant levels of arsenic significantly changed the expression of genes involved in cellular redox homeostasis and host defense to bacterial infection, and decreased genes that code for secreted antimicrobial factors such as lysozyme. Using pathway analysis, we identified Sox4 and Nrf2-regulated gene networks that are predicted to mediate the arsenic-induced decrease in lysozyme secretion. In addition, we demonstrated that arsenic decreased lysozyme in the airway surface liquid, resulting in reduced lysis of Microccocus luteus. Thus, arsenic alters the expression of genes and proteins in innate host defense pathways, thereby decreasing the ability of the lung epithelium to fight bacterial infection. Copyright © 2017 Elsevier Inc. All rights reserved.

Assessment of airway hyperreactivity: comparison of forced spirometry and body plethysmography for methacholine challenge tests

PubMed Central

2009-01-01

Introduction Bronchial challenge tests by inhalation of aerosolized methacholine (MCH) are commonly used in the clinical diagnosis of airway hyperresponsiveness (AHR). While the detection of airway narrowing relies on the patient's cooperation performing forced spirometry, body plethysmographic measurements of airway resistance are less depending on the patient's cooperation and do not alter the respiratory tract by maximal maneuvers. Hence we compared both methods concerning their clinical value and correlation during MCH challenges in patients with asthma. Materials and Methods Cumulative MCH challenges test, consisting of up to 5 steps, evaluated with body plethysmography on each step were performed in 155 patients with bronchial asthma. Airway responses were recorded at each step of MCH application (Master-Screen Body, Cardinal Health, Höchberg). At the baseline test and after crossing the provocation dose (PD) threshold in body plethysmography (PD+100 sReff), forced expirations were performed and FEV1, FVC, and FEV1 %FVC were measured. Using regression analysis of the airway parameters and taking the MCH dose as the covariate, we could extrapolate to missing spirometric values and interpolate the estimated MCH dose when crossing the PD threshold (PD-20 FEV1) between two consecutive measurements. The administered PD+100 MCH doses for specific airway resistance, sRtot, and sReff were compared with resistance parameters Rtot and Reff, and to PD-20 of FEV1 and FEV1 %FVC. Results Regarding sReff we found a mild, moderate, or severe AHR in 114 patients (75%), but only 50 (32%) according to FEV1. A statistical analysis showed strongly linear correlated parameters of airway resistance, but no significant correlation between the results of body plethysmography and forced spirometry Conclusions Using MCH challenges, we found specific airway resistance to be the most sensitive parameter to detect AHR. Raw is largely independent of height and gender facilitating the

Azithromycin ameliorates airway remodeling via inhibiting airway epithelium apoptosis.

PubMed

Liu, Yuanqi; Pu, Yue; Li, Diandian; Zhou, Liming; Wan, Lihong

2017-02-01

Azithromycin can benefit treating allergic airway inflammation and remodeling. In the present study, we hypothesized that azithromycin alleviated airway epithelium injury through inhibiting airway epithelium apoptosis via down regulation of caspase-3 and Bax/Bcl2 ratio in vivo and in vitro. Ovalbumin induced rat asthma model and TGF-β1-induced BEAS-2B cell apoptosis model were established, respectively. In vivo experiments, airway epithelium was stained with hematoxylin and eosin (HE) and periodic acid-Schiff (PAS) to histologically evaluate the airway inflammation and remodeling. Airway epithelium apoptotic index (AI) was further analyzed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), while expression of apoptosis related gene (Bax, Bcl2, Caspase-3) in lungs were measured by qRT-PCR and western blotting, respectively. In vitro experiments, apoptosis were evaluated by Flow cytometry (FCM) and TUNEL. Above apoptosis related gene were also measured by qRT-PCR and western blotting. Compared with the OVA group, azithromycin significantly reduced the inflammation score, peribronchial smooth muscle layer thickness, epithelial thickening and goblet cell metaplasia (P<0.05), and effectively suppressed AI of airway epithelium (P<0.05). Moreover, the increasing mRNA and protein expressions of Caspase-3 and Bax/Bcl-2 ratio in lung tissue were all significantly decreased in azithromycin-treated rats (P<0.05). In vitro, azithromycin significantly suppressed TGF-β1-induced BEAS-2B cells apoptosis (P<0.05) and reversed TGF-β1 elevated Caspase-3 mRNA level and Bax/Bcl-2 ratio (P<0.05). Azithromycin is an attractive treatment option for reducing airway epithelial cell apoptosis by improving the imbalance of Bax/Bcl-2 ratio and inhibiting Caspase-3 level in airway epithelium. Copyright © 2016 Elsevier Inc. All rights reserved.

Bronchial hyperresponsiveness testing in athletes of the Swiss Paralympic team

PubMed Central

2013-01-01

Background The aim of this study was to assess airway hyperresponsiveness to eucapnic voluntary hyperventilation and dry powder mannitol challenge in athletes aiming to participate at the Paralympic Games 2008 in Beijing, especially in athletes with spinal cord injury. Methods Forty-four athletes with a disability (27 with paraplegia (group 1), 3 with tetraplegia (group 2) and 14 with other disabilities such as blindness or single limb amputations (group 3) performed spirometry, skin prick testing, measurement of exhaled nitric oxide, eucapnic voluntary hyperventilation challenge test (EVH) and mannitol challenge test (MCT). A fall in FEV1 of ≥10% in either challenge test was deemed positive for exercise-induced bronchoconstriction. Results Fourteen (32%) athletes were atopic and 7 (16%) had a history of physician-diagnosed asthma. Absolute lung function values were significantly lower in patients of group 1 and 2 compared to group 3. Nine (20%) athletes were positive to EVH (8 paraplegics, 1 tetraplegic), and 8 (18%) athletes were positive to MCT (7 paraplegics, 1 tetraplegic). Fourteen (22.7%) subjects were positive to at least one challenge; only three athletes were positive to both tests. None of the athletes in group 3 had a positive test. Both challenge tests showed a significant association with physician-diagnosed asthma status (p = 0.0001). The positive and negative predictive value to diagnose physician-diagnosed asthma was 89% and 91% for EHV, and 75% and 86% for MCT, respectively. Conclusion EVH and MCT can be used to identify, but especially exclude asthma in Paralympic athletes. PMID:23845126

Local small airway epithelial injury induces global smooth muscle contraction and airway constriction

PubMed Central

Zhou, Jian; Alvarez-Elizondo, Martha B.; Botvinick, Elliot

2012-01-01

Small airway epithelial cells form a continuous sheet lining the conducting airways, which serves many functions including a physical barrier to protect the underlying tissue. In asthma, injury to epithelial cells can occur during bronchoconstriction, which may exacerbate airway hyperreactivity. To investigate the role of epithelial cell rupture in airway constriction, laser ablation was used to precisely rupture individual airway epithelial cells of small airways (<300-μm diameter) in rat lung slices (∼250-μm thick). Laser ablation of single epithelial cells using a femtosecond laser reproducibly induced airway contraction to ∼70% of the original cross-sectional area within several seconds, and the contraction lasted for up to 40 s. The airway constriction could be mimicked by mechanical rupture of a single epithelial cell using a sharp glass micropipette but not with a blunt glass pipette. These results suggest that soluble mediators released from the wounded epithelial cell induce global airway contraction. To confirm this hypothesis, the lysate of primary human small airway epithelial cells stimulated a similar airway contraction. Laser ablation of single epithelial cells triggered a single instantaneous Ca2+ wave in the epithelium, and multiple Ca2+ waves in smooth muscle cells, which were delayed by several seconds. Removal of extracellular Ca2+ or decreasing intracellular Ca2+ both blocked laser-induced airway contraction. We conclude that local epithelial cell rupture induces rapid and global airway constriction through release of soluble mediators and subsequent Ca2+-dependent smooth muscle shortening. PMID:22114176

Anatomic and physiopathologic changes affecting the airway of the elderly patient: implications for geriatric-focused airway management

PubMed Central

Johnson, Kathleen N; Botros, Daniel B; Groban, Leanne; Bryan, Yvon F

2015-01-01

There are many anatomical, physiopathological, and cognitive changes that occur in the elderly that affect different components of airway management: intubation, ventilation, oxygenation, and risk of aspiration. Anatomical changes occur in different areas of the airway from the oral cavity to the larynx. Common changes to the airway include tooth decay, oropharyngeal tumors, and significant decreases in neck range of motion. These changes may make intubation challenging by making it difficult to visualize the vocal cords and/or place the endotracheal tube. Also, some of these changes, including but not limited to, atrophy of the muscles around the lips and an edentulous mouth, affect bag mask ventilation due to a difficult face-mask seal. Physiopathologic changes may impact airway management as well. Common pulmonary issues in the elderly (eg, obstructive sleep apnea and COPD) increase the risk of an oxygen desaturation event, while gastrointestinal issues (eg, achalasia and gastroesophageal reflux disease) increase the risk of aspiration. Finally, cognitive changes (eg, dementia) not often seen as related to airway management may affect patient cooperation, especially if an awake intubation is required. Overall, degradation of the airway along with other physiopathologic and cognitive changes makes the elderly population more prone to complications related to airway management. When deciding which airway devices and techniques to use for intubation, the clinician should also consider the difficulty associated with ventilating the patient, the patient’s risk of oxygen desaturation, and/or aspiration. For patients who may be difficult to bag mask ventilate or who have a risk of aspiration, a specialized supralaryngeal device may be preferable over bag mask for ventilation. Patients with tumors or decreased neck range of motion may require a device with more finesse and maneuverability, such as a flexible fiberoptic broncho-scope. Overall, geriatric-focused airway

Lipoxin A4 stable analogs reduce allergic airway responses via mechanisms distinct from CysLT1 receptor antagonism.

PubMed

Levy, Bruce D; Lukacs, Nicholas W; Berlin, Aaron A; Schmidt, Birgitta; Guilford, William J; Serhan, Charles N; Parkinson, John F

2007-12-01

Cellular recruitment during inflammatory/immune responses is tightly regulated. The ability to dampen inflammation is imperative for prevention of chronic immune responses, as in asthma. Here we investigated the ability of lipoxin A4 (LXA4) stable analogs to regulate airway responses in two allergen-driven models of inflammation. A 15-epi-LXA4 analog (ATLa) and a 3-oxa-15-epi-LXA4 analog (ZK-994) prevented excessive eosinophil and T lymphocyte accumulation and activation after mice were sensitized and aerosol-challenged with ovalbumin. At <0.5 mg/kg, these LXA4 analogs reduced leukocyte trafficking into the lung by >50% and to a greater extent than equivalent doses of the CysLT1 receptor antagonist montelukast. Distinct from montelukast, ATLa treatment led to marked reductions in cysteinyl leukotrienes, interleukin-4 (IL-4), and IL-10, and both ATLa and ZK-994 inhibited levels of IL-13. In cockroach allergen-induced airway responses, both intraperitoneal and oral administration of ZK-994 significantly reduced parameters of airway inflammation and hyper-responsiveness in a dose-dependent manner. ZK-994 also significantly changed the balance of Th1/Th2-specific cytokine levels. Thus, the ATLa/LXA4 analog actions are distinct from CysLT1 antagonism and potently block both allergic airway inflammation and hyper-reactivity. Moreover, these results demonstrate these analogs' therapeutic potential as new agonists for the resolution of inflammation.

Airway structure and function in Eisenmenger's syndrome.

PubMed

McKay, K O; Johnson, P R; Black, J L; Glanville, A R; Armour, C L

1998-10-01

The responsiveness of airways from patients with Eisenmenger's syndrome (n = 5) was compared with that in airways from organ donors (n = 10). Enhanced contractile responses to cholinergic stimulation were found in airways from patients with Eisenmenger's syndrome. The maximal responses to acetylcholine, carbachol, and parasympathetic nerve stimulation in airway tissue from these patients were 221%, 139%, and 152%, respectively, of the maximal responses obtained in donor tissue. Further, relaxation responses to isoproterenol and levocromakalim were absent (n = 2) or markedly impaired (n = 3) in airways from patients with Eisenmenger's syndrome. This attenuated relaxation response was nonspecific in that it was also absent after vasoactive intestinal peptide, sodium nitroprusside, papaverine, and electrical field application. These observations can most likely be explained by a decrease in intrinsic smooth muscle tone, as precontraction of airways revealed relaxation responses that were equivalent to those obtained in donor tissues. Morphometric analysis of tissues used for the functional studies revealed no differences in the airway dimensions (internal perimeter) or airway wall components (e.g., smooth muscle, cartilage) or total area to explain these observations. Although the mechanism for this observed decrease in intrinsic airway smooth muscle tone is not certain, it may be due to alteration in the substructure of the airway wall or, alternatively, may result from the continued release of depressant factors in the vicinity of the smooth muscle which permanently alters smooth muscle responsiveness.

Modeling TH 2 responses and airway inflammation to understand fundamental mechanisms regulating the pathogenesis of asthma.

PubMed

Foster, Paul S; Maltby, Steven; Rosenberg, Helene F; Tay, Hock L; Hogan, Simon P; Collison, Adam M; Yang, Ming; Kaiko, Gerard E; Hansbro, Philip M; Kumar, Rakesh K; Mattes, Joerg

2017-07-01

In this review, we highlight experiments conducted in our laboratories that have elucidated functional roles for CD4 + T-helper type-2 lymphocytes (T H 2 cells), their associated cytokines, and eosinophils in the regulation of hallmark features of allergic asthma. Notably, we consider the complexity of type-2 responses and studies that have explored integrated signaling among classical T H 2 cytokines (IL-4, IL-5, and IL-13), which together with CCL11 (eotaxin-1) regulate critical aspects of eosinophil recruitment, allergic inflammation, and airway hyper-responsiveness (AHR). Among our most important findings, we have provided evidence that the initiation of T H 2 responses is regulated by airway epithelial cell-derived factors, including TRAIL and MID1, which promote T H 2 cell development via STAT6-dependent pathways. Further, we highlight studies demonstrating that microRNAs are key regulators of allergic inflammation and potential targets for anti-inflammatory therapy. On the background of T H 2 inflammation, we have demonstrated that innate immune cells (notably, airway macrophages) play essential roles in the generation of steroid-resistant inflammation and AHR secondary to allergen- and pathogen-induced exacerbations. Our work clearly indicates that understanding the diversity and spatiotemporal role of the inflammatory response and its interactions with resident airway cells is critical to advancing knowledge on asthma pathogenesis and the development of new therapeutic approaches. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Inhibitory effect of kefiran on ovalbumin-induced lung inflammation in a murine model of asthma.

PubMed

Kwon, Ok-Kyoung; Ahn, Kyung-Seop; Lee, Mee-Young; Kim, So-Young; Park, Bo-Young; Kim, Mi-Kyoung; Lee, In-Young; Oh, Sei-Ryang; Lee, Hyeong-Kyu

2008-12-01

Kefiran is a major component of kefir which is a microbial symbiont mixture that produces jelly-like grains. This study aimed to evaluate the therapeutic availability of kefiran on the ovalbumin-induced asthma mouse model in which airway inflammation and airway hyper-responsiveness were found in the lung. BALB/c mice sensitized and challenged to ovalbumin were treated intra-gastrically with kefiran 1 hour before the ovalbumin challenge. Kefiran significantly suppressed ovalbumin-induced airway hyper-responsiveness (AHR) to inhaled methacholine. Administration of kefiran significantly inhibited the release of both eosinophils and other inflammatory cells into bronchoalveolar lavage (BAL) fluid and lung tissue which was measured by Diff-Quik. Interleukin-4 (IL-4) and interleukin-5 (IL-5) were also reduced to normal levels after administration of kefiran in BAL fluid. Histological studies demonstrate that kefiran substantially inhibited ovalbumin-induced eosinophilia in lung tissue by H&E staining and goblet cell hyperplasia in the airway by PAS staining. Taken above data, kefiran may be useful for the treatment of inflammation of lung tissue and airway hyper-responsiveness in a murine model and may have therapeutic potential for the treatment of allergic bronchial asthma.

Role of prostaglandin D2/CRTH2 pathway on asthma exacerbation induced by Aspergillus fumigatus

PubMed Central

Liu, Haixia; Zheng, Mingrui; Qiao, Jianou; Dang, Yajie; Zhang, Pengyu; Jin, Xianqiao

2014-01-01

Aspergillus fumigatus is often associated in asthmatic patients with the exacerbation of asthma symptoms. The pathomechanism of this phenomenon has not been fully understood. Here, we evaluated the immunological mechanisms and the role of the prostaglandin D2/ Chemoattractant Receptor-Homologous Molecule Expressed on Th2 Cells (CRTH2) pathway in the development of Aspergillus-associated asthma exacerbation. We studied the effects of A. fumigatus on airway inflammation and bronchial hyper-responsiveness in a rat model of chronic asthma. Inhalation delivery of A. fumigatus conidia increased the airway eosinophilia and bronchial hyper-responsiveness in ovalbumin-sensitized, challenged rats. These changes were associated with prostaglandin D2 synthesis and CRTH2 expression in the lungs. Direct inflammation occurred in ovalbumin-sensitized, challenged animals, whereas pre-treatment with an antagonist against CRTH2 nearly completely eliminated the A. fumigatus-induced worsening of airway eosinophilia and bronchial hyper-responsiveness. Our data demonstrate that production of prostaglandin D2 followed by eosinophil recruitment into the airways via a CRTH2 receptor are the major pathogenic factors responsible for the A. fumigatus-induced enhancement of airway inflammation and responsiveness. PMID:24329550

Extracellular acidification induces connective tissue growth factor production through proton-sensing receptor OGR1 in human airway smooth muscle cells

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

Matsuzaki, Shinichi; Ishizuka, Tamotsu, E-mail: tamotsui@showa.gunma-u.ac.jp; Yamada, Hidenori

Highlights: {yields} The involvement of extracellular acidification in airway remodeling was investigated. {yields} Extracellular acidification alone induced CTGF production in human ASMCs. {yields} Extracellular acidification enhanced TGF-{beta}-induced CTGF production in human ASMCs. {yields} Proton-sensing receptor OGR1 was involved in acidic pH-stimulated CTGF production. {yields} OGR1 may play an important role in airway remodeling in asthma. -- Abstract: Asthma is characterized by airway inflammation, hyper-responsiveness and remodeling. Extracellular acidification is known to be associated with severe asthma; however, the role of extracellular acidification in airway remodeling remains elusive. In the present study, the effects of acidification on the expression of connectivemore » tissue growth factor (CTGF), a critical factor involved in the formation of extracellular matrix proteins and hence airway remodeling, were examined in human airway smooth muscle cells (ASMCs). Acidic pH alone induced a substantial production of CTGF, and enhanced transforming growth factor (TGF)-{beta}-induced CTGF mRNA and protein expression. The extracellular acidic pH-induced effects were inhibited by knockdown of a proton-sensing ovarian cancer G-protein-coupled receptor (OGR1) with its specific small interfering RNA and by addition of the G{sub q/11} protein-specific inhibitor, YM-254890, or the inositol-1,4,5-trisphosphate (IP{sub 3}) receptor antagonist, 2-APB. In conclusion, extracellular acidification induces CTGF production through the OGR1/G{sub q/11} protein and inositol-1,4,5-trisphosphate-induced Ca{sup 2+} mobilization in human ASMCs.« less

Airway remodelling and inflammation in asthma are dependent on the extracellular matrix protein fibulin-1c.

PubMed

Liu, Gang; Cooley, Marion A; Nair, Prema M; Donovan, Chantal; Hsu, Alan C; Jarnicki, Andrew G; Haw, Tatt Jhong; Hansbro, Nicole G; Ge, Qi; Brown, Alexandra C; Tay, Hock; Foster, Paul S; Wark, Peter A; Horvat, Jay C; Bourke, Jane E; Grainge, Chris L; Argraves, W Scott; Oliver, Brian G; Knight, Darryl A; Burgess, Janette K; Hansbro, Philip M

2017-12-01

Asthma is a chronic inflammatory disease of the airways. It is characterized by allergic airway inflammation, airway remodelling, and airway hyperresponsiveness (AHR). Asthma patients, in particular those with chronic or severe asthma, have airway remodelling that is associated with the accumulation of extracellular matrix (ECM) proteins, such as collagens. Fibulin-1 (Fbln1) is an important ECM protein that stabilizes collagen and other ECM proteins. The level of Fbln1c, one of the four Fbln1 variants, which predominates in both humans and mice, is increased in the serum and airways fluids in asthma but its function is unclear. We show that the level of Fbln1c was increased in the lungs of mice with house dust mite (HDM)-induced chronic allergic airway disease (AAD). Genetic deletion of Fbln1c and therapeutic inhibition of Fbln1c in mice with chronic AAD reduced airway collagen deposition, and protected against AHR. Fbln1c-deficient (Fbln1c -/- ) mice had reduced mucin (MUC) 5 AC levels, but not MUC5B levels, in the airways as compared with wild-type (WT) mice. Fbln1c interacted with fibronectin and periostin that was linked to collagen deposition around the small airways. Fbln1c -/- mice with AAD also had reduced numbers of α-smooth muscle actin-positive cells around the airways and reduced airway contractility as compared with WT mice. After HDM challenge, these mice also had fewer airway inflammatory cells, reduced interleukin (IL)-5, IL-13, IL-33, tumour necrosis factor (TNF) and CXCL1 levels in the lungs, and reduced IL-5, IL-33 and TNF levels in lung-draining lymph nodes. Therapeutic targeting of Fbln1c reduced the numbers of GATA3-positive Th2 cells in the lymph nodes and lungs after chronic HDM challenge. Treatment also reduced the secretion of IL-5 and IL-13 from co-cultured dendritic cells and T cells restimulated with HDM extract. Human epithelial cells cultured with Fbln1c peptide produced more CXCL1 mRNA than medium-treated controls. Our data show

Effect of Rho-kinase inhibition on complexity of breathing pattern in a guinea pig model of asthma

PubMed Central

Pazhoohan, Saeed; Javan, Mohammad; Hajizadeh, Sohrab

2017-01-01

Asthma represents an episodic and fluctuating behavior characterized with decreased complexity of respiratory dynamics. Several evidence indicate that asthma severity or control is associated with alteration in variability of lung function. The pathophysiological basis of alteration in complexity of breathing pattern in asthma has remained poorly understood. Regarding the point that Rho-kinase is involved in pathophysiology of asthma, in present study we investigated the effect of Rho-kinase inhibition on complexity of respiratory dynamics in a guinea pig model of asthma. Male Dunkin Hartley guinea pigs were exposed to 12 series of inhalations with ovalbumin or saline. Animals were treated by the Rho-kinase inhibitor Y-27632 (1mM aerosols) prior to each allergen challenge. We recorded respiration of conscious animals using whole-body plethysmography. Exposure to ovalbumin induced lung inflammation, airway hyperresponsiveness and remodeling including goblet cell hyperplasia, increase in the thickness of airways smooth muscles and subepithelial collagen deposition. Complexity analysis of respiratory dynamics revealed a dramatic decrease in irregularity of respiratory rhythm representing less complexity in asthmatic guinea pigs. Inhibition of Rho-kinase reduced the airway remodeling and hyperreponsiveness, but had no significant effect on lung inflammation and complexity of respiratory dynamics in asthmatic animals. It seems that airway hyperresponsiveness and remodeling do not significantly affect the complexity of respiratory dynamics. Our results suggest that inflammation might be the probable cause of shift in the respiratory dynamics away from the normal fluctuation in asthma. PMID:29088265

Perinatal paracetamol exposure in mice does not affect the development of allergic airways disease in early life

PubMed Central

Lee, Debbie C P; Walker, Simone A; Byrne, Adam J; Gregory, Lisa G; Buckley, James; Bush, Andrew; Shaheen, Seif O; Saglani, Sejal; Lloyd, Clare M

2015-01-01

Background Current data concerning maternal paracetamol intake during pregnancy, or intake during infancy and risk of wheezing or asthma in childhood is inconclusive based on epidemiological studies. We have investigated whether there is a causal link between maternal paracetamol intake during pregnancy and lactation and the development of house dust mite (HDM) induced allergic airways disease (AAD) in offspring using a neonatal mouse model. Methods Pregnant mice were administered paracetamol or saline by oral gavage from the day of mating throughout pregnancy and/or lactation. Subsequently, their pups were exposed to intranasal HDM or saline from day 3 of life for up to 6 weeks. Assessments of airway hyper-responsiveness, inflammation and remodelling were made at weaning (3 weeks) and 6 weeks of age. Results Maternal paracetamol exposure either during pregnancy and/or lactation did not affect development of AAD in offspring at weaning or at 6 weeks. There were no effects of maternal paracetamol at any time point on airway remodelling or IgE levels. Conclusions Maternal paracetamol did not enhance HDM induced AAD in offspring. Our mechanistic data do not support the hypothesis that prenatal paracetamol exposure increases the risk of childhood asthma. PMID:25841236

Eosinophilic airway disease in a patient with a negative skin prick test, but a positive patch test with platinum salts--implications for medical surveillance.

PubMed

Merget, Rolf; Fartasch, Manigé; Sander, Ingrid; Van Kampen, Vera; Raulf, Monika; Brüning, Thomas

2015-09-01

We present the case of a 52-year-old woman with a topic dermatitis since adolescence who developed work-related hand eczema, cough and runny nose 12 years after she had started working as a laboratory technician at a precious metals refinery. While skin prick test with sodium hexachloroplatinate (SPTPt ) was negative, patch testing with ammonium tetrachloroplatinate was positive after 24, 48, 72, and 96 hr. Inhalation challenge with sodium hexachloroplatinate yielded cough, mild shortness of breath, and a maximal decrease of FEV1 of 8% from baseline 24 hr after the challenge. Significant increases of bronchial hyperresponsiveness, exhaled nitric monoxide and sputum eosinophils were documented after the challenge. We conclude that eosinophilic airway disease due to platinum salts may occur in SPTPt negative subjects. Both, patch testing and inhalation challenge with platinum salts should be considered in SPT negative subjects with occupational exposure to precious metal salts and work-related allergic symptoms. © 2015 Wiley Periodicals, Inc.

Bromelain exerts anti-inflammatory effects in an ovalbumin-induced murine model of allergic airway disease ☆

PubMed Central

Secor, Eric R.; Carson, William F.; Cloutier, Michelle M.; Guernsey, Linda A.; Schramm, Craig M.; Wu, Carol A.; Thrall, Roger S.

2008-01-01

Objective Bromelain, a clinically used pineapple extract and natural product, has reported anti-inflammatory and immunomodulatory activities. The purpose of this study was to determine the effect of bromelain treatment in an ovalbumin (OVA)-induced murine model of allergic airway disease (AAD). Methods To establish AAD, mice were sensitized with intraperitoneal (i.p.) OVA/alum and challenged with daily OVA aerosols. Mice were treated i.p. with either saline, 2 or 6 mg/kg bromelain, twice daily for four consecutive days. Bronchoalveolar lavage leukocytes and cytokines, lung histology, airway hyperresponsiveness, and lymphocyte populations via flow cytometry were compared between groups. Results Bromelain treatment of AAD mice resulted in reduced total BAL leukocytes, eosinophils, CD4+ and CD8+ T lymphocytes, CD4+/CD8+ T cell ratio, and IL-13. Conclusion Bromelain attenuated development of AAD while altering CD4+ to CD8+ T lymphocyte populations. The reduction in AAD outcomes suggests that bromelain may have similar effects in the treatment of human asthma and hypersensitivity disorders. PMID:16337164

Cystic Fibrosis Transmembrane Conductance Regulator in Sarcoplasmic Reticulum of Airway Smooth Muscle. Implications for Airway Contractility

PubMed Central

Cook, Daniel P.; Rector, Michael V.; Bouzek, Drake C.; Michalski, Andrew S.; Gansemer, Nicholas D.; Reznikov, Leah R.; Li, Xiaopeng; Stroik, Mallory R.; Ostedgaard, Lynda S.; Abou Alaiwa, Mahmoud H.; Thompson, Michael A.; Prakash, Y. S.; Krishnan, Ramaswamy; Meyerholz, David K.; Seow, Chun Y.

2016-01-01

Rationale: An asthma-like airway phenotype has been described in people with cystic fibrosis (CF). Whether these findings are directly caused by loss of CF transmembrane conductance regulator (CFTR) function or secondary to chronic airway infection and/or inflammation has been difficult to determine. Objectives: Airway contractility is primarily determined by airway smooth muscle. We tested the hypothesis that CFTR is expressed in airway smooth muscle and directly affects airway smooth muscle contractility. Methods: Newborn pigs, both wild type and with CF (before the onset of airway infection and inflammation), were used in this study. High-resolution immunofluorescence was used to identify the subcellular localization of CFTR in airway smooth muscle. Airway smooth muscle function was determined with tissue myography, intracellular calcium measurements, and regulatory myosin light chain phosphorylation status. Precision-cut lung slices were used to investigate the therapeutic potential of CFTR modulation on airway reactivity. Measurements and Main Results: We found that CFTR localizes to the sarcoplasmic reticulum compartment of airway smooth muscle and regulates airway smooth muscle tone. Loss of CFTR function led to delayed calcium reuptake following cholinergic stimulation and increased myosin light chain phosphorylation. CFTR potentiation with ivacaftor decreased airway reactivity in precision-cut lung slices following cholinergic stimulation. Conclusions: Loss of CFTR alters porcine airway smooth muscle function and may contribute to the airflow obstruction phenotype observed in human CF. Airway smooth muscle CFTR may represent a therapeutic target in CF and other diseases of airway narrowing. PMID:26488271

Guideline-oriented perioperative management of patients with bronchial asthma and chronic obstructive pulmonary disease.

PubMed

Yamakage, Michiaki; Iwasaki, Sohshi; Namiki, Akiyoshi

2008-01-01

Increased airway hyperresponsiveness is a major concern in the perioperative management of patients with bronchial asthma and chronic obstructive pulmonary disease. Guidelines using evidence-based medicine are continually being updated and published regarding the diagnosis, treatment, and prevention of these respiratory disorders. Perioperative management in these patients involves: (1) adequate control of airway hyperresponsiveness, including detection of purulent sputum and infection before surgery; (2) evidence-based control of anesthesia; and (3) the aggressive use of beta-2 adrenergic stimulants and the systemic administration of steroids for the treatment of acute attacks. Good preoperative control, including the use of leukotriene antagonists, can reduce the incidence of life-threatening perioperative complications. Awareness of recent guidelines is thus important in the management of patients with airway hyperresponsiveness. This review covers the most recent guidelines for the perioperative management of patients with bronchial asthma and chronic obstructive pulmonary disease.

Low molecular weight fucoidan ameliorates streptozotocin-induced hyper-responsiveness of aortic smooth muscles in type 1 diabetes rats.

PubMed

Liang, Zhengyang; Zheng, Yuanyuan; Wang, Jing; Zhang, Quanbin; Ren, Shuang; Liu, Tiantian; Wang, Zhiqiang; Luo, Dali

2016-09-15

Low molecular weight fucoidan (LMWF) was prepared from Laminaria japonica Areschoug, a popular seafood and medicinal plant consumed in Asia. Chinese have long been using it as a traditional medicine for curing hypertension and edema. This study was intent to investigate the possible beneficial effect of LMWF on hyper-responsiveness of aortic smooth muscles instreptozotocin (STZ)-induced type 1 diabetic rats. Sprague-Dawley rats were made diabetic by injection of STZ, followed by the administration of LMWF (50 or 100mg/kg/day) or probucol (100mg/kg/day) for 12 weeks. Body weight, blood glucose level, basal blood pressure, serum lipid profiles, oxidative stress, prostanoids production, and vasoconstriction response of endothelium-denuded aorta rings to phenylephrine were measured by Real time-PCR, Western blots, ELISA assay, and force myograph, respectively. LMWF (100mg/kg/day)-treated group showed robust improvements on STZ-induced body weight-loss, hypertension, and hyperlipidaemia as indicated by decreased serum level of total cholesterol, triglyceride, and low density lipoprotein cholesterol; while probucol, a lipid-modifying drug with antioxidant properties, displayed mild effects. In addition, LMWF appreciably ameliorated STZ-elicited hyper-responsiveness and oxidative stress in aortic smooth muscles as indicated by decreased superoxide level, increased glutathione content and higher superoxide dismutase activity. Furthermore, administration with LMWF dramatically prevented cyclooxygenase-2 stimulation and restored the up-regulation of thromboxane synthase and down-regulation of 6-keto-PGF1α (a stable metabolic product of prostaglandin I2) in the STZ-administered rats. This study demonstrates for the first time that LMWF can protect against hyperlipidaemia, hypertension, and hyper-responsiveness of aortic smooth muscles in type 1 diabetic rat via, at least in part, amelioration of oxidative stress and restoration of prostanoids levels in aortic smooth muscles

Protease-activated receptor 2 activation of myeloid dendritic cells regulates allergic airway inflammation

PubMed Central

2011-01-01

Background A common characteristic of allergens is that they contain proteases that can activate protease-activated receptor (PAR-2); however the mechanism by which PAR-2 regulates allergic airway inflammation is unclear. Methods Mice (wild type and PAR-2-deficient) were sensitized using German cockroach (GC) feces (frass), the isolated protease from GC frass, or through adoptive transfer of GC frass-treated bone marrow-derived dendritic cells (BMDC) and measurements of airway inflammation (cellular infiltration, cytokine expression, and mucin production), serum IgE levels and airway hyperresponsiveness (AHR) were assessed. BMDC were cultured, treated with GC frass and assessed for cytokine production. PAR-2 expression on pulmonary mDCs was determined by flow cytometry. Results Exposure to GC frass induced AHR and airway inflammation in wild type mice; however PAR-2-deficient mice had significantly attenuated responses. To directly investigate the role of the protease, we isolated the protease from GC frass and administered the endotoxin-free protease into the airways of mice in the presence of OVA. GC frass proteases were sufficient to promote the development of AHR, serum IgE, and Th2 cytokine production. PAR-2 expression on mDC was upregulated following GC frass exposure, but the presence of a functional PAR-2 did not alter antigen uptake. To determine if PAR-2 activation led to differential cytokine production, we cultured BMDC in the presence of GM-CSF and treated these cells ex vivo with GC frass. PAR-2-deficient BMDC released significantly less IL-6, IL-23 and TNFα compared to BMDC from wild type mice, suggesting PAR-2 activation was important in Th2/Th17 skewing cytokine production. To determine the role for PAR-2 on mDCs on the initiation of allergic airway inflammation, BMDCs from wild type and PAR-2-deficient mice were treated in the presence or absence of GC frass and then adoptively transferred into the airway of wild type mice. Importantly, GC frass

The plant extract Isatis tinctoria L. extract (ITE) inhibits allergen-induced airway inflammation and hyperreactivity in mice.

PubMed

Brattström, A; Schapowal, A; Kamal, M A; Maillet, I; Ryffel, B; Moser, R

2010-07-01

The herbal Isatis tinctoria extract (ITE) inhibits the inducible isoform of cyclooxygenase (COX-2) as well as lipoxygenase (5-LOX) and therefore possesses anti-inflammatory properties. The extract might also be useful in allergic airway diseases which are characterized by chronic inflammation. ITE obtained from leaves by supercritical carbon dioxide extraction was investigated in ovalbumin (OVA) immunised BALB/c mice given intranasally together with antigen challenge in the murine model of allergic airway disease (asthma) with the analysis of the inflammatory and immune parameters in the lung. ITE given with the antigen challenge inhibited in a dose related manner the allergic response. ITE diminished airway hyperresponsiveness (AHR) and eosinophil recruitment into the bronchoalveolar lavage (BAL) fluid upon allergen challenge, but had no effect in the saline control mice. Eosinophil recruitment was further assessed in the lung by eosinophil peroxidase (EPO) activity at a dose of 30 microg ITE per mouse. Microscopic investigations revealed less inflammation, eosinophil recruitment and mucus hyperproduction in the lung in a dose related manner. Diminution of AHR and inflammation was associated with reduced IL-4, IL-5, and RANTES production in the BAL fluid at the 30 microg ITE dose, while OVA specific IgE and eotaxin serum levels remained unchanged. ITE, which has been reported inhibiting COX-2 and 5-LOX, reduced allergic airway inflammation and AHR by inhibiting the production of the Th2 cytokines IL-4 and IL-5, and RANTES. (c) 2009 Elsevier GmbH. All rights reserved.

Antibronchospastic activity of MEN10,627, a novel tachykinin NK2 receptor antagonist, in guinea-pig airways.

PubMed

Perretti, F; Ballati, L; Manzini, S; Maggi, C A; Evangelista, S

1995-01-24

The antibronchospastic activity against acetylcholine, antigen, histamine plus platelet-activating factor (PAF) or the selective tachykinin neurokinin (NK)1 and NK2 receptor agonists of the novel tachykinin NK2 receptor antagonist, MEN10,627 (cyclo(Met-Asp-Trp-Phe-Dap-Leu)cyclo(2 beta-5 beta)), was studied in anesthetized guinea-pigs. MEN10,627 (30-100 nmol/kg i.v.) reduced in a dose-dependent manner the bronchospasm induced by the tachykinin NK2 receptor agonist [beta Ala8]neurokinin A-(4-10) and the effect of the highest dose lasted up to 5 h from its administration. Conversely, airway constriction induced by the NK1 receptor agonist [Sar9]substance P sulfone or acetylcholine was unaffected by MEN10,627 up to a dose of 3 mumol/kg i.v. In animals sensitized with ovalbumin and pretreated with the endopeptidase inhibitor phosphoramidon, the aerosolized antigen produced a bronchospasm which was inhibited by MEN10,627 (30-100 nmol/kg i.v.) but not by the tachykinin NK1 receptor antagonist, (+/-)-CP96,345 ([2R,3R-cis- and [2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1- azabicyclo[2.2.2]octan-3-amine]) (3 mumol/kg i.v.). Both MEN10,627 (30-100 nmol/kg i.v.) and (+/-)-CP96,345 (30-300 nmol/kg i.v.) reduced the PAF-induced hyperresponsiveness to histamine, without affecting the hypotension induced by PAF or the bronchospasm induced by histamine in guinea-pigs not exposed to PAF, showing the involvement of both tachykinin NK1 and NK2 receptors in this model. In summary, MEN10,627 behaves as a potent, selective and long-lasting tachykinin NK2 receptor antagonist in vivo. Further, tachykinin NK2 receptors could be activated during allergic responses and in the development of airway hyperresponsiveness.

Radical-Containing Ultrafine Particulate Matter Initiates Epithelial-to-Mesenchymal Transitions in Airway Epithelial Cells

PubMed Central

Thevenot, Paul T.; Saravia, Jordy; Jin, Nili; Giaimo, Joseph D.; Chustz, Regina E.; Mahne, Sarah; Kelley, Matthew A.; Hebert, Valeria Y.; Dellinger, Barry; Dugas, Tammy R.; DeMayo, Francesco J.

2013-01-01

Environmentally persistent free radicals (EPFRs) in combustion-generated particulate matter (PM) are capable of inducing pulmonary pathologies and contributing to the development of environmental asthma. In vivo exposure of infant rats to EPFRs demonstrates their ability to induce airway hyperresponsiveness to methacholine, a hallmark of asthma. However, the mechanisms by which combustion-derived EPFRs elicit in vivo responses remain elusive. In this study, we used a chemically defined EPFR consisting of approximately 0.2 μm amorphrous silica containing 3% cupric oxide with the organic pollutant 1,2-dichlorobenzene (DCB-230). DCB-230 possesses similar radical content to urban-collected EPFRs but offers several advantages, including lack of contaminants and chemical uniformity. DCB-230 was readily taken up by BEAS-2B and at high doses (200 μg/cm2) caused substantial necrosis. At low doses (20 μg/cm2), DCB-230 particles caused lysosomal membrane permeabilization, oxidative stress, and lipid peroxidation within 24 hours of exposure. During this period, BEAS-2B underwent epithelial-to-mesenchymal transition (EMT), including loss of epithelial cell morphology, decreased E-cadherin expression, and increased α–smooth muscle actin (α-SMA) and collagen I production. Similar results were observed in neonatal air–liquid interface culture (i.e., disruption of epithelial integrity and EMT). Acute exposure of infant mice to DCB-230 resulted in EMT, as confirmed by lineage tracing studies and evidenced by coexpression of epithelial E-cadherin and mesenchymal α-SMA proteins in airway cells and increased SNAI1 expression in the lungs. EMT in neonatal mouse lungs after EPFR exposure may provide an explanation for epidemiological evidence supporting PM exposure and increased risk of asthma. PMID:23087054

Oxidative stress–induced mitochondrial dysfunction drives inflammation and airway smooth muscle remodeling in patients with chronic obstructive pulmonary disease

PubMed Central

Wiegman, Coen H.; Michaeloudes, Charalambos; Haji, Gulammehdi; Narang, Priyanka; Clarke, Colin J.; Russell, Kirsty E.; Bao, Wuping; Pavlidis, Stelios; Barnes, Peter J.; Kanerva, Justin; Bittner, Anton; Rao, Navin; Murphy, Michael P.; Kirkham, Paul A.; Chung, Kian Fan; Adcock, Ian M.; Brightling, Christopher E.; Davies, Donna E.; Finch, Donna K.; Fisher, Andrew J.; Gaw, Alasdair; Knox, Alan J.; Mayer, Ruth J.; Polkey, Michael; Salmon, Michael; Singh, David

2015-01-01

Background Inflammation and oxidative stress play critical roles in patients with chronic obstructive pulmonary disease (COPD). Mitochondrial oxidative stress might be involved in driving the oxidative stress–induced pathology. Objective We sought to determine the effects of oxidative stress on mitochondrial function in the pathophysiology of airway inflammation in ozone-exposed mice and human airway smooth muscle (ASM) cells. Methods Mice were exposed to ozone, and lung inflammation, airway hyperresponsiveness (AHR), and mitochondrial function were determined. Human ASM cells were isolated from bronchial biopsy specimens from healthy subjects, smokers, and patients with COPD. Inflammation and mitochondrial function in mice and human ASM cells were measured with and without the presence of the mitochondria-targeted antioxidant MitoQ. Results Mice exposed to ozone, a source of oxidative stress, had lung inflammation and AHR associated with mitochondrial dysfunction and reflected by decreased mitochondrial membrane potential (ΔΨm), increased mitochondrial oxidative stress, and reduced mitochondrial complex I, III, and V expression. Reversal of mitochondrial dysfunction by the mitochondria-targeted antioxidant MitoQ reduced inflammation and AHR. ASM cells from patients with COPD have reduced ΔΨm, adenosine triphosphate content, complex expression, basal and maximum respiration levels, and respiratory reserve capacity compared with those from healthy control subjects, whereas mitochondrial reactive oxygen species (ROS) levels were increased. Healthy smokers were intermediate between healthy nonsmokers and patients with COPD. Hydrogen peroxide induced mitochondrial dysfunction in ASM cells from healthy subjects. MitoQ and Tiron inhibited TGF-β–induced ASM cell proliferation and CXCL8 release. Conclusions Mitochondrial dysfunction in patients with COPD is associated with excessive mitochondrial ROS levels, which contribute to enhanced inflammation and cell

An extract of Crataegus pinnatifida fruit attenuates airway inflammation by modulation of matrix metalloproteinase-9 in ovalbumin induced asthma.

PubMed

Shin, In Sik; Lee, Mee Young; Lim, Hye Sun; Ha, Hyekyung; Seo, Chang Seob; Kim, Jong-Choon; Shin, Hyeun Kyoo

2012-01-01

Crataegus pinnatifida (Chinese hawthorn) has long been used as a herbal medicine in Asia and Europe. It has been used for the treatment of various cardiovascular diseases such as myocardial weakness, tachycardia, hypertension and arteriosclerosis. In this study, we investigated the anti-inflammatory effects of Crataegus pinnatifida ethanolic extracts (CPEE) on Th2-type cytokines, eosinophil infiltration, expression of matrix metalloproteinase (MMP)-9, and other factors, using an ovalbumin (OVA)-induced murine asthma model. Airways of OVA-sensitized mice exposed to OVA challenge developed eosinophilia, mucus hypersecretion and increased cytokine levels. CPEE was applied 1 h prior to OVA challenge. Mice were administered CPEE orally at doses of 100 and 200 mg/kg once daily on days 18-23. Bronchoalveolar lavage fluid (BALF) was collected 48 h after the final OVA challenge. Levels of interleukin (IL)-4 and IL-5 in BALF were measured using enzyme-linked immunosorbent (ELISA) assays. Lung tissue sections 4 µm in thickness were stained with Mayer's hematoxylin and eosin for assessment of cell infiltration and mucus production with PAS staining, in conjunction with ELISA, and Western blot analyses for the expression of MMP-9, intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 protein expression. CPEE significantly decreased the Th2 cytokines including IL-4 and IL-5 levels, reduced the number of inflammatory cells in BALF and airway hyperresponsiveness, suppressed the infiltration of eosinophil-rich inflammatory cells and mucus hypersecretion and reduced the expression of ICAM-1, VCAM-1 and MMP-9 and the activity of MMP-9 in lung tissue of OVA-challenged mice. These results showed that CPEE can protect against allergic airway inflammation and can act as an MMP-9 modulator to induce a reduction in ICAM-1 and VCAM-1 expression. In conclusion, we strongly suggest the feasibility of CPEE as a therapeutic drug for allergic asthma.

Oxidative stress-induced mitochondrial dysfunction drives inflammation and airway smooth muscle remodeling in patients with chronic obstructive pulmonary disease.

PubMed

Wiegman, Coen H; Michaeloudes, Charalambos; Haji, Gulammehdi; Narang, Priyanka; Clarke, Colin J; Russell, Kirsty E; Bao, Wuping; Pavlidis, Stelios; Barnes, Peter J; Kanerva, Justin; Bittner, Anton; Rao, Navin; Murphy, Michael P; Kirkham, Paul A; Chung, Kian Fan; Adcock, Ian M

2015-09-01

Inflammation and oxidative stress play critical roles in patients with chronic obstructive pulmonary disease (COPD). Mitochondrial oxidative stress might be involved in driving the oxidative stress-induced pathology. We sought to determine the effects of oxidative stress on mitochondrial function in the pathophysiology of airway inflammation in ozone-exposed mice and human airway smooth muscle (ASM) cells. Mice were exposed to ozone, and lung inflammation, airway hyperresponsiveness (AHR), and mitochondrial function were determined. Human ASM cells were isolated from bronchial biopsy specimens from healthy subjects, smokers, and patients with COPD. Inflammation and mitochondrial function in mice and human ASM cells were measured with and without the presence of the mitochondria-targeted antioxidant MitoQ. Mice exposed to ozone, a source of oxidative stress, had lung inflammation and AHR associated with mitochondrial dysfunction and reflected by decreased mitochondrial membrane potential (ΔΨm), increased mitochondrial oxidative stress, and reduced mitochondrial complex I, III, and V expression. Reversal of mitochondrial dysfunction by the mitochondria-targeted antioxidant MitoQ reduced inflammation and AHR. ASM cells from patients with COPD have reduced ΔΨm, adenosine triphosphate content, complex expression, basal and maximum respiration levels, and respiratory reserve capacity compared with those from healthy control subjects, whereas mitochondrial reactive oxygen species (ROS) levels were increased. Healthy smokers were intermediate between healthy nonsmokers and patients with COPD. Hydrogen peroxide induced mitochondrial dysfunction in ASM cells from healthy subjects. MitoQ and Tiron inhibited TGF-β-induced ASM cell proliferation and CXCL8 release. Mitochondrial dysfunction in patients with COPD is associated with excessive mitochondrial ROS levels, which contribute to enhanced inflammation and cell hyperproliferation. Targeting mitochondrial ROS represents

Sex, stress and sleep apnoea: Decreased susceptibility to upper airway muscle dysfunction following intermittent hypoxia in females.

PubMed

O'Halloran, Ken D; Lewis, Philip; McDonald, Fiona

2017-11-01

Obstructive sleep apnoea syndrome (OSAS) is a devastating respiratory control disorder more common in men than women. The reasons for the sex difference in prevalence are multifactorial, but are partly attributable to protective effects of oestrogen. Indeed, OSAS prevalence increases in post-menopausal women. OSAS is characterized by repeated occlusions of the pharyngeal airway during sleep. Dysfunction of the upper airway muscles controlling airway calibre and collapsibility is implicated in the pathophysiology of OSAS, and sex differences in the neuro-mechanical control of upper airway patency are described. It is widely recognized that chronic intermittent hypoxia (CIH), a cardinal feature of OSAS due to recurrent apnoea, drives many of the morbid consequences characteristic of the disorder. In rodents, exposure to CIH-related redox stress causes upper airway muscle weakness and fatigue, associated with mitochondrial dysfunction. Of interest, in adults, there is female resilience to CIH-induced muscle dysfunction. Conversely, exposure to CIH in early life, results in upper airway muscle weakness equivalent between the two sexes at 3 and 6 weeks of age. Ovariectomy exacerbates the deleterious effects of exposure to CIH in adult female upper airway muscle, an effect partially restored by oestrogen replacement therapy. Intriguingly, female advantage intrinsic to upper airway muscle exists with evidence of substantially greater loss of performance in male muscle during acute exposure to severe hypoxic stress. Sex differences in upper airway muscle physiology may have relevance to human OSAS. The oestrogen-oestrogen receptor α axis represents a potential therapeutic target in OSAS, particularly in post-menopausal women. Copyright © 2016 Elsevier B.V. All rights reserved.

Diesel exhaust particles up-regulate interleukin-17A expression via ROS/NF-κB in airway epithelium.

PubMed

Weng, Chih-Ming; Lee, Meng-Jung; He, Jung-Re; Chao, Ming-Wei; Wang, Chun-Hua; Kuo, Han-Pin

2018-05-01

IL-17A is implicated in many aspects of pathogenesis of severe asthma, including inducing neutrophilic inflammation, airway hyperresponsiveness, steroid insensitivity and airway remodeling. Diesel exhaust particles (DEP) emission from vehicles has been shown to expand Th17 cells to increase IL-17A release that contributes to DEP-mediated exacerbation of asthma severity. It is not known whether non-immune cells in airways may also release IL-17A in response to DEP exposure. In this study, We found IL-17A expression was upregulated in the epithelium of severe allergic asthma patients from high road traffic pollution areas compared to those in low. Furthermore, we found DEP concentration-dependently increased IL-17A synthesis and release by 122.3 ± 15.72% and 235.5 ± 18.37%, respectively in primary bronchial epithelial cells (PBEC), accompanied with increased ROS production. Pretreatment of ROS scavenger (NAC) significantly inhibited DEP-induced IL-17A mRNA expression. DEP-induced IκBα degradation can be inhibited by NAC. We also found DEP increased p65 and RelB subunits expression, and pretreatment of NF-κB inhibitor (SN50) also inhibited DEP-induced IL-17A expression. We further found DEP increased NF-κB subunit RelB recruitment to IL-17A promoter in PBEC and airway tissue of severe allergic asthma patients from high road traffic pollution areas. These results indicate DEP stimulates IL-17A expression in airway epithelium through ROS/NF-κB pathway, and provide a possible link between traffic pollution exposure and IL-17A-related responses in severe allergic asthma patients. Copyright © 2018 Elsevier Inc. All rights reserved.

Functional expression of the TMEM16 family of calcium-activated chloride channels in airway smooth muscle

PubMed Central

Remy, Kenneth E.; Danielsson, Jennifer; Funayama, Hiromi; Fu, Xiao Wen; Chang, Herng-Yu Sucie; Yim, Peter; Xu, Dingbang; Emala, Charles W.

2013-01-01

Airway smooth muscle hyperresponsiveness is a key component in the pathophysiology of asthma. Although calcium-activated chloride channel (CaCC) flux has been described in many cell types, including human airway smooth muscle (HASM), the true molecular identity of the channels responsible for this chloride conductance remains controversial. Recently, a new family of proteins thought to represent the true CaCCs was identified as the TMEM16 family. This led us to question whether members of this family are functionally expressed in native and cultured HASM. We further questioned whether expression of these channels contributes to the contractile function of HASM. We identified the mRNA expression of eight members of the TMEM16 family in HASM cells and show immunohistochemical evidence of TMEM16A in both cultured and native HASM. Functionally, we demonstrate that the classic chloride channel inhibitor, 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB), inhibited halide flux in cultured HASM cells. Moreover, HASM cells displayed classical electrophysiological properties of CaCCs during whole cell electrophysiological recordings, which were blocked by using an antibody selective for TMEM16A. Furthermore, two distinct TMEM16A antagonists (tannic acid and benzbromarone) impaired a substance P-induced contraction in isolated guinea pig tracheal rings. These findings demonstrate that multiple members of this recently described family of CaCCs are expressed in HASM cells, they display classic electrophysiological properties of CaCCs, and they modulate contractile tone in airway smooth muscle. The TMEM16 family may provide a novel therapeutic target for limiting airway constriction in asthma. PMID:23997176

Functional expression of the TMEM16 family of calcium-activated chloride channels in airway smooth muscle.

PubMed

Gallos, George; Remy, Kenneth E; Danielsson, Jennifer; Funayama, Hiromi; Fu, Xiao Wen; Chang, Herng-Yu Sucie; Yim, Peter; Xu, Dingbang; Emala, Charles W

2013-11-01

Airway smooth muscle hyperresponsiveness is a key component in the pathophysiology of asthma. Although calcium-activated chloride channel (CaCC) flux has been described in many cell types, including human airway smooth muscle (HASM), the true molecular identity of the channels responsible for this chloride conductance remains controversial. Recently, a new family of proteins thought to represent the true CaCCs was identified as the TMEM16 family. This led us to question whether members of this family are functionally expressed in native and cultured HASM. We further questioned whether expression of these channels contributes to the contractile function of HASM. We identified the mRNA expression of eight members of the TMEM16 family in HASM cells and show immunohistochemical evidence of TMEM16A in both cultured and native HASM. Functionally, we demonstrate that the classic chloride channel inhibitor, 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB), inhibited halide flux in cultured HASM cells. Moreover, HASM cells displayed classical electrophysiological properties of CaCCs during whole cell electrophysiological recordings, which were blocked by using an antibody selective for TMEM16A. Furthermore, two distinct TMEM16A antagonists (tannic acid and benzbromarone) impaired a substance P-induced contraction in isolated guinea pig tracheal rings. These findings demonstrate that multiple members of this recently described family of CaCCs are expressed in HASM cells, they display classic electrophysiological properties of CaCCs, and they modulate contractile tone in airway smooth muscle. The TMEM16 family may provide a novel therapeutic target for limiting airway constriction in asthma.

Variation in Airway Responsiveness of Male C57BL/6 Mice from 5 Vendors

PubMed Central

Chang, Herng-Yu Sucie; Mitzner, Wayne; Watson, Julie

2012-01-01

Mice are now the most commonly used animal model for the study of asthma. The mouse asthma model has many characteristics of the human pathology, including allergic sensitization and airway hyperresponsiveness. Inbred strains are commonly used to avoid variations due to genetic background, but variations due to rearing environment are not as well recognized. After a change in mouse vendors and a switch from C57BL/6J mice to C57BL/6N mice, we noted significant differences in airway responsiveness between the substrains. To further investigate the effect of vendor, we tested C57BL/6N mice from 3 other vendors and found significant differences between several of the substrains. To test whether this difference was due to genetic drift or rearing environment, we purchased new groups of mice from all 5 vendors, bred them in separate vendor-specific groups under uniform environmental conditions, and tested male first generation (F1) offspring at 8 to 10 wk of age. These F1 mice showed no significant differences in airway responsiveness, indicating that the rearing environment rather than genetic differences was responsible for the initial variation in pulmonary phenotype. The environmental factors that caused the phenotypic variation are unknown. However, differences between vendor in feed components, bedding type, or microbiome could have contributed. Whatever the basis, investigators using mouse models of asthma should be cautious in comparing data from mice obtained from different vendors. PMID:23043804

Inflammatory airway responses by nasal inoculation of suspended particulate matter in NC/Nga mice.

PubMed

Ogino, Keiki; Takahashi, Noriko; Kubo, Masayuki; Takeuchi, Akihito; Nakagiri, Motoharu; Fujikura, Yoshihisa

2014-06-01

To evaluate the allergic effect of airborne particulate matter (PM) on the airway, separated soluble supernatant (Sup) and insoluble precipitate (Pre) in suspended PM were inoculated into NC/Nga mice with a high sensitivity for mite allergens. Sup, Pre, or both Sup and Pre with or without pronase treatment were inoculated via the nasal route five times for sensitization and a challenge inoculation on the 11th day in NC/Nga mice. On the 14th day, mice were examined for airway hyperresponsiveness (AHR), bronchoalveolar lavage fluid (BALF) cell count, mRNA expression of Th1 and Th2 cytokines in the lung tissue, and histopathology. Synergistic effects of Sup and Pre were observed as increases in AHR and a histopathological change of Periodic acid-Schiff (PAS) staining. Increases in neutrophils, macrophages, and lymphocytes of BALF cells were dependent on Pre. The expression of IL-4 mRNA was increased by Sup, and those of IL-5 mRNA and Il-13 mRNA was increased by Sup and Pre. Augmented AHR, mRNA expression of IL-4, peribronchial inflammation, and PAS staining by Sup plus Pre were attenuated by treatment of Sup with pronase to digest proteins. These results suggest that some proteins of ambient PM may be important environmental factors for AHR and airway inflammation with the aid of insoluble particulates, although some soluble factors such as endotoxins cannot be ruled out. Copyright © 2012 Wiley Periodicals, Inc.

Objective Cough Frequency, Airway Inflammation, and Disease Control in Asthma.

PubMed

Marsden, Paul A; Satia, Imran; Ibrahim, Baharudin; Woodcock, Ashley; Yates, Lucy; Donnelly, Iona; Jolly, Lisa; Thomson, Neil C; Fowler, Stephen J; Smith, Jaclyn A

2016-06-01

Cough is recognized as an important troublesome symptom in the diagnosis and monitoring of asthma. Asthma control is thought to be determined by the degree of airway inflammation and hyperresponsiveness but how these factors relate to cough frequency is unclear. The goal of this study was to investigate the relationships between objective cough frequency, disease control, airflow obstruction, and airway inflammation in asthma. Participants with asthma underwent 24-h ambulatory cough monitoring and assessment of exhaled nitric oxide, spirometry, methacholine challenge, and sputum induction (cell counts and inflammatory mediator levels). Asthma control was assessed by using the Global Initiative for Asthma (GINA) classification and the Asthma Control Questionnaire (ACQ). The number of cough sounds was manually counted and expressed as coughs per hour (c/h). Eighty-nine subjects with asthma (mean ± SD age, 57 ± 12 years; 57% female) were recruited. According to GINA criteria, 18 (20.2%) patients were classified as controlled, 39 (43.8%) partly controlled, and 32 (36%) uncontrolled; the median ACQ score was 1 (range, 0.0-4.4). The 6-item ACQ correlated with 24-h cough frequency (r = 0.40; P < .001), and patients with uncontrolled asthma (per GINA criteria) had higher median 24-h cough frequency (4.2 c/h; range, 0.3-27.6) compared with partially controlled asthma (1.8 c/h; range, 0.2-25.3; P = .01) and controlled asthma (1.7 c/h; range, 0.3-6.7; P = .002). Measures of airway inflammation were not significantly different between GINA categories and were not correlated with ACQ. In multivariate analyses, increasing cough frequency and worsening FEV1 independently predicted measures of asthma control. Ambulatory cough frequency monitoring provides an objective assessment of asthma symptoms that correlates with standard measures of asthma control but not airflow obstruction or airway inflammation. Moreover, cough frequency and airflow obstruction represent

Lymphocyte Gene Expression Characteristic of Immediate Airway Responses (IAR) and Methacholine (MCH) Hyperresponsiveness in Mice Sensitized and Challenged with Isocyanates

EPA Science Inventory

Exposure to isocyanates has been associated with occupational airway diseases, including asthma. Previously we reported on respiratory and immune responses following dermal sensitization and intranasal challenge of BALB/c mice with 6 different isocyanates. The purpose of this st...

Transient receptor potential cation channel, subfamily V, member 4 and airway sensory afferent activation: Role of adenosine triphosphate.

PubMed

Bonvini, Sara J; Birrell, Mark A; Grace, Megan S; Maher, Sarah A; Adcock, John J; Wortley, Michael A; Dubuis, Eric; Ching, Yee-Man; Ford, Anthony P; Shala, Fisnik; Miralpeix, Montserrat; Tarrason, Gema; Smith, Jaclyn A; Belvisi, Maria G

2016-07-01

Sensory nerves innervating the airways play an important role in regulating various cardiopulmonary functions, maintaining homeostasis under healthy conditions and contributing to pathophysiology in disease states. Hypo-osmotic solutions elicit sensory reflexes, including cough, and are a potent stimulus for airway narrowing in asthmatic patients, but the mechanisms involved are not known. Transient receptor potential cation channel, subfamily V, member 4 (TRPV4) is widely expressed in the respiratory tract, but its role as a peripheral nociceptor has not been explored. We hypothesized that TRPV4 is expressed on airway afferents and is a key osmosensor initiating reflex events in the lung. We used guinea pig primary cells, tissue bioassay, in vivo electrophysiology, and a guinea pig conscious cough model to investigate a role for TRPV4 in mediating sensory nerve activation in vagal afferents and the possible downstream signaling mechanisms. Human vagus nerve was used to confirm key observations in animal tissues. Here we show TRPV4-induced activation of guinea pig airway-specific primary nodose ganglion cells. TRPV4 ligands and hypo-osmotic solutions caused depolarization of murine, guinea pig, and human vagus and firing of Aδ-fibers (not C-fibers), which was inhibited by TRPV4 and P2X3 receptor antagonists. Both antagonists blocked TRPV4-induced cough. This study identifies the TRPV4-ATP-P2X3 interaction as a key osmosensing pathway involved in airway sensory nerve reflexes. The absence of TRPV4-ATP-mediated effects on C-fibers indicates a distinct neurobiology for this ion channel and implicates TRPV4 as a novel therapeutic target for neuronal hyperresponsiveness in the airways and symptoms, such as cough. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Copper oxide nanoparticles aggravate airway inflammation and mucus production in asthmatic mice via MAPK signaling.

PubMed

Park, Ji-Won; Lee, In-Chul; Shin, Na-Rae; Jeon, Chan-Mi; Kwon, Ok-Kyoung; Ko, Je-Won; Kim, Jong-Choon; Oh, Sei-Ryang; Shin, In-Sik; Ahn, Kyung-Seop

2016-01-01

Copper oxide nanoparticles (CuONPs), metal oxide nanoparticles were used in multiple applications including wood preservation, antimicrobial textiles, catalysts for carbon monoxide oxidation and heat transfer fluid in machines. We investigated the effects of CuONPs on the respiratory system in Balb/c mice. In addition, to investigate the effects of CuONPs on asthma development, we used a murine model of ovalbumin (OVA)-induced asthma. CuONPs markedly increased airway hyper-responsiveness (AHR), inflammatory cell counts, proinflammatory cytokines and reactive oxygen species (ROS). CuONPs induced airway inflammation and mucus secretion with increases in phosphorylation of the MAPKs (Erk, JNK and p38). In the OVA-induced asthma model, CuONPs aggravated the increased AHR, inflammatory cell count, proinflammatory cytokines, ROS and immunoglobulin E induced by OVA exposure. In addition, CuONPs markedly increased inflammatory cell infiltration into the lung and mucus secretions, and MAPK phosphorylation was elevated compared to OVA-induced asthmatic mice. Taken together, CuONPs exhibited toxicity on the respiratory system, which was associated with the MAPK phosphorylation. In addition, CuONPs exposure aggravated the development of asthma. We conclude that CuONPs exposure has a potential toxicity in humans with respiratory disease.

Effect of heat-inactivated kefir-isolated Lactobacillus kefiranofaciens M1 on preventing an allergic airway response in mice.

PubMed

Hong, Wei-Sheng; Chen, Yen-Po; Dai, Ting-Yeu; Huang, I-Nung; Chen, Ming-Ju

2011-08-24

In this study, we assessed the anti-asthmatic effects of heat-inactivated Lactobacillus kefiranofaciens M1 (HI-M1) and its fermented milk using different feeding procedures and at various dosage levels. The possible mechanisms whereby HI-M1 has anti-allergic asthmatic effects were also evaluated. Ovalbumin (OVA)-allergic asthma mice that have been orally administrated the HI-M1 samples showed strong inhibition of production of T helper cell (Th) 2 cytokines, pro-inflammatory cytokines, and Th17 cytokines in splenocytes and bronchoalveolar fluid compared to control mice. An increase in regulatory T cell population in splenocytes in the allergic asthma mice after oral administration of H1-M1 was also observed. In addition, all of the features of the asthmatic phenotype, including specific IgE production, airway inflammation, and development of airway hyperresponsiveness, were depressed in a dose-dependent manner by treatment. These findings support the possibility that oral feeding of H1-M1 may be an effective way of alleviating asthmatic symptoms in humans.

Effect of airway acidosis and alkalosis on airway vascular smooth muscle responsiveness to albuterol.

PubMed

Cancado, Jose E; Mendes, Eliana S; Arana, Johana; Horvath, Gabor; Monzon, Maria E; Salathe, Matthias; Wanner, Adam

2015-04-02

In vitro and animal experiments have shown that the transport and signaling of β2-adrenergic agonists are pH-sensitive. Inhaled albuterol, a hydrophilic β2-adrenergic agonist, is widely used for the treatment of obstructive airway diseases. Acute exacerbations of obstructive airway diseases can be associated with changes in ventilation leading to either respiratory acidosis or alkalosis thereby affecting albuterol responsiveness in the airway. The purpose of this study was to determine if airway pH has an effect on albuterol-induced vasodilation in the airway. Ten healthy volunteers performed the following respiratory maneuvers: quiet breathing, hypocapnic hyperventilation, hypercapnic hyperventilation, and eucapnic hyperventilation (to dissociate the effect of pH from the effect of ventilation). During these breathing maneuvers, exhaled breath condensate (EBC) pH and airway blood flow response to inhaled albuterol (ΔQ̇aw) were assessed. Mean ± SE EBC pH (units) and ΔQ̇aw (μl.min(-1).mL(-1)) were 6.4 ± 0.1 and 16.8 ± 1.9 during quiet breathing, 6.3 ± 0.1 and 14.5 ± 2.4 during eucapnic hyperventilation, 6.6 ± 0.2 and -0.2 ± 1.8 during hypocapnic hyperventilation (p = 0.02 and <0.01 vs. quiet breathing), and 5.9 ± 0.1 and 2.0 ± 1.5 during hypercapnic hyperventilation (p = 0.02 and <0.02 vs quiet breathing). Albuterol responsiveness in the airway as assessed by ΔQ̇aw is pH sensitive. The breathing maneuver associated with decreased and increased EBC pH both resulted in a decreased responsiveness independent of the level of ventilation. These findings suggest an attenuated response to hydrophilic β2-adrenergic agonists during airway disease exacerbations associated with changes in pH. Registered at clinicaltrials.gov: NCT01216748 .

TRPV1 inhibition attenuates IL-13 mediated asthma features in mice by reducing airway epithelial injury.

PubMed

Rehman, Rakhshinda; Bhat, Younus Ahmad; Panda, Lipsa; Mabalirajan, Ulaganathan

2013-03-01

Even though neurogenic axis is well known in asthma pathogenesis much attention had not been given on this aspect. Recent studies have reported the importance of TRP channels, calcium-permeable ion channels and key molecules in neurogenic axis, in asthma therapeutics. The role of TRPV1 channels has been underestimated in chronic respiratory diseases as TRPV1 knockout mice of C57BL/6 strains did not attenuate the features of these diseases. However, this could be due to strain differences in the distribution of airway capsaicin receptors. Here, we show that TRPV1 inhibition attenuates IL-13 induced asthma features by reducing airway epithelial injury in BALB/c mice. We found that IL-13 increased not only the lung TRPV1 levels but also TRPV1 expression in bronchial epithelia in BALB/c rather than in C57BL/6 mice. TRPV1 knockdown attenuated airway hyperresponsiveness, airway inflammation, goblet cell metaplasia and subepithelial fibrosis induced by IL-13 in BALB/c mice. Further, TRPV1 siRNA treatment reduced not only the cytosolic calpain and mitochondrial calpain 10 activities in the lung but also bronchial epithelial apoptosis indicating that TRPV1 siRNA might have corrected the intracellular and intramitochondrial calcium overload and its consequent apoptosis. Knockdown of IL-13 in allergen induced asthmatic mice reduced TRPV1, cytochrome c, and activities of calpain and caspase 3 in lung cytosol. Thus, these findings suggest that induction of TRPV1 with IL-13 in bronchial epithelia could lead to epithelial injury in in vivo condition. Since TRPV1 expression is correlated with human asthma severity, TRPV1 inhibition could be beneficial in attenuating airway epithelial injury and asthma features. Copyright © 2013 Elsevier B.V. All rights reserved.

Improvement in bronchial hyper-responsiveness in patients with moderate asthma after treatment with a hypnotic technique: a randomised controlled trial.

PubMed Central

Ewer, T C; Stewart, D E

1986-01-01

A prospective, randomised, single blind, and controlled trial of a hypnotic technique was undertaken in 39 adults with mild to moderate asthma graded for low and high susceptibility to hypnosis. After a six week course of hypnotherapy 12 patients with a high susceptibility score showed a 74.9% improvement (p less than 0.01) in the degree of bronchial hyper-responsiveness to a standardised methacholine challenge test. Daily home recordings of symptoms improved by 41% (p less than 0.01), peak expiratory flow rates improved by 5.5% (p less than 0.01), and use of bronchodilators decreased by 26.2% (p less than 0.05). The improvement in bronchial hyper-reactivity occurred without a change in subjective appreciation of the degree of bronchoconstriction. A control group 17 patients and 10 patients undergoing treatment with low susceptibility to hypnosis had no change in either bronchial hyper-responsiveness or any of the symptoms recorded at home. This study shows the efficacy of a hypnotic technique in adult asthmatics who are moderately to highly susceptible to hypnosis. PMID:3094804

A geranyl acetophenone targeting cysteinyl leukotriene synthesis prevents allergic airway inflammation in ovalbumin-sensitized mice

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

Ismail, Norazren; Jambari, Nuzul Nurahya; Zareen, Seema

Asthma is associated with increased pulmonary inflammation and airway hyperresponsiveness. The current use of corticosteroids in the management of asthma has recently raised issues regarding safety and lack of responsiveness in 5–10% of asthmatic individuals. The aim of the present study was to investigate the therapeutic effect of a non-steroidal small molecule that has cysteinyl leukotriene (cysLT) inhibitory activity, upon attenuation of allergic lung inflammation in an acute murine model. Mice were sensitized with ovalbumin (OVA) and treated with several intraperitoneal doses (100, 20, 2 and 0.2 mg/kg) of 2,4,6,-trihydroxy-3-geranylacetophenone (tHGA). Bronchoalveolar lavage was performed, blood and lung samples weremore » obtained and respiratory function was measured. OVA sensitization increased pulmonary inflammation and pulmonary allergic inflammation was significantly reduced at doses of 100, 20 and 2 mg/kg with no effect at the lowest dose of 0.2 mg/kg. The beneficial effects in the lung were associated with reduced eosinophilic infiltration and reduced secretion of Th2 cytokines and cysLTs. Peripheral blood reduction of total IgE was also a prominent feature. Treatment with tHGA significantly attenuated altered airway hyperresponsiveness as measured by the enhanced pause (Penh) response to incremental doses of methacholine. These data demonstrate that tHGA, a synthetic non-steroidal small molecule, can prevent acute allergic inflammation. This proof of concept opens further avenues of research and development of tHGA as an additional option to the current armamentarium of anti-asthma therapeutics. -- Highlights: ► Safer and effective anti-asthmatic drugs are in great demand. ► tHGA is a new 5-LO/cysLT inhibitor that inhibits allergic asthma in mice. ► tHGA is a natural compound that can be synthesized. ► Doses as low as 2 mg/kg alleviate lung pathology in experimental asthma. ► tHGA is a potential drug lead for the treatment of allergic

Role of tachykinins in airway responses to ozone in rats.

PubMed

Takebayashi, T; Abraham, J; Murthy, G G; Lilly, C; Rodger, I; Shore, S A

1998-08-01

Previous studies that used neonatal capsaicin (Cap) treatment to ablate C fibers indicate that C fibers act to inhibit lung damage and airway hyperresponsiveness after ozone (O3) exposure in rats. The purpose of this study was to determine 1) the role of tachykinins in these protective effects and 2) whether differences in minute ventilation (VE) during O3 exposure might account for the effect of Cap. In the first study, male Sprague-Dawley rats were exposed to 1 part/million O3 or air for 3 h. Four hours later, a bronchoalveolar lavage (BAL) was performed or airway responsiveness was measured. Rats were treated with CP-99994 and SR-48968, selective neurokinin-1- and -2-receptor antagonists, respectively, or with vehicle (Veh). O3 caused an increase in the number of neutrophils recovered from BAL fluid in both the Veh-treated and tachykinin-receptor antagonist (TKRA)-treated rats, but the number of neutrophils was approximately twofold greater in the TKRA-treated rats. In contrast, TKRA treatment had no effect on baseline pulmonary mechanics or airway responsiveness. After O3 exposure, the number of neutrophils in BAL fluid was also greater in Cap- than in Veh-treated rats. O3 reduced VE in both Veh- and Cap-treated rats, but the response was greater (reduction of 44.7 +/- 3.7 vs. 27.8 +/- 6.8%) and occurred earlier (10 vs. 70 min) in Cap- than in Veh-treated rats (P < 0.02). These results suggest that tachykinins mediate protective effects of C fibers against O3-induced lung inflammation. The results also indicate that the more pronounced effect of O3 on BAL neutrophils in Cap-treated rats is not the result of a greater inhaled dose of O3 resulting from greater VE.

A critical role of Gas6/Axl signal in allergic airway responses during RSV vaccine-enhanced disease.

PubMed

Shibata, Takehiko; Ato, Manabu

2017-11-01

Respiratory syncytial virus (RSV) is a common virus that causes lower respiratory infections across a wide range of ages. A licensed RSV vaccine is not available because vaccination with formalin-inactivated RSV (FI-RSV) and the subsequent RSV infection cause not only insufficient induction of neutralizing antibodies but also severe allergic airway responses, termed FI-RSV vaccine-enhanced disease (FI-RSV VED). However, the underlying mechanism has not been identified, although a Th2-biased immune response is known to be a hallmark of this disease. Our previous studies have shown that growth arrest-specific 6 (Gas6)/Axl signaling leads to Th2-biased immune responses during fungus-induced allergic airway inflammation. Here, we show that Gas6/Axl signaling also leads to FI-RSV VED and partially identify the mechanism in mice. Inhibiting Gas6/Axl signaling using Gas6-deficient mice, neutralizing antibodies, and a specific inhibitor of Axl attenuated allergic airway hyperresponsiveness, including airway inflammation, goblet cell hyperplasia, and Th2 cytokine production, in addition to increasing interferon-γ levels and the production of RSV-neutralizing IgG2a in FI-RSV VED. Gas6 was produced in lymph nodes during immunization with FI-RSV. Lymph node cells derived from immunized mice produced high levels of Gas6 and Th2 cytokines, but not IFN-γ, after restimulation with RSV. Finally, we found that dendritic cells stimulated with RSV-glycoprotein (G protein) produced Gas6 and that Axl signaling suppressed DC maturation and the induction of IL-12 production by the toll-like receptor 4 agonist RSV-fusion protein. Taken together, these results indicate that RSV-G protein-induced Gas6/Axl signaling causes allergic airway responses during FI-RSV VED.

Airway exchange of highly soluble gases.

PubMed

Hlastala, Michael P; Powell, Frank L; Anderson, Joseph C

2013-03-01

Highly blood soluble gases exchange with the bronchial circulation in the airways. On inhalation, air absorbs highly soluble gases from the airway mucosa and equilibrates with the blood before reaching the alveoli. Highly soluble gas partial pressure is identical throughout all alveoli. At the end of exhalation the partial pressure of a highly soluble gas decreases from the alveolar level in the terminal bronchioles to the end-exhaled partial pressure at the mouth. A mathematical model simulated the airway exchange of four gases (methyl isobutyl ketone, acetone, ethanol, and propylene glycol monomethyl ether) that have high water and blood solubility. The impact of solubility on the relative distribution of airway exchange was studied. We conclude that an increase in water solubility shifts the distribution of gas exchange toward the mouth. Of the four gases studied, ethanol had the greatest decrease in partial pressure from the alveolus to the mouth at end exhalation. Single exhalation breath tests are inappropriate for estimating alveolar levels of highly soluble gases, particularly for ethanol.

Airway exchange of highly soluble gases

PubMed Central

Powell, Frank L.; Anderson, Joseph C.

2013-01-01

Highly blood soluble gases exchange with the bronchial circulation in the airways. On inhalation, air absorbs highly soluble gases from the airway mucosa and equilibrates with the blood before reaching the alveoli. Highly soluble gas partial pressure is identical throughout all alveoli. At the end of exhalation the partial pressure of a highly soluble gas decreases from the alveolar level in the terminal bronchioles to the end-exhaled partial pressure at the mouth. A mathematical model simulated the airway exchange of four gases (methyl isobutyl ketone, acetone, ethanol, and propylene glycol monomethyl ether) that have high water and blood solubility. The impact of solubility on the relative distribution of airway exchange was studied. We conclude that an increase in water solubility shifts the distribution of gas exchange toward the mouth. Of the four gases studied, ethanol had the greatest decrease in partial pressure from the alveolus to the mouth at end exhalation. Single exhalation breath tests are inappropriate for estimating alveolar levels of highly soluble gases, particularly for ethanol. PMID:23305981

Phenotype and Functional Features of Human Telomerase Reverse Transcriptase Immortalized Human Airway Smooth Muscle Cells from Asthmatic and Non-Asthmatic Donors.

PubMed

Burgess, J K; Ketheson, A; Faiz, A; Limbert Rempel, K A; Oliver, B G; Ward, J P T; Halayko, A J

2018-01-16

Asthma is an obstructive respiratory disease characterised by chronic inflammation with airway hyperresponsiveness. In asthmatic airways, there is an increase in airway smooth muscle (ASM) cell bulk, which differs from non-asthmatic ASM in characteristics. This study aimed to assess the usefulness of hTERT immortalisation of human ASM cells as a research tool. Specifically we compared proliferative capacity, inflammatory mediator release and extracellular matrix (ECM) production in hTERT immortalised and parent primary ASM cells from asthmatic and non-asthmatic donors. Our studies revealed no significant differences in proliferation, IL-6 and eotaxin-1 production, or CTGF synthesis between donor-matched parent and hTERT immortalised ASM cell lines. However, deposition of ECM proteins fibronectin and fibulin-1 was significantly lower in immortalised ASM cells compared to corresponding primary cells. Notably, previously reported differences in proliferation and inflammatory mediator release between asthmatic and non-asthmatic ASM cells were retained, but excessive ECM protein deposition in asthmatic ASM cells was lost in hTERT ASM cells. This study shows that hTERT immortalised ASM cells mirror primary ASM cells in proliferation and inflammatory profile characteristics. Moreover, we demonstrate both strengths and weaknesses of this immortalised cell model as a representation of primary ASM cells for future asthma pathophysiological research.

Cytochrome c oxidase subunit 4 isoform 2-knockout mice show reduced enzyme activity, airway hyporeactivity, and lung pathology

PubMed Central

Hüttemann, Maik; Lee, Icksoo; Gao, Xiufeng; Pecina, Petr; Pecinova, Alena; Liu, Jenney; Aras, Siddhesh; Sommer, Natascha; Sanderson, Thomas H.; Tost, Monica; Neff, Frauke; Aguilar-Pimentel, Juan Antonio; Becker, Lore; Naton, Beatrix; Rathkolb, Birgit; Rozman, Jan; Favor, Jack; Hans, Wolfgang; Prehn, Cornelia; Puk, Oliver; Schrewe, Anja; Sun, Minxuan; Höfler, Heinz; Adamski, Jerzy; Bekeredjian, Raffi; Graw, Jochen; Adler, Thure; Busch, Dirk H.; Klingenspor, Martin; Klopstock, Thomas; Ollert, Markus; Wolf, Eckhard; Fuchs, Helmut; Gailus-Durner, Valérie; Hrabě de Angelis, Martin; Weissmann, Norbert; Doan, Jeffrey W.; Bassett, David J. P.; Grossman, Lawrence I.

2012-01-01

Cytochrome c oxidase (COX) is the terminal enzyme of the mitochondrial electron transport chain. The purpose of this study was to analyze the function of lung-specific cytochrome c oxidase subunit 4 isoform 2 (COX4i2) in vitro and in COX4i2-knockout mice in vivo. COX was isolated from cow lung and liver as control and functionally analyzed. COX4i2-knockout mice were generated and the effect of the gene knockout was determined, including COX activity, tissue energy levels, noninvasive and invasive lung function, and lung pathology. These studies were complemented by a comprehensive functional screen performed at the German Mouse Clinic (Neuherberg, Germany). We show that isolated cow lung COX containing COX4i2 is about twice as active (88 and 102% increased activity in the presence of allosteric activator ADP and inhibitor ATP, respectively) as liver COX, which lacks COX4i2. In COX4i2-knockout mice, lung COX activity and cellular ATP levels were significantly reduced (−50 and −29%, respectively). Knockout mice showed decreased airway responsiveness (60% reduced Penh and 58% reduced airway resistance upon challenge with 25 and 100 mg methacholine, respectively), and they developed a lung pathology deteriorating with age that included the appearance of Charcot-Leyden crystals. In addition, there was an interesting sex-specific phenotype, in which the knockout females showed reduced lean mass (−12%), reduced total oxygen consumption rate (−8%), improved glucose tolerance, and reduced grip force (−14%) compared to wild-type females. Our data suggest that high activity lung COX is a central determinant of airway function and is required for maximal airway responsiveness and healthy lung function. Since airway constriction requires energy, we propose a model in which reduced tissue ATP levels explain protection from airway hyperresponsiveness, i.e., absence of COX4i2 leads to reduced lung COX activity and ATP levels, which results in impaired airway constriction

Low Doses of Exogenous Interferon-γ Attenuated Airway Inflammation Through Enhancing Fas/FasL-Induced CD4+ T Cell Apoptosis in a Mouse Asthma Model

PubMed Central

Yao, Yinan; Lu, Shan; Lu, Guohua

2012-01-01

To investigate whether low doses of exogenous interferon (IFN)-γ attenuate airway inflammation, and the underlying mechanisms, in asthma. C57BL/6 mice (n=42), after intraperitoneal ovalbumin (OVA) sensitization on day 0 and day 12, were challenged with OVA aerosol for 6 consecutive days. Different doses of IFN-γ were then administered intraperitoneally 5 min before each inhalation during OVA challenge. Airway hyperresponsiveness, airway inflammatory cells, cytokine profiles, and Fas/FasL expression on CD4+ T cells were evaluated in an asthma model. The effect of various IFN-γ doses on Fas/FasL expression and CD4+ T cell apoptosis were assessed in vitro. We demonstrated that low doses of IFN-γ reduced pulmonary infiltration of inflammatory cells, Th2 cytokine production, and goblet cells hyperplasia (P<0.05), while high doses of endogenous IFN-γ had almost no effect. We also found that low doses of IFN-γ relocated Fas/FasL to the CD4+ T cell surface in the asthma model (P<0.05) and increased FasL-induced apoptosis in vitro (P<0.05). Furthermore, treatment with MFL-3, an anti-FasL antibody, partially abolished the anti- inflammatory properties of IFN-γ in the airway rather than affecting the Th1/Th2 balance. This research has revealed an alternative mechanism in asthma that involves low doses of IFN-γ, which attenuate airway inflammation through enhancing Fas/FasL-induced CD4+ T cell apoptosis. PMID:22994871

Quality of Life and Bronchial Hyper-Responsiveness in Subjects With Bronchiectasis: Validation of the Seattle Obstructive Lung Disease Questionnaire in Bronchiectasis.

PubMed

Bulcun, Emel; Arslan, Mesut; Ekici, Aydanur; Ekici, Mehmet

2015-11-01

Bronchiectasis can adversely affect quality of life. However, the tests examining quality of life in bronchiectasis are not sufficient. We examined the validity of a measure designed for COPD, the Seattle Obstructive Lung Disease Questionnaire (SOLQ), in bronchiectasis. In addition, we aimed to compare the quality of life of subjects with bronchiectasis and bronchial hyper-responsiveness with that of those without to identify the effective factors. We studied 78 subjects with clinically stable bronchiectasis and 41 healthy controls matched for age and sex. Subjects were assessed by the SOLQ. A detailed history, physical examination, the Medical Outcomes Study 36-Item Short Form questionnaire, the Hospital Anxiety and Depression Scale, and spirometric measurements were obtained. Cronbach α coefficients, which reflected internal consistency, were >0.70 for all SOLQ components except for treatment satisfaction. SOLQ component scores correlated with all of the component scores of the Medical Outcomes Study 36-Item Short Form questionnaire and the Hospital Anxiety and Depression Scale, confirming their concurrent validity. All SOLQ scores correlated positively with percent-of-predicted FEV1, whereas the physical function, treatment satisfaction, and emotional function correlated negatively with the exacerbation frequency in Pearson analysis. Emotional and physical functions were positively associated with percent-of-predicted FEV1 in linear regression analysis. Compared with subjects without bronchial hyper-responsiveness, those with bronchial hyper-responsiveness had lower FEV1/FVC and more exacerbations/y. Compared with bronchiectasis subjects without bronchial hyper-responsiveness, those with bronchial hyper-responsiveness had significantly lower SOLQ, physical function, and coping skills scores but not emotional function and treatment satisfaction. The SOLQ is a valid instrument for determining quality of life in subjects with bronchiectasis. Subjects with

IL-13 and its genetic variants: effect on current asthma treatments.

PubMed

Townley, Robert G; Sapkota, Muna; Sapkota, Kiran

2011-12-01

Airway hyperresponsiveness is an essential part of the definition of asthma associated temporally with exposure to allergens, certain respiratory viruses, pollutants such as ozone, and certain organic chemicals. Interleukin-13 (IL-13) is implicated as a central regulator in immunoglobulin E (IgE) synthesis, mucus hypersecretion, airway hyperresponsiveness, and fibrosis. The importance of IL-13 in allergic disorders in humans is supported by consistent associations between tissue IL-13 levels and genetic variants in the IL-13 gene and asthma and related traits. Single-nucleotide polymorphisms in IL-13 are associated with allergic phenotypes in several ethnically diverse populations. Glucocorticoids are anti-inflammatory medications often used as maintenance therapy in acute and chronic asthma; however, some patients with severe asthma are steroid resistant. IL-13 remains elevated in glucocorticoid insensitive asthma but not in glucocorticoid sensitive asthma. Thus targeting IL-13 and its associated receptors may be a therapeutic approach to the treatment of asthma and/or allergy. This review focuses on the role of IL-13 on airway hyperresponsiveness and corticosteroids resistant asthma both preclinically and clinically. © Discovery Medicine

Effect of a 5-lipoxygenase inhibitor and leukotriene antagonist (PF 5901) on antigen-induced airway responses in neonatally immunized rabbits.

PubMed Central

Herd, C. M.; Donigi-Gale, D.; Shoupe, T. S.; Burroughs, D. A.; Yeadon, M.; Page, C. P.

1994-01-01

1. The effect of a single intratracheal dose (10 mg) of PF 5901 (2-[3(1-hydroxyhexyl) phenoxymethyl] quinoline hydrochloride, a specific inhibitor of the 5-lipoxygenase pathway of arachidonic acid metabolism and a leukotriene D4 antagonist) on airway changes induced in response to Alternaria tenuis aerosol challenge was assessed in adult rabbits neonatally immunized. Leukotriene generation was determined in vivo by measuring leukotriene B4 (LTB4) levels in bronchoalveolar lavage (BAL) fluid and ex vivo by measuring calcium ionophore-stimulated production of LTB4 in whole blood. 2. While PF 5901 (10 mg) had no significant effect on the acute bronchoconstriction induced by antigen, this dose was sufficient to inhibit significantly the increase in airway responsiveness to inhaled histamine 24 h following antigen challenge (P < 0.05). 3. Total leucocyte infiltration into the airways induced by antigen, as assessed by bronchoalveolar lavage, was significantly inhibited by pretreatment with PF 5901 (10 mg). However, the pulmonary infiltration of neutrophils and eosinophils induced by antigen was unaltered by prior treatment with PF 5901 (10 mg). 4. PF 5901 (10 mg) had no effect on ex vivo LTB4 synthesis in whole blood. However, the antigen-induced increase in LTB4 levels in BAL 24 h following challenge was significantly inhibited (P < 0.05). 5. We suggest from the results of the present study that the antigen-induced airway hyperresponsiveness to inhaled histamine in immunized rabbits is mediated, at least in part, by products of the 5-lipoxygenase metabolic pathway, and is not dependent on the extent of eosinophil or neutrophil influx into the airway lumen. PMID:8032653

MECHANISTIC CONSIDERATIONS FOR FORMALDEHYDE-INDUCED BRONCHOCONSTRICTION INVOLVING S-NITROSOGLUTATHIONE REDUCTASE

EPA Science Inventory

Inhalation of formaldehyde vapor has long been suspected of producing airway pathophysiology such as asthma and hyperresponsivity, presumably via irritant mechanisms. Recent studies on asthma and airway biology implicate changes in nitric oxide (NO) disposition in the adverse eff...

Reduction in polyamine catabolism leads to spermine-mediated airway epithelial injury and induces asthma features.

PubMed

Jain, Vaibhav; Raina, Shikha; Gheware, Atish Prabhakar; Singh, Rita; Rehman, Rakhshinda; Negi, Vinny; Murray Stewart, Tracy; Mabalirajan, Ulaganathan; Mishra, Adarsh Kumar; Casero, Robert A; Agrawal, Anurag; Ghosh, Balaram

2018-05-05

Airway epithelial injury is a crucial component of acute and severe asthma pathogenesis and a promising target for treatment of refractory asthma. However, the underlying mechanism of epithelial injury remains poorly explored. Though high levels of polyamines, mainly spermine, have been found in asthma and co-morbidity, their role in airway epithelial injury and the cause of their altered levels in asthma has not been explored. We measured key polyamine metabolic enzymes in lung samples from normal and asthmatic subjects and in mice with OVA-induced allergic airway inflammation (AAI). Polyamine metabolism was modulated using pharmacologic/genetic modulators. Epithelial stress and apoptosis were measured by TSLP levels and TUNEL assay, respectively. We found loss of the polyamine catabolic enzymes spermidine/spermine-N (1)-acetyltransferase-1 (SAT1) and spermine oxidase (SMOX) predominantly in bronchial epithelial cells (BECs) of human asthmatic lung samples and mice with AAI. In naïve mice, SAT1 or SMOX knockdown led to airway hyper-responsiveness, remodeling and BEC apoptosis. Conversely, in mice with AAI, overexpression of either SAT1 or SMOX alleviated asthmatic features and reduced TSLP levels and BEC apoptosis. Similarly, while pharmacological induction of SAT1 and SMOX using the polyamine analogue bis(ethyl)norspermine (BENSPM) alleviated asthmatic features with reduced TSLP levels and BEC apoptosis, pharmacological inhibition of these enzymes using BERENIL or MDL72527, respectively, worsened them. Spermine accumulation in lungs correlated with BEC apoptosis, and spermine treatment caused apoptosis of human BEAS-2B cells in vitro. Spermine induces BEC injury. Induction of polyamine catabolism may represent a novel therapeutic approach for asthma via reversing BEC stress. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Emergence of airway smooth muscle mechanical behavior through dynamic reorganization of contractile units and force transmission pathways

PubMed Central

2014-01-01

Airway hyperresponsiveness (AHR) in asthma remains poorly understood despite significant research effort to elucidate relevant underlying mechanisms. In particular, a significant body of experimental work has focused on the effect of tidal fluctuations on airway smooth muscle (ASM) cells, tissues, lung slices, and whole airways to understand the bronchodilating effect of tidal breathing and deep inspirations. These studies have motivated conceptual models that involve dynamic reorganization of both cytoskeletal components as well as contractile machinery. In this article, a biophysical model of the whole ASM cell is presented that combines 1) crossbridge cycling between actin and myosin; 2) actin-myosin disconnectivity, under imposed length changes, to allow dynamic reconfiguration of “force transmission pathways”; and 3) dynamic parallel-to-serial transitions of contractile units within these pathways that occur through a length fluctuation. Results of this theoretical model suggest that behavior characteristic of experimentally observed force-length loops of maximally activated ASM strips can be explained by interactions among the three mechanisms. Crucially, both sustained disconnectivity and parallel-to-serial transitions are necessary to explain the nature of hysteresis and strain stiffening observed experimentally. The results provide strong evidence that dynamic rearrangement of contractile machinery is a likely mechanism underlying many of the phenomena observed at timescales associated with tidal breathing. This theoretical cell-level model captures many of the salient features of mechanical behavior observed experimentally and should provide a useful starting block for a bottom-up approach to understanding tissue-level mechanical behavior. PMID:24481961

WORLD TRADE CENTER FINE PARTICULATE MATTER CAUSES RESPIRATORY TRACT HYPERRESPONSIVENESS IN MICE

EPA Science Inventory

World Trade Center Fine Particulate Matter Causes Respiratory Tract Hyperresponsiveness in Mice

Stephen H. Gavett1, Najwa Haykal-Coates1, Jerry W. Highfill1, Allen D. Ledbetter1, Lung Chi Chen2, Mitchell D. Cohen2, Jack R. Harkema3, James G. Wagner3, and Daniel L. Costa1.<...

Sequential Stenting for Extensive Malignant Airway Stenosis

PubMed Central

Takahama, Makoto; Nakajima, Ryu; Kimura, Michitaka; Tei, Keiko; Yamamoto, Ryoji

2014-01-01

Purpose: Malignant airway stenosis extending from the bronchial bifurcation to the lower lobar orifice was treated with airway stenting. We herein examine the effectiveness of airway stenting for extensive malignant airway stenosis. Methods: Twelve patients with extensive malignant airway stenosis underwent placement of a silicone Dumon Y stent (Novatech, La Ciotat, France) at the tracheal bifurcation and a metallic Spiral Z-stent (Medico’s Hirata, Osaka, Japan) at either distal side of the Y stent. We retrospectively analyzed the therapeutic efficacy of the sequential placement of these silicone and metallic stents in these 12 patients. Results: The primary disease was lung cancer in eight patients, breast cancer in two patients, tracheal cancer in one patient, and thyroid cancer in one patient. The median survival period after airway stent placement was 46 days. The Hugh–Jones classification and performance status improved in nine patients after airway stenting. One patient had prolonged hemoptysis and died of respiratory tract hemorrhage 15 days after the treatment. Conclusion: Because the initial disease was advanced and aggressive, the prognosis after sequential airway stent placement was significantly poor. However, because respiratory distress decreased after the treatment in most patients, this treatment may be acceptable for selected patients with extensive malignant airway stenosis. PMID:25273272

Decrease of airway smooth muscle contractility induced by simulated breathing maneuvers is not simply proportional to strain.

PubMed

Pascoe, Chris D; Seow, Chun Y; Paré, Peter D; Bossé, Ynuk

2013-02-01

The lung is a dynamic organ and the oscillating stress applied to the airway wall during breathing maneuvers can decrease airway smooth muscle (ASM) contractility. However, it is unclear whether it is the stress or the attendant strain that is responsible for the decline of ASM force associated with breathing maneuvers, and whether tone can prevent the decline of force by attenuating the strain. To investigate these questions, ovine tracheal strips were subjected to oscillating stress that simulates breathing maneuvers, and the resulting strain and decline of force were measured in the absence or presence of different levels of tone elicited by acetylcholine. In relaxed ASM, high stress simulating 20 cm H(2)O-transpulmonary pressure excursions strained ASM strips by 20.7% and decreased force by 17.1%. When stress oscillations were initiated during measurement of ACh concentration-response curves, tone almost abrogated strain at an ACh concentration of 10(-6) M (1.1%) but the decline of force was not affected (18.9%). When stress oscillations were initiated after ACh-induced contraction had reached its maximal force, strain was almost abrogated at an ACh concentration of 10(-6) M (0.9%) and the decline of force was attenuated (10.1%). However, even at the highest ACh concentration (10(-4) M), substantial decline of force (6.1%) was still observed despite very small strain (0.7%). As expected, the results indicate that tone attenuated the strain experienced by ASM during breathing maneuver simulations. More surprisingly, the reduction of strain induced by tone was not proportional to its effect on the decline of force induced by simulated breathing maneuvers.

An Extract of Crataegus pinnatifida Fruit Attenuates Airway Inflammation by Modulation of Matrix Metalloproteinase-9 in Ovalbumin Induced Asthma

PubMed Central

Lim, Hye Sun; Ha, Hyekyung; Seo, Chang Seob; Kim, Jong-Choon; Shin, Hyeun Kyoo

2012-01-01

Background Crataegus pinnatifida (Chinese hawthorn) has long been used as a herbal medicine in Asia and Europe. It has been used for the treatment of various cardiovascular diseases such as myocardial weakness, tachycardia, hypertension and arteriosclerosis. In this study, we investigated the anti-inflammatory effects of Crataegus pinnatifida ethanolic extracts (CPEE) on Th2-type cytokines, eosinophil infiltration, expression of matrix metalloproteinase (MMP)-9, and other factors, using an ovalbumin (OVA)-induced murine asthma model. Methods/Principal Finding Airways of OVA-sensitized mice exposed to OVA challenge developed eosinophilia, mucus hypersecretion and increased cytokine levels. CPEE was applied 1 h prior to OVA challenge. Mice were administered CPEE orally at doses of 100 and 200 mg/kg once daily on days 18–23. Bronchoalveolar lavage fluid (BALF) was collected 48 h after the final OVA challenge. Levels of interleukin (IL)-4 and IL-5 in BALF were measured using enzyme-linked immunosorbent (ELISA) assays. Lung tissue sections 4 µm in thickness were stained with Mayer’s hematoxylin and eosin for assessment of cell infiltration and mucus production with PAS staining, in conjunction with ELISA, and Western blot analyses for the expression of MMP-9, intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 protein expression. CPEE significantly decreased the Th2 cytokines including IL-4 and IL-5 levels, reduced the number of inflammatory cells in BALF and airway hyperresponsiveness, suppressed the infiltration of eosinophil-rich inflammatory cells and mucus hypersecretion and reduced the expression of ICAM-1, VCAM-1 and MMP-9 and the activity of MMP-9 in lung tissue of OVA-challenged mice. Conclusions These results showed that CPEE can protect against allergic airway inflammation and can act as an MMP-9 modulator to induce a reduction in ICAM-1 and VCAM-1 expression. In conclusion, we strongly suggest the feasibility of CPEE as

The effect of body weight on distal airway function and airway inflammation.

PubMed

van de Kant, Kim D G; Paredi, Paolo; Meah, Sally; Kalsi, Harpal S; Barnes, Peter J; Usmani, Omar S

Obesity is a global health problem that adversely influences the respiratory system. We assessed the effects of body mass index (BMI) on distal airway function and airway inflammation. Impulse oscillometry (IOS) as a measure of distal airway function, together with spirometry, were assessed in adults with a range of different BMIs. Airway inflammation was assessed with the fraction of exhaled nitric oxide (FeNO) and participants exhaled at various exhalation flows to determine alveolar and bronchial NO. In total 34 subjects were enrolled in the study; 19 subjects had a normal BMI (18.50-24.99), whilst 15 subjects were overweight (BMI 25.00-29.99), or obese (BMI ≥30). All subjects had normal spirometry. However, IOS measures of airway resistance (R) at 5Hz, 20Hz and frequency dependence (R 5-20 ) were elevated in overweight/obese individuals, compared to subjects with a normal BMI (median (interquartile range)); 5Hz: 0.41 (0.37, 0.45) vs. 0.32 (0.30, 0.37)kPa/l/s; 20Hz: 0.34 (0.30, 0.37) vs. 0.30 (0.26, 0.33)kPa/l/s; R 5-20 : 0.06 (0.04, 0.11) vs. 0.03 (0.01, 0.05)kPa/l/s; p<0.05), whereas airway reactance at 20Hz was decreased in overweight/obese individuals (20Hz: 0.07 (0.03, 0.09) vs. 0.10 (0.07, 0.13)kPa/l/s, p=0.009; 5Hz: -0.12 (-0.15, -0.10) vs. -0.10 (-0.13, -0.09)kPa/l/s, p=0.07). In contrast, within-breath IOS measures (a sign of expiratory flow limitation) and FeNO inflammatory measures, did not differ between groups (p>0.05). Being overweight has significant effects on distal and central airway function as determined by IOS, which is not detected by spirometry. Obesity does not influence airway inflammation as measured by FeNO. IOS is a reliable technique to identify airway abnormalities in the presence of normal spirometry in overweight people. Copyright © 2015 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

Effects of surface tension and intraluminal fluid on mechanics of small airways.

PubMed

Hill, M J; Wilson, T A; Lambert, R K

1997-01-01

Airway constriction is accompanied by folding of the mucosa to form ridges that run axially along the inner surface of the airways. The mucosa has been modeled (R. K. Lambert. J. Appl. Physiol. 71:666-673, 1991) as a thin elastic layer with a finite bending stiffness, and the contribution of its bending stiffness to airway elastance has been computed. In this study, we extend that work by including surface tension and intraluminal fluid in the model. With surface tension, the pressure on the inner surface of the elastic mucosa is modified by the pressure difference across the air-liquid interface. As folds form in the mucosa, intraluminal fluid collects in pools in the depressions formed by the folds, and the curvature of the air-liquid interface becomes nonuniform. If the amount of intraluminal fluid is small, < 2% of luminal volume, the pools of intraluminal fluid are small, the air-liquid interface nearly coincides with the surface of the mucosa, and the area of the air-liquid interface remains constant as airway cross-sectional area decreases. In that case, surface energy is independent of airway area, and surface tension has no effect on airway mechanics. If the amount of intraluminal fluid is > 2%, the area of the air-liquid interface decreases as airway cross-sectional area decreases. and surface tension contributes to airway compression. The model predicts that surface tension plus intraluminal fluid can cause an instability in the area-pressure curve of small airways. This instability provides a mechanism for abrupt airway closure and abrupt reopening at a higher opening pressure.

Airway Delivery of Soluble Factors from Plastic-Adherent Bone Marrow Cells Prevents Murine Asthma

PubMed Central

Ionescu, Lavinia I.; Alphonse, Rajesh S.; Arizmendi, Narcy; Morgan, Beverly; Abel, Melanie; Eaton, Farah; Duszyk, Marek; Vliagoftis, Harissios; Aprahamian, Tamar R.; Walsh, Kenneth

2012-01-01

Asthma affects an estimated 300 million people worldwide and accounts for 1 of 250 deaths and 15 million disability-adjusted life years lost annually. Plastic-adherent bone marrow–derived cell (BMC) administration holds therapeutic promise in regenerative medicine. However, given the low cell engraftment in target organs, including the lung, cell replacement cannot solely account for the reported therapeutic benefits. This suggests that BMCs may act by secreting soluble factors. BMCs also possess antiinflammatory and immunomodulatory properties and may therefore be beneficial for asthma. Our objective was to investigate the therapeutic potential of BMC-secreted factors in murine asthma. In a model of acute and chronic asthma, intranasal instillation of BMC conditioned medium (CdM) prevented airway hyperresponsiveness (AHR) and inflammation. In the chronic asthma model, CdM prevented airway smooth muscle thickening and peribronchial inflammation while restoring blunted salbutamol-induced bronchodilation. CdM reduced lung levels of the TH2 inflammatory cytokines IL-4 and IL-13 and increased levels of IL-10. CdM up-regulated an IL-10–induced and IL-10–secreting subset of T regulatory lymphocytes and promoted IL-10 expression by lung macrophages. Adiponectin (APN), an antiinflammatory adipokine found in CdM, prevented AHR, airway smooth muscle thickening, and peribronchial inflammation, whereas the effect of CdM in which APN was neutralized or from APN knock-out mice was attenuated compared with wild-type CdM. Our study provides evidence that BMC-derived soluble factors prevent murine asthma and suggests APN as one of the protective factors. Further identification of BMC-derived factors may hold promise for novel approaches in the treatment of asthma. PMID:21903873

Airway delivery of soluble factors from plastic-adherent bone marrow cells prevents murine asthma.

PubMed

Ionescu, Lavinia I; Alphonse, Rajesh S; Arizmendi, Narcy; Morgan, Beverly; Abel, Melanie; Eaton, Farah; Duszyk, Marek; Vliagoftis, Harissios; Aprahamian, Tamar R; Walsh, Kenneth; Thébaud, Bernard

2012-02-01

Asthma affects an estimated 300 million people worldwide and accounts for 1 of 250 deaths and 15 million disability-adjusted life years lost annually. Plastic-adherent bone marrow-derived cell (BMC) administration holds therapeutic promise in regenerative medicine. However, given the low cell engraftment in target organs, including the lung, cell replacement cannot solely account for the reported therapeutic benefits. This suggests that BMCs may act by secreting soluble factors. BMCs also possess antiinflammatory and immunomodulatory properties and may therefore be beneficial for asthma. Our objective was to investigate the therapeutic potential of BMC-secreted factors in murine asthma. In a model of acute and chronic asthma, intranasal instillation of BMC conditioned medium (CdM) prevented airway hyperresponsiveness (AHR) and inflammation. In the chronic asthma model, CdM prevented airway smooth muscle thickening and peribronchial inflammation while restoring blunted salbutamol-induced bronchodilation. CdM reduced lung levels of the T(H)2 inflammatory cytokines IL-4 and IL-13 and increased levels of IL-10. CdM up-regulated an IL-10-induced and IL-10-secreting subset of T regulatory lymphocytes and promoted IL-10 expression by lung macrophages. Adiponectin (APN), an antiinflammatory adipokine found in CdM, prevented AHR, airway smooth muscle thickening, and peribronchial inflammation, whereas the effect of CdM in which APN was neutralized or from APN knock-out mice was attenuated compared with wild-type CdM. Our study provides evidence that BMC-derived soluble factors prevent murine asthma and suggests APN as one of the protective factors. Further identification of BMC-derived factors may hold promise for novel approaches in the treatment of asthma.

Development of a tool to recognize small airways dysfunction in asthma (SADT).

PubMed

Schiphof-Godart, Lieke; van der Wiel, Erica; Ten Hacken, Nick H T; van den Berge, Maarten; Postma, Dirkje S; van der Molen, Thys

2014-11-22

Small airways dysfunction (SAD) contributes to the clinical expression of asthma. The identification of patients who suffer from SAD is important from a clinical perspective, as targeted therapy may improve patients' well-being and treatment efficacy. We aimed to realize the first step in the development of a simple small airways dysfunction tool (SADT) that may help to identify asthma patients having SAD. Asthma patients with and without SAD were interviewed. Patients were selected to participate in this study based on FEF50% and R5-R20 values from spirometry and impulse oscillometry respectively. Ten in depth interviews and two focus groups revealed that patients with and without SAD perceived differences in symptoms and signs, habits and health related issues. For example, patients with SAD reported to wheeze easily, were unable to breathe in deeply, mentioned more symptoms related to bronchial hyperresponsiveness, experienced more pronounced exercise-induced symptoms and more frequently had allergic respiratory symptoms after exposure to cats and birds. Based on these differences, 63 items were retained to be further explored for the SADT. The first step of the development of the SADT tool shows that there are relevant differences in signs and respiratory symptoms between asthma patients with and without SAD. The next step is to test and validate all items in order to retain the most relevant items to create a short and simple tool, which should be useful to identify asthma patients with SAD in clinical practice.

Quantification of atopy, lung function and airway hypersensitivity in adults

PubMed Central

2011-01-01

Background Studies in children have shown that concentration of specific serum IgE (sIgE) and size of skin tests to inhalant allergens better predict wheezing and reduced lung function than the information on presence or absence of atopy. However, very few studies in adults have investigated the relationship of quantitative atopy with lung function and airway hyperresponsiveness (AHR). Objective To determine the association between lung function and AHR and quantitative atopy in a large sample of adults from the UK. Methods FEV1 and FVC (% predicted) were measured using spirometry and airway responsiveness by methacholine challenge (5-breath dosimeter protocol) in 983 subjects (random sample of 800 parents of children enrolled in a population-based birth cohort enriched with 183 patients with physician-diagnosed asthma). Atopic status was assessed by skin prick tests (SPT) and measurement of sIgE (common inhalant allergens). We also measured indoor allergen exposure in subjects' homes. Results Spirometry was completed by 792 subjects and 626 underwent methacholine challenge, with 100 (16.0%) having AHR (dose-response slope>25). Using sIgE as a continuous variable in a multiple linear regression analysis, we found that increasing levels of sIgE to mite, cat and dog were significantly associated with lower FEV1 (mite p = 0.001, cat p = 0.0001, dog p = 2.95 × 10-8). Similar findings were observed when using the size of wheal on skin testing as a continuous variable, with significantly poorer lung function with increasing skin test size (mite p = 8.23 × 10-8, cat p = 3.93 × 10-10, dog p = 3.03 × 10-15, grass p = 2.95 × 10-9). The association between quantitative atopy with lung function and AHR remained unchanged when we repeated the analyses amongst subjects defined as sensitised using standard definitions (sIgE>0.35 kUa/l, SPT-3 mm>negative control). Conclusions In the studied population, lung function decreased and AHR increased with increasing sIgE levels or

Use of an Airway Exchange Catheter-Assisted Extubation With Continuous End-Tidal Carbon Dioxide Monitoring in a Pediatric Patient With a Known Difficult Airway: A Case Report.

PubMed

Yegian, Courtney C; Volz, Lana M; Galgon, Richard E

2018-05-11

Tracheal extubation in children with known difficult airways is associated with an increased risk of adverse events. Currently, there is no reliable measure to predict the need for emergent reintubation due to airway inadequacy. Airway exchange catheter-assisted extubation has been shown to be a useful adjunct in decreasing the risk of adverse events due to failed extubation. We report a case of using an airway exchange catheter-assisted extubation with continuous end-tidal carbon dioxide monitoring for a pediatric patient with a known difficult airway.

FABP4 regulates eosinophil recruitment and activation in allergic airway inflammation.

PubMed

Ge, Xiao Na; Bastan, Idil; Dileepan, Mythili; Greenberg, Yana; Ha, Sung Gil; Steen, Kaylee A; Bernlohr, David A; Rao, Savita P; Sriramarao, P

2018-04-26

Fatty acid binding protein 4 (FABP4), a member of a family of lipid-binding proteins, is known to play a role in inflammation by virtue of its ability to regulate intracellular events such as lipid fluxes and signaling. Studies have indicated a pro-inflammatory role for FABP4 in allergic asthma, although its expression and function in eosinophils, the predominant inflammatory cells recruited to allergic airways, was not investigated. We examined expression of FABP4 in murine eosinophils and its role in regulating cell recruitment in vitro as well as in cockroach antigen (CRA)-induced allergic airway inflammation. CRA exposure led to airway recruitment of FABP4-expressing inflammatory cells, specifically eosinophils, in wild type (WT) mice. FABP4 expression in eosinophils was induced by TNF-α as well as IL-4 and IL-13. FABP4-deficient eosinophils exhibited markedly decreased cell spreading/formation of leading edges on vascular cell adhesion molecule-1 and significantly decreased adhesion to intercellular adhesion molecule-1 associated with reduced β2 integrin expression relative to WT cells. Further, FABP4-deficient eosinophils exhibited decreased migration, F-actin polymerization, calcium flux and ERK (1/2) phosphorylation in response to eotaxin-1. In vivo, CRA-challenged FABP4-deficient mice exhibited attenuated eosinophilia and significantly reduced airway inflammation (improved airway reactivity, lower IL-5, IL-13, TNFα and LTC4 levels, decreased airway structural changes) compared to WT mice. In conclusion, expression of FABP4 in eosinophils is induced during conditions of inflammation and plays a pro-inflammatory role in the development of allergic asthma by promoting eosinophil adhesion and migration and contributing to the development of various aspects of airway inflammation.

Long term evaluation of mesenchymal stem cell therapy in a feline model of chronic allergic asthma

PubMed Central

Trzil, Julie E; Masseau, Isabelle; Webb, Tracy L; Chang, Chee-hoon; Dodam, John R; Cohn, Leah A; Liu, Hong; Quimby, Jessica M; Dow, Steven W; Reinero, Carol R

2014-01-01

Background Mesenchymal stem cells (MSCs) decrease airway eosinophilia, airway hyperresponsiveness (AHR), and remodeling in murine models of acutely induced asthma. We hypothesized that MSCs would diminish these hallmark features in a chronic feline asthma model. Objective To document effects of allogeneic, adipose-derived MSCs on airway inflammation, airway hyperresponsiveness (AHR), and remodeling over time and investigate mechanisms by which MSCs alter local and systemic immunologic responses in chronic experimental feline allergic asthma. Methods Cats with chronic, experimentally-induced asthma received six intravenous infusions of MSCs (0.36–2.5X10E7 MSCs/infusion) or placebo bimonthly at the time of study enrollment. Cats were evaluated at baseline and longitudinally for one year. Outcome measures included: bronchoalveolar lavage fluid cytology to assess airway eosinophilia; pulmonary mechanics and clinical scoring to assess AHR; and thoracic computed tomographic (CT) scans to assess structural changes (airway remodeling). CT scans were evaluated using a scoring system for lung attenuation (LA) and bronchial wall thickening (BWT). To assess mechanisms of MSC action, immunologic assays including allergen-specific IgE, cellular IL-10 production, and allergen-specific lymphocyte proliferation were performed. Results There were no differences between treatment groups or over time with respect to airway eosinophilia or AHR. However, significantly lower LA and BWT scores were noted in CT images of MSC-treated animals compared to placebo-treated cats at month 8 of the study (LA p=0.0311; BWT p=0.0489). No differences were noted between groups in the immunologic assays. Conclusions and Clinical Relevance When administered after development of chronic allergic feline asthma, MSCs failed to reduce airway inflammation and AHR. However, repeated administration of MSCs at the start of study did reduce computed tomographic measures of airway remodeling by month 8, though

Wnt/β-catenin signaling modulates human airway sensitization induced by β2-adrenoceptor stimulation.

PubMed

Faisy, Christophe; Grassin-Delyle, Stanislas; Blouquit-Laye, Sabine; Brollo, Marion; Naline, Emmanuel; Chapelier, Alain; Devillier, Philippe

2014-01-01

Regular use of β2-agonists may enhance non-specific airway responsiveness. The wingless/integrated (Wnt) signaling pathways are responsible for several cellular processes, including airway inflammation and remodeling while cAMP-PKA cascade can activate the Wnt signaling. We aimed to investigate whether the Wnt signaling pathways are involved in the bronchial hyperresponsiveness induced by prolonged exposure to β2-adrenoceptor agonists in human isolated airways. Bronchi were surgically removed from 44 thoracic surgery patients. After preparation, bronchial rings and primary cultures of bronchial epithelial cells were incubated with fenoterol (0.1 µM, 15 hours, 37 °C), a β2-agonist with high intrinsic efficacy. The effects of inhibitors/blockers of Wnt signaling on the fenoterol-induced airway sensitization were examined and the impact of fenoterol exposure on the mRNA expression of genes interacting with Wnt signaling or cAMP-PKA cascade was assessed in complete bronchi and in cultured epithelial cells. Compared to paired controls, fenoterol-sensitization was abolished by inhibition/blockage of the Wnt/β-catenin signaling, especially the cell-surface LRP5/6 co-receptors or Fzd receptors (1 µM SFRP1 or 1 µM DKK1) and the nuclear recruitment of TCF/LEF transcriptions factors (0.3 µM FH535). Wnt proteins secretion did not seem to be involved in the fenoterol-induced sensitization since the mRNA expression of Wnt remained low after fenoterol exposure and the inactivator of Wnt secretion (1 µM IWP2) had no effect on the fenoterol-sensitization. Fenoterol exposure did not change the mRNA expression of genes regulating Wnt signaling or cAMP-PKA cascade. Collectively, our pharmacological investigations indicate that fenoterol-sensitization is modulated by the inhibition/blockage of canonical Wnt/β-catenin pathway, suggesting a phenomenon of biased agonism in connection with the β2-adrenoceptor stimulation. Future experiments based on the results of the present

Contribution of sensory nerves to LPS-induced hyperresponsiveness of human isolated bronchi.

PubMed

Calzetta, Luigino; Luongo, Livio; Cazzola, Mario; Page, Clive; Rogliani, Paola; Facciolo, Francesco; Maione, Sabatino; Capuano, Annalisa; Rinaldi, Barbara; Matera, Maria Gabriella

2015-06-15

Bacterial lipopolysaccharide (LPS) can induce bronchial hyperresponsiveness (BHR), but the underlying mechanisms remain to be determined. Here, the possible contribution of sensory nerves to LPS-induced BHR was examined in human isolated bronchi to pharmacologically identify the mechanisms underlying this phenomenon. Human isolated bronchial tone was induced by electrical field stimulation (EFS). The responses of airways to LPS, with or without capsaicin desensitization or thiorphan treatment were studied and the transient receptor potential vanilloid type 1 (TRPV1) expression was assessed. We performed similar experiments in the presence of a TRPV1 or a neurokinin (NK) 2 receptor antagonist using SB366791 and GR159897, respectively. LPS increased (≃2.3-fold, P<0.001) the contraction induced by EFS, compared to control tissues. Acute administration of capsaicin enhanced (≃2.3-fold, P<0.001) the EFS-mediated contraction, but did not potentiate the effect of LPS. Thiorphan increased (≃1.3-fold, P<0.05) the contractile response of LPS treated tissues and, at lower frequencies, it enhanced (≃1.7-fold, P<0.001) the capsaicin-induced contraction. In capsaicin-desensitized bronchi, LPS did not modify (P>0.05) the EFS contractile response, nor after treatment with thiorphan. Capsaicin desensitization reduced (≃0.4-fold, P<0.001) the LPS-induced BHR. SB366791 and GR159897 prevented the LPS-induced BHR and the release of NKA. LPS increased (+85.3±9.5%, P<0.01) the surface membrane expression of TRPV1 in parasympathetic ganglia. Our results demonstrate the involvement of capsaicin-sensitive sensory nerves and neutral endopeptidases in LPS-induced BHR of the human bronchi, associated with an upregulation of TRPV1 and release of NKA. Copyright © 2015. Published by Elsevier Inc.

Bakery flour dust exposure causes non-allergic inflammation and enhances allergic airway inflammation in mice

PubMed Central

Marraccini, Paolo; Brass, David M.; Hollingsworth, John W.; Maruoka, Shuichiro; Garantziotis, Stavros; Schwartz, David A.

2014-01-01

Background Baker’s asthma is one of the most commonly reported occupational lung diseases in countries where fresh bread is baked daily in large quantities, and is characterized by rhinitis, bronchial hyperresponsiveness, and reversible airflow obstruction. Epidemiological studies have identified pre-existing atopy as an important risk factor for developing baker’s asthma, yet the etiology and pathogenesis of baker’s asthma remain poorly understood. Objective We sought to develop a mouse model of baker’s asthma that could be used to characterize the development and progression of baker’s asthma. Methods We were unable to sensitize mice to bakery flour dust or flour dust extract. We assessed total inflammatory cells, cellular differential, total serum IgE and the pro-inflammatory cytokine response to oropharyngeally instilled bakery flour dust or flour dust extract by itself or in the context of OVA sensitization and challenge. Results Both bakery flour dust and flour dust extract consistently elicited a neutrophilic inflammation in a tlr4-independent manner; suggesting that endotoxin is not playing a role in the inflammatory response to flour dust. Moreover, bakery flour dust and dust extract significantly enhance the inflammatory response in OVA sensitized and challenged mice. Conclusions Bakery flour dust and flour dust extract are strongly pro-inflammatory and can cause non-allergic airway inflammation and can enhance allergen-mediated airway inflammation. PMID:18564331

Ca2+-Activated K+ Channel–3.1 Blocker TRAM-34 Attenuates Airway Remodeling and Eosinophilia in a Murine Asthma Model

PubMed Central

Girodet, Pierre-Olivier; Ozier, Annaig; Carvalho, Gabrielle; Ilina, Olga; Ousova, Olga; Gadeau, Alain-Pierre; Begueret, Hugues; Wulff, Heike; Marthan, Roger; Bradding, Peter

2013-01-01

Key features of asthma include bronchial hyperresponsiveness (BHR), eosinophilic airway inflammation, and bronchial remodeling, characterized by subepithelial collagen deposition, airway fibrosis, and increased bronchial smooth muscle (BSM) mass. The calcium-activated K+ channel KCa3.1 is expressed by many cells implicated in the pathogenesis of asthma, and is involved in both inflammatory and remodeling responses in a number of tissues. The specific KCa3.1 blocker 5-[(2-chlorophenyl)(diphenyl)methyl]-1H-pyrazole (TRAM-34) attenuates BSM cell proliferation, and both mast cell and fibrocyte recruitment in vitro. We aimed to examine the effects of KCa3.1 blockade on BSM remodeling, airway inflammation, and BHR in a murine model of chronic asthma. BALB/c mice were sensitized with intraperitoneal ovalbumin (OVA) on Days 0 and 14, and then challenged with intranasal OVA during Days 14–75. OVA-sensitized/challenged mice received TRAM-34 (120 mg/kg/day, subcutaneous) from Days −7 to 75 (combined treatment), Days −7 to 20 (preventive treatment), or Days 21 to 75 (curative treatment). Untreated mice received daily injections of vehicle (n = 8 per group). Bronchial remodeling was assessed by histological and immunohistochemical analyses. Inflammation was evaluated using bronchoalveolar lavage and flow cytometry. We also determined BHR in both conscious and anesthetized mice via plethysmography. We demonstrated that curative treatment with TRAM-34 abolishes BSM remodeling and subbasement collagen deposition, and attenuates airway eosinophilia. Although curative treatment alone did not significantly reduce BHR, the combined treatment attenuated nonspecific BHR to methacholine. This study indicates that KCa3.1 blockade could provide a new therapeutic strategy in asthma. PMID:23204391

Ca(2+)-activated K(+) channel-3.1 blocker TRAM-34 attenuates airway remodeling and eosinophilia in a murine asthma model.

PubMed

Girodet, Pierre-Olivier; Ozier, Annaig; Carvalho, Gabrielle; Ilina, Olga; Ousova, Olga; Gadeau, Alain-Pierre; Begueret, Hugues; Wulff, Heike; Marthan, Roger; Bradding, Peter; Berger, Patrick

2013-02-01

Key features of asthma include bronchial hyperresponsiveness (BHR), eosinophilic airway inflammation, and bronchial remodeling, characterized by subepithelial collagen deposition, airway fibrosis, and increased bronchial smooth muscle (BSM) mass. The calcium-activated K(+) channel K(Ca)3.1 is expressed by many cells implicated in the pathogenesis of asthma, and is involved in both inflammatory and remodeling responses in a number of tissues. The specific K(Ca)3.1 blocker 5-[(2-chlorophenyl)(diphenyl)methyl]-1H-pyrazole (TRAM-34) attenuates BSM cell proliferation, and both mast cell and fibrocyte recruitment in vitro. We aimed to examine the effects of K(Ca)3.1 blockade on BSM remodeling, airway inflammation, and BHR in a murine model of chronic asthma. BALB/c mice were sensitized with intraperitoneal ovalbumin (OVA) on Days 0 and 14, and then challenged with intranasal OVA during Days 14-75. OVA-sensitized/challenged mice received TRAM-34 (120 mg/kg/day, subcutaneous) from Days -7 to 75 (combined treatment), Days -7 to 20 (preventive treatment), or Days 21 to 75 (curative treatment). Untreated mice received daily injections of vehicle (n = 8 per group). Bronchial remodeling was assessed by histological and immunohistochemical analyses. Inflammation was evaluated using bronchoalveolar lavage and flow cytometry. We also determined BHR in both conscious and anesthetized mice via plethysmography. We demonstrated that curative treatment with TRAM-34 abolishes BSM remodeling and subbasement collagen deposition, and attenuates airway eosinophilia. Although curative treatment alone did not significantly reduce BHR, the combined treatment attenuated nonspecific BHR to methacholine. This study indicates that K(Ca)3.1 blockade could provide a new therapeutic strategy in asthma.

Role of tachykinins in bronchial hyper-responsiveness.

PubMed

Reynolds, P N; Holmes, M D; Scicchitano, R

1997-01-01

1. Sensory afferent fibres mediate important protective reflexes in the lung. Small, unmyelinated C-fibre nerves have both sensory afferent and effector functions. C-fibres contain a number of neuropeptides, including the tachykinins, which have pro-inflammatory effects in the airways. Following stimulation with capsaicin and other stimuli, neuropeptides are released from the nerve endings, either directly or by axonal reflexes. 2. Important tachykinin effects include smooth muscle contraction, vasodilatation and oedema, mucus secretion and inflammatory cell activation. There are also trophic effects, including proliferation of fibroblasts, smooth muscle and epithelial cells. 3. Tachykinins mediate their effects by binding to G-proteinlinked receptors. Receptor-specific agonists and antagonists are available, which have helped clarify the effects of tachykinins. These agents may have therapeutic potential. 4. Tachykinins are degraded by the enzyme neutral endo-peptidase. 5. Studies in humans in vivo show an increase in airways resistance following challenge with tachykinins. There is some evidence for an increase in tachykinins and their receptors in airway inflammation, but this has not been found in all studies. A reduction in neutral endopeptidase has been seen in some animal models of airway inflammation, but this has not been shown in human disease. 6. Trials of tachykinin receptor antagonists in human asthma have begun, but it is too early to say what their therapeutic impact will be.

The cervical spine in maxillofacial trauma. Assessment and airway management.

PubMed

Kellman, R

1991-02-01

Although the presence of a real or potential cervical spine injury limits the options for emergency airway management, many choices still remain. The otolaryngologist-head and neck surgeon frequently is called on to treat patients with airway emergencies; therefore, familiarity with the risk of spinal cord damage and methods to avoid it when establishing a safe airway constitute important knowledge. Experience with the variety of airway techniques available increases the number of options and decreases the risks of morbidity and mortality for the patient with cervical spine injury.

Airway morphometry in the lungs as depicted in chest CT examinations variability of measurements

NASA Astrophysics Data System (ADS)

Leader, J. K.; Zheng, Bin; Scuirba, Frank C.; Coxson, Harvey O.; Weissfeld, Joel L.; Fuhrman, Carl R.; Maitz, Glenn S.; Gur, David

2006-03-01

The purpose of the study was to decrease the variability of computed tomographic airway measurements. We to developed and evaluated a novel computer scheme to automatically segment airways depicted on chest CT examinations at the level of the lobar and segmental bronchi and to decrease. The computer scheme begins with manual selection of a seed point within the airway from which the airway wall and lumen are automatically segmented and airway pixels were assigned full or partial membership to the lumen or wall. Airway pixels not assigned full membership to the lumen (< -900 HU) or wall (> 0 HU) were assigned partial membership to the lumen and wall. In fifteen subjects with no visible signs of emphysema and a range of pulmonary obstruction from none to severe, airway measures were compared to pulmonary function parameters in a rank order analysis to evaluate measuring a single airway versus multiple airways. The quality of the automated airway segmentation was visually acceptable. The Pearson Correlation coefficients for the ranking of FEV I versus wall area percent (percent of total airway size) and FVC versus wall area percent were 0.164 and 0.175 for a single measurement, respectively, and were 0.243 and 0.239 for multiple measurements, respectively. Our preliminary results suggest that averaging the measurements from multiple airways may improve the relation between airway measures and lung function compared to measurement from a single airway, which improve quantification of airway remodeling in COPD patients.

Cigarette Smoke Upregulates PDE3 and PDE4 to Decrease cAMP in Airway Cells.

PubMed

Zuo, Haoxiao; Han, Bing; Poppinga, Wilfred J; Ringnalda, Lennard; Kistemaker, Loes E M; Halayko, Andrew J; Gosens, Reinoud; Nikolaev, Viacheslav O; Schmidt, Martina

2018-05-03

3', 5'-cyclic adenosine monophosphate (cAMP) is a central second messenger that broadly regulates cell function and can underpin pathophysiology. In chronic obstructive pulmonary disease (COPD), a lung disease primarily provoked by cigarette smoke (CS), the induction of cAMP-dependent pathways, via inhibition of hydrolyzing phosphodiesterases (PDEs), is a prime therapeutic strategy. Mechanisms that disrupt cAMP signaling in airway cells, in particular regulation of endogenous PDEs are poorly understood. We used a novel Förster resonance energy transfer (FRET) based cAMP biosensor in mouse in vivo, ex vivo precision cut lung slices (PCLS), and in human in vitro cell models to track the effects of CS exposure. Under fenoterol stimulated conditions, FRET responses to cilostamide were significantly increased in in vivo, ex vivo PCLS exposed to CS and in human airway smooth muscle cells exposed to CS extract. FRET signals to rolipram were only increased in the in vivo CS model. Under basal conditions, FRET responses to cilostamide and rolipram were significantly increased in in vivo, ex vivo PCLS exposed to CS. Elevated FRET signals to rolipram correlated with a protein upregulation of PDE4 subtypes. In ex vivo PCLS exposed to CS extract, rolipram reversed downregulation of ciliary beating frequency, whereas only cilostamide significantly increased airway relaxation of methacholine pre-contracted airways. We show that CS upregulates expression and activity of both PDE3 and PDE4, which regulate real-time cAMP dynamics. These mechanisms determine the availability of cAMP and can contribute to CS-induced pulmonary pathophysiology. This article is protected by copyright. All rights reserved.

ASCORBIC ACID IS DECREASED IN INDUCED SPUTUM OF MILD ASTHMATICS

EPA Science Inventory

Asthma is primarily an airways inflammatory disease, and the bronchial airways have been shown to be particularly susceptible to oxidant-induced tissue damage. The antioxidant ascorbic acid (AA) plays an essential role in defending against oxidant attack in the airways. Decreased...

GARP inhibits allergic airway inflammation in a humanized mouse model.

PubMed

Meyer-Martin, H; Hahn, S A; Beckert, H; Belz, C; Heinz, A; Jonuleit, H; Becker, C; Taube, C; Korn, S; Buhl, R; Reuter, S; Tuettenberg, A

2016-09-01

Regulatory T cells (Treg) represent a promising target for novel treatment strategies in patients with inflammatory/allergic diseases. A soluble derivate of the Treg surface molecule glycoprotein A repetitions predominant (sGARP) has strong anti-inflammatory and regulatory effects on human cells in vitro as well as in vivo through de novo induction of peripheral Treg. The aim of this study was to investigate the immunomodulatory function of sGARP and its possible role as a new therapeutic option in allergic diseases using a humanized mouse model. To analyze the therapeutic effects of sGARP, adult NOD/Scidγc(-/-) (NSG) mice received peripheral blood mononuclear cells (PBMC) derived from allergic patients with sensitization against birch allergen. Subsequently, allergic inflammation was induced in the presence of Treg alone or in combination with sGARP. In comparison with mice that received Treg alone, additional treatment with sGARP reduced airway hyperresponsiveness (AHR), influx of neutrophils and macrophages into the bronchoalveolar lavage (BAL), and human CD45(+) cells in the lungs. Furthermore, the numbers of mucus-producing goblet cells and inflammatory cell infiltrates were reduced. To elucidate whether the mechanism of action of sGARP involves the TGF-β receptor pathway, mice additionally received anti-TGF-β receptor II (TGF-βRII) antibodies. Blocking the signaling of TGF-β through TGF-βRII abrogated the anti-inflammatory effects of sGARP, confirming its essential role in inhibiting the allergic inflammation. Induction of peripheral tolerance via sGARP is a promising potential approach to treat allergic airway diseases. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Intravenous adipose-derived mesenchymal stem cell therapy for the treatment of feline asthma: a pilot study.

PubMed

Trzil, Julie E; Masseau, Isabelle; Webb, Tracy L; Chang, Chee-Hoon; Dodam, John R; Liu, Hong; Quimby, Jessica M; Dow, Steven W; Reinero, Carol R

2016-12-01

The aim of this study was to evaluate the feasibility and efficacy of serially administered adipose-derived mesenchymal stem cells (MSCs) in an experimental feline asthma model. Allergic asthma was acutely induced with Bermuda grass allergen in six purpose-bred cats. Five intravenous infusions of allogeneic MSCs (n = 4; MSC-treated) or saline (n = 2; placebo-treated) were administered over the first 130 days after asthma induction. Infusions contained 2 × 10 6 , 4 × 10 6 , 4.7 × 10 6 , 1 × 10 7 and 1 × 10 7 cryopreserved MSCs/cat. For thoracic imaging additional cats were enrolled as control groups: four untreated, experimentally asthmatic cats (combined with placebo-treated cats), and six healthy, non-asthmatic cats. Outcome measures included airway eosinophilia, pulmonary mechanics, thoracic computed tomography and several immunologic assays. Cats were assessed for 9 months after treatment. At early points, airway eosinophil percentage was not affected by MSC administration (post-treatment average of days 12, 26, 47, 108 and 133 in MSC-treated cats was 41 ± 15% and in placebo-treated cats it was 34 ± 16%). By month 9, eosinophil percentages in all MSC-treated cats decreased to normal reference intervals (MSC-treated 6%; placebo-treated 20%; normal <17%). Diminished airway hyper-responsiveness was noted in all MSC-treated compared with placebo-treated cats at day 133 (dose of methacholine to double baseline airway resistance: MSC-treated median 22.9 mg/ml [range 6.4-64.0]; individual placebo-treated cats 1.1 and 5.0 mg/ml). Lung attenuation (mean ± SEM MSC-treated -865 ± 12 Hounsfield units [HU]; untreated asthmatics -820 ± 11 HU; P = 0.004) and bronchial wall thickening scores (median [interquartile range] MSC-treated 0 [0-1.5]; untreated asthmatic 11.6 [7.3-27.3]; P = 0.010) were significantly reduced in MSC-treated vs untreated asthmatic cats, consistent with decreased airway remodeling at month 9. No clear immunologic mechanisms by which MSCs act

Pressure-volume behavior of the upper airway.

PubMed

Fouke, J M; Teeter, J P; Strohl, K P

1986-09-01

The study was performed to investigate the relationship between force generation and upper airway expansion during respiratory efforts by upper airway muscles. In 11 anesthetized dogs we isolated the upper airway (nasal, oral, pharyngeal, and laryngeal regions) by transecting the cervical trachea and sealing the nasal and oral openings. During spontaneous respiratory efforts the pressure within the sealed upper airway, used as an index of dilating force, decreased during inspiration. On alternate breaths the upper airway was opened to a pneumotachograph, and an increase in volume occurred, also during inspiration. Progressive hyperoxic hypercapnia produced by rebreathing increased the magnitude of change in pressure and volume. At any level of drive, peak pressure or volume occurred at the same point during inspiration. At any level of drive, volume and pressure changes increased with end-expiratory occlusion of the trachea. The force-volume relationship determined from measurements during rebreathing was compared with pressure-volume curves performed by passive inflation of the airway while the animal was apneic. The relationship during apnea was 1.06 +/- 0.55 (SD) ml/cmH2O, while the force-volume relationship from rebreathing trials was -1.09 +/- 0.45 ml/cmH2O. We conclude that there is a correspondence between force production and volume expansion in the upper airway during active respiratory efforts.

Expression of nitric oxide synthase-2 in the lungs decreases airway resistance and responsiveness.

PubMed

Hjoberg, Josephine; Shore, Stephanie; Kobzik, Lester; Okinaga, Shoji; Hallock, Arlene; Vallone, Joseph; Subramaniam, Venkat; De Sanctis, George T; Elias, Jack A; Drazen, Jeffrey M; Silverman, Eric S

2004-07-01

Individuals with asthma have increased levels of nitric oxide in their exhaled air. To explore its role, we have developed a regulatable transgenic mouse capable of overexpressing inducible nitric oxide synthase in a lung-specific fashion. The CC10-rtTA-NOS-2 mouse contains two transgenes, a reverse tetracycline transactivator under the control of the Clara cell protein promoter and the mouse nitric oxide synthase-2 (NOS-2) coding region under control of a tetracycline operator. Addition of doxycycline to the drinking water of CC10-rtTA-NOS-2 mice causes an increase in nitric oxide synthase-2 that is largely confined to the airway epithelium. The fraction of expired nitric oxide increases over the first 24 h from approximately 10 parts per billion to a plateau of approximately 20 parts per billion. There were no obvious differences between CC10-rtTA-NOS-2 mice, with or without doxycycline, and wild-type mice in lung histology, bronchoalveolar protein, total cell count, or count differentials. However, airway resistance was lower in CC10-rtTA-NOS-2 mice with doxycycline than in CC10-rtTA-NOS-2 mice without doxycycline or wild-type mice with doxycycline. Moreover, doxycycline-treated CC10-rtTA-NOS-2 mice were hyporesponsive to methacholine compared with other groups. These data suggest that increased nitric oxide in the airways has no proinflammatory effects per se and may have beneficial effects on pulmonary function.

Clonorchis sinensis-derived total protein attenuates airway inflammation in murine asthma model by inducing regulatory T cells and modulating dendritic cell functions

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

Jeong, Young-Il; Kim, Seung Hyun; Ju, Jung Won

Highlights: {yields} Treatment with Clonorchis sinensis-derived total protein attenuates OVA-induced airway inflammation and AHR to methacholine. {yields} Induction of CD4{sup +}CD25{sup +}Foxp3{sup +} T cells and IL-10 along with suppression of splenocyte proliferation by C. sinensis-derived total protein. {yields} C. sinensis-derived total protein interferes with the expression of co-stimulatory molecules in DCs. -- Abstract: Asthma is characterized by Th2-mediated inflammation, resulting in airway hyperresponsiveness (AHR) through airway remodeling. Recent epidemiological and experimental reports have suggested an inverse relationship between the development of allergy and helminth infections. Infection by Clonorchis sinensis, a liver fluke that resides in the bile duct ofmore » humans, is endemic predominantly in Asia including Korea and China. Using a murine model for asthma, we investigated the effects of C. sinensis-derived total protein (Cs-TP) on allergen-induced airway inflammation and the mechanism underlying the protective effects of Cs-TP administration on asthma. Treatment with Cs-TP attenuated OVA-induced airway inflammation and methacholine-induced AHR, as well as eosinophilia development, lymphocyte infiltration into the lung, and goblet cell metaplasia. This protective effect of Cs-TP is associated with markedly reduced OVA-specific IgE and Th1/Th2 cytokine production. Moreover, Cs-TP increased the number of CD4{sup +}CD25{sup +}Foxp3{sup +} regulatory T (Treg) cells as well as their suppressive activity. In fact, proliferation of OVA-restimulated splenocytes was suppressed significantly. Cs-TP also inhibited the expression of such co-stimulatory molecules as CD80, CD86, and CD40 in LPS- or OVA-stimulated dendritic cells (DCs), suggesting that Cs-TP could interfere with the capacity of airway DCs to prime naive T cells. These data demonstrate the capacity of C. sinensis to ameliorate allergic asthma and broaden our understanding of the

Computed tomography-guided tissue engineering of upper airway cartilage.

PubMed

Brown, Bryan N; Siebenlist, Nicholas J; Cheetham, Jonathan; Ducharme, Norm G; Rawlinson, Jeremy J; Bonassar, Lawrence J

2014-06-01

Normal laryngeal function has a large impact on quality of life, and dysfunction can be life threatening. In general, airway obstructions arise from a reduction in neuromuscular function or a decrease in mechanical stiffness of the structures of the upper airway. These reductions decrease the ability of the airway to resist inspiratory or expiratory pressures, causing laryngeal collapse. We propose to restore airway patency through methods that replace damaged tissue and improve the stiffness of airway structures. A number of recent studies have utilized image-guided approaches to create cell-seeded constructs that reproduce the shape and size of the tissue of interest with high geometric fidelity. The objective of the present study was to establish a tissue engineering approach to the creation of viable constructs that approximate the shape and size of equine airway structures, in particular the epiglottis. Computed tomography images were used to create three-dimensional computer models of the cartilaginous structures of the larynx. Anatomically shaped injection molds were created from the three-dimensional models and were seeded with bovine auricular chondrocytes that were suspended within alginate before static culture. Constructs were then cultured for approximately 4 weeks post-seeding and evaluated for biochemical content, biomechanical properties, and histologic architecture. Results showed that the three-dimensional molded constructs had the approximate size and shape of the equine epiglottis and that it is possible to seed such constructs while maintaining 75%+ cell viability. Extracellular matrix content was observed to increase with time in culture and was accompanied by an increase in the mechanical stiffness of the construct. If successful, such an approach may represent a significant improvement on the currently available treatments for damaged airway cartilage and may provide clinical options for replacement of damaged tissue during treatment of

Tube Law of the Pharyngeal Airway in Sleeping Patients with Obstructive Sleep Apnea.

PubMed

Genta, Pedro R; Edwards, Bradley A; Sands, Scott A; Owens, Robert L; Butler, James P; Loring, Stephen H; White, David P; Wellman, Andrew

2016-02-01

Obstructive sleep apnea (OSA) is characterized by repetitive pharyngeal collapse during sleep. However, the dynamics of pharyngeal narrowing and re-expansion during flow-limited breathing are not well described. The static pharyngeal tube law (end-expiratory area versus luminal pressure) has demonstrated increasing pharyngeal compliance as luminal pressure decreases, indicating that the airway would be sucked closed with sufficient inspiratory effort. On the contrary, the airway is rarely sucked closed during inspiratory flow limitation, suggesting that the airway is getting stiffer. Therefore, we hypothesized that during inspiratory flow limitation, as opposed to static conditions, the pharynx becomes stiffer as luminal pressure decreases. Upper airway endoscopy and simultaneous measurements of airflow and epiglottic pressure were performed during natural nonrapid eye movement sleep. Continuous positive (or negative) airway pressure was used to induce flow limitation. Flow-limited breaths were selected for airway cross-sectional area measurements. Relative airway area was quantified as a percentage of end-expiratory area. Inspiratory airway radial compliance was calculated at each quintile of epiglottic pressure versus airway area plot (tube law). Eighteen subjects (14 males) with OSA (apnea-hypopnea index = 57 ± 27 events/h), aged 49 ± 8 y, with a body mass index of 35 ± 6 kg/m(2) were studied. A total of 163 flow limited breaths were analyzed (9 ± 3 breaths per subject). Compliances at the fourth (2.0 ± 4.7 % area/cmH2O) and fifth (0.0 ± 1.7 % area/cmH2O) quintiles were significantly lower than the first (12.2 ± 5.5 % area/cmH2O) pressure quintile (P < 0.05). The pharyngeal tube law is concave (airway gets stiffer as luminal pressure decreases) during respiratory cycles under inspiratory flow limitation. © 2016 Associated Professional Sleep Societies, LLC.

Airway-parenchymal interdependence

PubMed Central

Paré, Peter D; Mitzner, Wayne

2015-01-01

In this manuscript we discuss the interaction of the lung parenchyma and the airways as well as the physiological and pathophysiological significance of this interaction. These two components of the respiratory organ can be thought of as two independent elastic structures but in fact the mechanical properties of one influence the behavior of the other. Traditionally the interaction has focused on the effects of the lung on the airways but there is good evidence that the opposite is also true, i.e., that the mechanical properties of the airways influence the elastic properties of the parenchyma. The interplay between components of the respiratory system including the airways, parenchyma and vasculature is often referred to as “interdependence.” This interdependence transmits the elastic recoil of the lung to create an effective pressure that dilates the airways as transpulmonary pressure and lung volume increase. By using a continuum mechanics analysis of the lung parenchyma, it is possible to predict the effective pressure between the airways and parenchyma, and these predictions can be empirically evaluated. Normal airway caliber is maintained by this pressure in the adventitial interstitium of the airway, and it counteracts airway compression during forced expiration as well as the ability of airway smooth muscle to narrow airways. Interdependence has physiological and pathophysiological significance. Weakening of the forces of interdependence contributes to airway dysfunction and gas exchange impairment in acute and chronic airway diseases including asthma and emphysema. PMID:23723029

Defective parasympathetic innervation is associated with airway branching abnormalities in experimental CDH

PubMed Central

Rhodes, Julie; Saxena, Deeksha; Zhang, GuangFeng; Gittes, George K.

2015-01-01

Developmental mechanisms leading to lung hypoplasia in congenital diaphragmatic hernia (CDH) remain poorly defined. Pulmonary innervation is defective in the human disease and in the rodent models of CDH. We hypothesize that defective parasympathetic innervation may contribute to airway branching abnormalities and, therefore, lung hypoplasia, during lung development in CDH. The murine nitrofen model of CDH was utilized to study the effect of the cholinergic agonist carbachol on embryonic day 11.5 (E11.5) lung explant cultures. Airway branching and contractions were quantified. In a subset of experiments, verapamil was added to inhibit airway contractions. Sox9 immunostaining and 5-bromo-2-deoxyuridine incorporation were used to identify and quantify the number and proliferation of distal airway epithelial progenitor cells. Intra-amniotic injections were used to determine the in vivo effect of carbachol. Airway branching and airway contractions were significantly decreased in nitrofen-treated lungs compared with controls. Carbachol resulted in increased airway contractions and branching in nitrofen-treated lungs. Nitrofen-treated lungs exhibited an increased number of proliferating Sox9-positive distal epithelial progenitor cells, which were decreased and normalized by treatment with carbachol. Verapamil inhibited the carbachol-induced airway contractions in nitrofen-treated lungs but had no effect on the carbachol-induced increase in airway branching, suggesting a direct carbachol effect independent of airway contractions. In vivo treatment of nitrofen-treated embryos via amniotic injection of carbachol at E10.5 resulted in modest increases in lung size and branching at E17.5. These results suggest that defective parasympathetic innervation may contribute to airway branching abnormalities in CDH. PMID:25934671

[Physical activity and respiratory tract diseases asthma and allergy].

PubMed

Carlsen, K H

2000-11-10

This article presents a review of the relationship between physical training and airways diseases: the relationship between physical activity and the development of airways diseases, and the effect of physical training in rehabilitation after airways diseases. The article is a systematic review of exercise-induced asthma (EIA), the effect of physical training upon bronchial hyperresponsiveness and the development of asthma; how chronic lung diseases affect the ability to participate in physical activity; and the use of physical training in rehabilitation after airways diseases. Physical training may provoke EIA in asthmatic patients. Furthermore, heavy regular training over long periods of time may contribute to the development of asthma. Mastering EIA is an important goal in the management of asthma, especially in children and adolescents, in order to foster normal physical and mental development. Physical training improves fitness and the mastering of asthma, but not of bronchial hyperresponsiveness and asthma activity. In other airways disorders like cystic fibrosis or chronic obstructive lung disease, a reduced lung function may limit the ability to participate in physical activity. Training is an important tool in the rehabilitation of patients with pulmonary disorders as it improves physical fitness and quality of life.

K+-induced alterations in airway muscle responsiveness to electrical field stimulation

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

Murlas, C.; Ehring, G.; Suszkiw, J.

1986-07-01

We investigated possible pre- and postsynaptic effects of K+-induced depolarization on ferret tracheal smooth muscle (TSM) responsiveness to cholinergic stimulation. To assess electromechanical activity, cell membrane potential (Em) and tension (Tm) were simultaneously recorded in buffer containing 6, 12, 18, or 24 mM K+ before and after electrical field stimulation (EFS) or exogenous acetylcholine (ACh). In 6 mM K+, Em was -58.1 +/- 1.0 mV (mean +/- SE). In 12 mM K+, Em was depolarized to -52.3 +/- 0.9 mV, basal Tm did not change, and both excitatory junctional potentials and contractile responses to EFS at short stimulus duration weremore » larger than in 6 mM K+. No such potentiation occurred at a higher K+, although resting Em and Tm increased progressively above 12 mM K+. The sensitivity of ferret TSM to exogenous ACh appeared unaffected by K+. To determine whether the hyperresponsiveness in 12 mM K+ was due, in part, to augmented ACh release from intramural airway nerves, experiments were done using TSM preparations incubated with (3H)choline to measure (3H)ACh release at rest and during EFS. Although resting (3H)ACh release increased progressively in higher K+, release evoked by EFS was maximal in 12 mM K+ and declined in higher concentrations. We conclude that small elevations in the extracellular K+ concentration augment responsiveness of the airways, by increasing the release of ACh both at rest and during EFS from intramural cholinergic nerve terminals. Larger increases in K+ appear to be inhibitory, possibly due to voltage-dependent effects that occur both pre- and postsynaptically.« less

Airway growth and development: a computerized 3-dimensional analysis.

PubMed

Schendel, Stephen A; Jacobson, Richard; Khalessi, Sadri

2012-09-01

The present study was undertaken to investigate the changes in the normal upper airway during growth and development using 3-dimensional computer analysis from cone-beam computed tomography (CBCT) data to provide a normative reference. The airway size and respiratory mode are known to have a relationship to facial morphology and the development of a malocclusion. The use of CBCT, 3-dimensional imaging, and automated computer analysis in treatment planning allows the upper airway to be precisely evaluated. In the present study, we evaluated the growth of the airway using 3-dimensional analysis and CBCT data from age 6 through old age, in 1300 normal individuals. The airway size and length increase until age 20 at which time a variable period of stability occurs. Next, the airway at first decreases slowly in size and then, after age 40, more rapidly. Normative data are provided in the present study for age groups from 6 to 60 years in relation to the airway total volume, smallest cross-sectional area and vertical length of the airway. This 3-dimensional data of the upper airway will provide a normative reference as an aid in the early understanding of respiration and dentofacial anatomy, which will help in early treatment planning. Copyright © 2012 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

Accurate Measurement of Small Airways on Low-Dose Thoracic CT Scans in Smokers

PubMed Central

Conradi, Susan H.; Atkinson, Jeffrey J.; Zheng, Jie; Schechtman, Kenneth B.; Senior, Robert M.; Gierada, David S.

2013-01-01

Background: Partial volume averaging and tilt relative to the scan plane on transverse images limit the accuracy of airway wall thickness measurements on CT scan, confounding assessment of the relationship between airway remodeling and clinical status in COPD. The purpose of this study was to assess the effect of partial volume averaging and tilt corrections on airway wall thickness measurement accuracy and on relationships between airway wall thickening and clinical status in COPD. Methods: Airway wall thickness measurements in 80 heavy smokers were obtained on transverse images from low-dose CT scan using the open-source program Airway Inspector. Measurements were corrected for partial volume averaging and tilt effects using an attenuation- and geometry-based algorithm and compared with functional status. Results: The algorithm reduced wall thickness measurements of smaller airways to a greater degree than larger airways, increasing the overall range. When restricted to analyses of airways with an inner diameter < 3.0 mm, for a theoretical airway of 2.0 mm inner diameter, the wall thickness decreased from 1.07 ± 0.07 to 0.29 ± 0.10 mm, and the square root of the wall area decreased from 3.34 ± 0.15 to 1.58 ± 0.29 mm, comparable to histologic measurement studies. Corrected measurements had higher correlation with FEV1, differed more between BMI, airflow obstruction, dyspnea, and exercise capacity (BODE) index scores, and explained a greater proportion of FEV1 variability in multivariate models. Conclusions: Correcting for partial volume averaging improves accuracy of airway wall thickness estimation, allowing direct measurement of the small airways to better define their role in COPD. PMID:23172175

ITGB5 and AGFG1 variants are associated with severity of airway responsiveness.

PubMed

Himes, Blanca E; Qiu, Weiliang; Klanderman, Barbara; Ziniti, John; Senter-Sylvia, Jody; Szefler, Stanley J; Lemanske, Robert F; Zeiger, Robert S; Strunk, Robert C; Martinez, Fernando D; Boushey, Homer; Chinchilli, Vernon M; Israel, Elliot; Mauger, David; Koppelman, Gerard H; Nieuwenhuis, Maartje A E; Postma, Dirkje S; Vonk, Judith M; Rafaels, Nicholas; Hansel, Nadia N; Barnes, Kathleen; Raby, Benjamin; Tantisira, Kelan G; Weiss, Scott T

2013-08-28

Airway hyperresponsiveness (AHR), a primary characteristic of asthma, involves increased airway smooth muscle contractility in response to certain exposures. We sought to determine whether common genetic variants were associated with AHR severity. A genome-wide association study (GWAS) of AHR, quantified as the natural log of the dosage of methacholine causing a 20% drop in FEV1, was performed with 994 non-Hispanic white asthmatic subjects from three drug clinical trials: CAMP, CARE, and ACRN. Genotyping was performed on Affymetrix 6.0 arrays, and imputed data based on HapMap Phase 2, was used to measure the association of SNPs with AHR using a linear regression model. Replication of primary findings was attempted in 650 white subjects from DAG, and 3,354 white subjects from LHS. Evidence that the top SNPs were eQTL of their respective genes was sought using expression data available for 419 white CAMP subjects. The top primary GWAS associations were in rs848788 (P-value 7.2E-07) and rs6731443 (P-value 2.5E-06), located within the ITGB5 and AGFG1 genes, respectively. The AGFG1 result replicated at a nominally significant level in one independent population (LHS P-value 0.012), and the SNP had a nominally significant unadjusted P-value (0.0067) for being an eQTL of AGFG1. Based on current knowledge of ITGB5 and AGFG1, our results suggest that variants within these genes may be involved in modulating AHR. Future functional studies are required to confirm that our associations represent true biologically significant findings.

Patterns of recruitment and injury in a heterogeneous airway network model

PubMed Central

Stewart, Peter S.; Jensen, Oliver E.

2015-01-01

In respiratory distress, lung airways become flooded with liquid and may collapse due to surface-tension forces acting on air–liquid interfaces, inhibiting gas exchange. This paper proposes a mathematical multiscale model for the mechanical ventilation of a network of occluded airways, where air is forced into the network at a fixed tidal volume, allowing investigation of optimal recruitment strategies. The temporal response is derived from mechanistic models of individual airway reopening, incorporating feedback on the airway pressure due to recruitment. The model accounts for stochastic variability in airway diameter and stiffness across and between generations. For weak heterogeneity, the network is completely ventilated via one or more avalanches of recruitment (with airways recruited in quick succession), each characterized by a transient decrease in the airway pressure; avalanches become more erratic for airways that are initially more flooded. However, the time taken for complete ventilation of the network increases significantly as the network becomes more heterogeneous, leading to increased stresses on airway walls. The model predicts that the most peripheral airways are most at risk of ventilation-induced damage. A positive-end-expiratory pressure reduces the total recruitment time but at the cost of larger stresses exerted on airway walls. PMID:26423440

Effect of inhaled formyl-methionyl-leucyl-phenylalanine on airway function.

PubMed Central

Berend, N; Peters, M J; Armour, C L; Black, J L; Ward, H E

1988-01-01

Formyl-methionyl-leucyl-phenylalanine (FMLP), a synthetic, acylated tripeptide analogous to bacterial chemotactic factors, has been shown to cause bronchoconstriction in guinea pig, rabbit, and human airways in vitro. To determine whether FMLP causes bronchoconstriction in man in vivo, a preliminary study was undertaken in which five non-smokers (mean age 35 years, FEV1 94% (SEM 5%) predicted) and five smokers (mean age 34 years, FEV1 93% (6%) predicted) inhaled aerosols of FMLP. None of the subjects showed airway hyperresponsiveness to histamine (the provocative concentrations of histamine causing a fall of greater than or equal to 20% in FEV1 (PC20) were over 8 mg/ml). FMLP dissolved in 50% dimethylsulphoxide and 50% saline in concentrations of 0, 0.06, 0.12, 0.25, 0.5, 1.0, 2.0, and 4.0 mg/ml was administered to the subjects by means of a French-Rosenthal dosimeter, FEV1 being recorded after inhalation of each concentration. Dose dependent falls in FEV1 occurred in five non-smokers (geometric mean 1.76, 95% confidence limits 0.87-3.53 mg/ml) and three smokers (0.23, 0.07-0.78 mg/ml), with two smokers not responding by 20% to the highest concentration of FMLP. On a separate day the FMLP dose-response curves were repeated after nebulisation of 500 micrograms of ipratropium bromide. The PC20 FMLP in the responders more than doubled. In six additional normal subjects a histamine inhalation test was performed before and four and 24 hours after inhalation of FMLP. All subjects remained unresponsive to histamine. These results show that FMLP is a potent bronchoconstrictor in some non-asthmatic individuals in vivo and this may be important in bronchoconstriction related to infection in patients with chronic obstructive lung disease. PMID:2965425

Effect of once daily and twice daily sustained release theophylline formulations on daytime variation of bronchial hyperresponsiveness in asthmatic patients

PubMed Central

Ferrari, M.; Olivieri, M.; Lampronti, G.; Bonazza, L.; Biasin, C.; Nacci, P.; Talamini, G.; Lo, C

1997-01-01

BACKGROUND: Previous studies evaluating spirometric values and symptoms have shown that once daily theophylline administered in the evening produces greater stabilisation of the airway function in asthmatic patients than the prototype theophylline given twice a day. The aim of this study was to compare the effects on bronchial responsiveness to methacholine of an ultrasustained release theophylline formulation (Diffumal-24, Malesci, Florence, Italy) administered once a day, a sustained release theophylline formulation (Theo-Dur, Recordati, Milan, Italy) administered twice a day, and placebo. METHODS: The study was performed in 12 adult patients with asthma using a randomised, double blind, three phase, cross-over design. Each phase lasted seven days and was followed or preceded by at least three days of theophylline washout. Diffumal-24 was administered once a day at 20.00 hours whereas Theo-Dur was given twice a day at 08.00 hours and 20.00 hours. In each patient the total daily dose of theophylline was the same during both phases. The dose of the two active preparations was titrated to individual needs before the beginning of the study and then given in divided or once daily doses. At 08.00, 14.00, and 20.00 hours on day 7 of each phase serum theophylline concentrations were measured and spirometric tests (FEV1) and bronchial challenge with methacholine were also performed. RESULTS: When the administration of Diffumal-24 was compared with that of Theo-Dur, a higher serum theophylline concentration of the former was seen in the morning whereas at 20.00 hours the reverse was true. Compared with placebo, at 08.00 hours Diffumal-24 improved FEV1 whereas Theo-Dur did not (difference between treatments 0.29 1, 95% CI 0.12 to 0.45). At 08.00 hours Diffumal-24 decreased bronchial sensitivity to methacholine, expressed as a natural logarithm of PD20, to a greater extent than Theo-Dur (difference between treatments 0.54 log units, 95% CI 0.016 to 1.08). The morning

Supplemental Carbon Dioxide Stabilizes the Upper Airway in Volunteers Anesthetized with Propofol.

PubMed

Ruscic, Katarina Jennifer; Bøgh Stokholm, Janne; Patlak, Johann; Deng, Hao; Simons, Jeroen Cedric Peter; Houle, Timothy; Peters, Jürgen; Eikermann, Matthias

2018-05-10

Propofol impairs upper airway dilator muscle tone and increases upper airway collapsibility. Preclinical studies show that carbon dioxide decreases propofol-mediated respiratory depression. We studied whether elevation of end-tidal carbon dioxide (PETCO2) via carbon dioxide insufflation reverses the airway collapsibility (primary hypothesis) and impaired genioglossus muscle electromyogram that accompany propofol anesthesia. We present a prespecified, secondary analysis of previously published experiments in 12 volunteers breathing via a high-flow respiratory circuit used to control upper airway pressure under propofol anesthesia at two levels, with the deep level titrated to suppression of motor response. Ventilation, mask pressure, negative pharyngeal pressure, upper airway closing pressure, genioglossus electromyogram, bispectral index, and change in end-expiratory lung volume were measured as a function of elevation of PETCO2 above baseline and depth of propofol anesthesia. PETCO2 augmentation dose-dependently lowered upper airway closing pressure with a decrease of 3.1 cm H2O (95% CI, 2.2 to 3.9; P < 0.001) under deep anesthesia, indicating improved upper airway stability. In parallel, the phasic genioglossus electromyogram increased by 28% (23 to 34; P < 0.001). We found that genioglossus electromyogram activity was a significant modifier of the effect of PETCO2 elevation on closing pressure (P = 0.005 for interaction term). Upper airway collapsibility induced by propofol anesthesia can be reversed in a dose-dependent manner by insufflation of supplemental carbon dioxide. This effect is at least partly mediated by increased genioglossus muscle activity.

Intervention effect and dose-dependent response of tanreqing injection on airway inflammation in lipopolysaccharide-induced rats.

PubMed

Dong, Shoujin; Zhong, Yunqing; Yang, Kun; Xiong, Xiaoling; Mao, Bing

2013-08-01

To assess the effect of Tanreqing injection on airway inflammation in rats. A rat model of airway inflammation was generated with lipopolysaccharide (LPS). Tanreqing injection was given by intratracheal instillation, and bronchoalveolar lavage fluid (BALF) from the right lung was collected. BALF total cell and neutrophil counts were then determined. In addition, BALF levels of inflammatory cytokines interleukin-13, cytokine-induced neutrophil chemoat-tractant-1, and tumor necrosis factor-alpha were measured using enzyme linked immunosorbent assay. The middle lobe of the right lung was stained with hematoxylin-eosin and histological changes examined. LPS increased airway inflammation, decreased BALF inflammatory cell count, inflammatory cytokine levels, and suppressed leukocyte influx of the lung. The LPS-induced airway inflammation peaked at 24 h, decreased beginning at 48 h, and had decreased markedly by 96 h. Tanreqing injection contains anti-inflammatory properties, and inhibits airway inflammation in a dose-dependent manner.

Wnt/β-Catenin Signaling Modulates Human Airway Sensitization Induced by β2-Adrenoceptor Stimulation

PubMed Central

Faisy, Christophe; Grassin-Delyle, Stanislas; Blouquit-Laye, Sabine; Brollo, Marion; Naline, Emmanuel; Chapelier, Alain; Devillier, Philippe

2014-01-01

Background Regular use of β2-agonists may enhance non-specific airway responsiveness. The wingless/integrated (Wnt) signaling pathways are responsible for several cellular processes, including airway inflammation and remodeling while cAMP–PKA cascade can activate the Wnt signaling. We aimed to investigate whether the Wnt signaling pathways are involved in the bronchial hyperresponsiveness induced by prolonged exposure to β2-adrenoceptor agonists in human isolated airways. Methods Bronchi were surgically removed from 44 thoracic surgery patients. After preparation, bronchial rings and primary cultures of bronchial epithelial cells were incubated with fenoterol (0.1 µM, 15 hours, 37°C), a β2-agonist with high intrinsic efficacy. The effects of inhibitors/blockers of Wnt signaling on the fenoterol-induced airway sensitization were examined and the impact of fenoterol exposure on the mRNA expression of genes interacting with Wnt signaling or cAMP–PKA cascade was assessed in complete bronchi and in cultured epithelial cells. Results Compared to paired controls, fenoterol-sensitization was abolished by inhibition/blockage of the Wnt/β-catenin signaling, especially the cell-surface LRP5/6 co-receptors or Fzd receptors (1 µM SFRP1 or 1 µM DKK1) and the nuclear recruitment of TCF/LEF transcriptions factors (0.3 µM FH535). Wnt proteins secretion did not seem to be involved in the fenoterol-induced sensitization since the mRNA expression of Wnt remained low after fenoterol exposure and the inactivator of Wnt secretion (1 µM IWP2) had no effect on the fenoterol-sensitization. Fenoterol exposure did not change the mRNA expression of genes regulating Wnt signaling or cAMP–PKA cascade. Conclusions Collectively, our pharmacological investigations indicate that fenoterol-sensitization is modulated by the inhibition/blockage of canonical Wnt/β-catenin pathway, suggesting a phenomenon of biased agonism in connection with the β2-adrenoceptor stimulation. Future

Quercetin inhibits rhinovirus replication in vitro and in vivo

PubMed Central

Ganesan, Shyamala; Faris, Andrea N.; Comstock, Adam T.; Wang, Qiong; Nanua, Suparna; Hershenson, Marc B.; Sajjan, Uma S.

2012-01-01

Summary Rhinovirus (RV), which is responsible for the majority of common colds, also causes exacerbations in patients with asthma and chronic obstructive pulmonary disease. So far, there are no drugs available for treatment of rhinovirus infection. We examined the effect of quercetin, a plant flavanol on RV infection in vitro and in vivo. Pretreatment of airway epithelial cells with quercetin decreased Akt phosphosphorylation, viral endocytosis and IL-8 responses. Addition of quercetin 6 h after RV infection (after viral endocytosis) reduced viral load, IL-8 and IFN responses in airway epithelial cells. This was associated with decreased levels of negative and positive strand viral RNA, and RV capsid protein, abrogation of RV-induced eIF4GI cleavage and increased phosphorylation of eIF2α. In mice infected with RV, quercetin treatment decreased viral replication as well as expression of chemokines and cytokines. Quercetin treatment also attenuated RV-induced airway cholinergic hyperresponsiveness. Together, our results suggest that quercetin inhibits RV endocytosis and replication in airway epithelial cells at multiple stages of the RV life cycle. Quercetin also decreases expression of pro-inflammatory cytokines and improves lung function in RV-infected mice. Based on these observations, further studies examining the potential benefits of quercetin in the prevention and treatment of RV infection are warranted. PMID:22465313

Mechanism for substance P-induced relaxation of precontracted airway smooth muscle during development.

PubMed

Mhanna, M J; Dreshaj, I A; Haxhiu, M A; Martin, R J

1999-01-01

Release of substance P (SP) from sensory nerve endings of the tracheobronchial system modulates airway smooth muscle contraction and may cause relaxation of precontracted airways. We sought to elucidate the effect of postnatal maturation on SP-induced relaxation of precontracted airways and determine the roles of endogenously generated nitric oxide (NO) and prostaglandins (PGs). Cylindrical airway segments were isolated from the midtrachea of rats at four different ages, 1, 2, and 4 wk and 3 mo, and contracted to 50-75% of the maximum response induced by bethanechol. SP was then administered in the absence and presence of the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME), the PG inhibitor indomethacin, or both. Relaxation of airways with SP decreased significantly with advancing postnatal age. SP-induced tracheal relaxation was consistently attenuated by pretreatment with L-NAME, indomethacin, or both. In a different group of animals, L-NAME significantly attenuated the relaxant response of airways to PGE2 exposure, but indomethacin had no significant effect on the relaxant response to exogenous NO. We conclude that SP induces a relaxant effect on precontracted airway smooth muscle, which decreases with advancing age and is mediated via SP-induced release of NO and/or PG.

Design and Implementation of an Educational Program in Advanced Airway Management for Anesthesiology Residents

PubMed Central

Borovcanin, Zana; Shapiro, Janine R.

2012-01-01

Education and training in advanced airway management as part of an anesthesiology residency program is necessary to help residents attain the status of expert in difficult airway management. The Accreditation Council for Graduate Medical Education (ACGME) emphasizes that residents in anesthesiology must obtain significant experience with a broad spectrum of airway management techniques. However, there is no specific number required as a minimum clinical experience that should be obtained in order to ensure competency. We have developed a curriculum for a new Advanced Airway Techniques rotation. This rotation is supplemented with a hands-on Difficult Airway Workshop. We describe here this comprehensive advanced airway management educational program at our institution. Future studies will focus on determining if education in advanced airway management results in a decrease in airway related morbidity and mortality and overall better patients' outcome during difficult airway management. PMID:22505885

Chloride and potassium channels in cystic fibrosis airway epithelia

NASA Astrophysics Data System (ADS)

Welsh, Michael J.; Liedtke, Carole M.

1986-07-01

Cystic fibrosis, the most common lethal genetic disease in Caucasians, is characterized by a decreased permeability in sweat gland duct and airway epithelia. In sweat duct epithelium, a decreased Cl- permeability accounts for the abnormally increased salt content of sweat1. In airway epithelia a decreased Cl- permeability, and possibly increased sodium absorption, may account for the abnormal respiratory tract fluid2,3. The Cl- impermeability has been localized to the apical membrane of cystic fibrosis airway epithelial cells4. The finding that hormonally regulated Cl- channels make the apical membrane Cl- permeable in normal airway epithelial cells5 suggested abnormal Cl- channel function in cystic fibrosis. Here we report that excised, cell-free patches of membrane from cystic fibrosis epithelial cells contain Cl- channels that have the same conductive properties as Cl- channels from normal cells. However, Cl- channels from cystic fibrosis cells did not open when they were attached to the cell. These findings suggest defective regulation of Cl- channels in cystic fibrosis epithelia; to begin to address this issue, we performed two studies. First, we found that isoprenaline, which stimulates Cl- secretion, increases cellular levels of cyclic AMP in a similar manner in cystic fibrosis and non-cystic fibrosis epithelial cells. Second, we show that adrenergic agonists open calcium-activated potassium channels, indirectly suggesting that calcium-dependent stimulus-response coupling is intact in cystic fibrosis. These data suggest defective regulation of Cl- channels at a site distal to cAMP accumulation.

Airway responsiveness to mannitol 24 h after allergen challenge in atopic asthmatics.

PubMed

Davis, B E; Amakye, D O; Cockcroft, D W

2015-06-01

Airway responsiveness to indirect stimuli correlates positively with airway inflammation. In atopic asthmatics, allergen inhalation is associated with an influx of inflammatory cells and increased responsiveness to the direct-acting stimuli methacholine at 3 and 24 h after exposure. We have shown mannitol responsiveness decreases 3 h after allergen inhalation. The current investigation assessed mannitol responsiveness 24 h after allergen challenge. Eleven mild atopic asthmatics completed allergen challenges on two separate occasions. In random order, methacholine or mannitol challenges were performed 24 h pre- and post-allergen challenge. Levels of fractional exhaled nitric oxide were also measured. Allergen challenge increased airway responsiveness to methacholine 24 h postchallenge; the geometric mean (95% CI) methacholine PC20 decreased from 5.9 mg/ml (1.8-19.4) to 2.2 mg/ml (0.81-5.89); P = 0.01. This coincided with a significant increase (P = 0.02) in FeNO levels. Conversely, allergen challenge decreased airway responsiveness to mannitol; geometric mean (95% CI) dose-response ratio was significantly higher after allergen exposure (57 mg/% FEV1 fall [27-121] to 147 mg/% FEV1 fall [57-379]; P = 0.03), and FeNO levels were not significantly increased (P = 0.054). Allergen-induced changes in airway responsiveness to direct and indirect stimuli are markedly different. The loss in responsiveness to mannitol is likely not explainable by a refractory state. The effect(s) of allergen exposure on airway responsiveness to indirect-acting stimuli require further investigation. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The role of anaerobic bacteria in the cystic fibrosis airway.

PubMed

Sherrard, Laura J; Bell, Scott C; Tunney, Michael M

2016-11-01

Anaerobic bacteria are not only normal commensals, but are also considered opportunistic pathogens and have been identified as persistent members of the lower airway community in people with cystic fibrosis of all ages and stages of disease. Currently, the role of anaerobic bacteria in cystic fibrosis lower airway disease is not well understood. Therefore, this review describes the recent studies relating to the potential pathophysiological role(s) of anaerobes within the cystic fibrosis lungs. The most frequently identified anaerobic bacteria in the lower airways are common to both cystic fibrosis and healthy lungs. Studies have shown that in cystic fibrosis, the relative abundance of anaerobes fluctuates in the lower airways with reduced lung function and increased inflammation associated with a decreased anaerobic load. However, anaerobes found within the lower airways also produce virulence factors, may cause a host inflammatory response and interact synergistically with recognized pathogens. Anaerobic bacteria are potentially members of the airway microbiota in health but could also contribute to the pathogenesis of lower airway disease in cystic fibrosis via both direct and indirect mechanisms. A personalized treatment strategy that maintains a normal microbial community may be possible in the future.

Air quality and exercise-induced bronchoconstriction in elite athletes.

PubMed

Rundell, Kenneth W; Sue-Chu, Malcolm

2013-08-01

A higher prevalence of airway hyperresponsiveness, airway remodeling, and asthma has been identified among athletes who compete and train in environmental conditions of cold dry air and/or high air pollution. Repeated long-duration exposure to cold/dry air at high minute ventilation rates can cause airway damage. Competition or training at venues close to busy roadways, or in indoor ice arenas or chlorinated swimming pools, harbors a risk for acute and chronic airway disorders from high pollutant exposure. This article discusses the effects of these harsh environments on the airways, and summarizes potential mechanisms and prevalence of airway disorders in elite athletes. Copyright © 2013 Elsevier Inc. All rights reserved.

Airway stents

PubMed Central

Keyes, Colleen

2018-01-01

Stents and tubes to maintain the patency of the airways are commonly used for malignant obstruction and are occasionally employed in benign disease. Malignant airway obstruction usually results from direct involvement of bronchogenic carcinoma, or by extension of carcinomas occurring in the esophagus or the thyroid. External compression from lymph nodes or metastatic disease from other organs can also cause central airway obstruction. Most malignant airway lesions are surgically inoperable due to advanced disease stage and require multimodality palliation, including stent placement. As with any other medical device, stents have significantly evolved over the last 50 years and deserve an in-depth understanding of their true capabilities and complications. Not every silicone stent is created equal and the same holds for metallic stents. Herein, we present an overview of the topic as well as some of the more practical and controversial issues surrounding airway stents. We also try to dispel the myths surrounding stent removal and their supposed use only in central airways. At the end, we come to the long-held conclusion that stents should not be used as first line treatment of choice, but after ruling out the possibility of curative surgical resection or repair. PMID:29707506

Acid-Sensing Ion Channel 1a Contributes to Airway Hyperreactivity in Mice

PubMed Central

Reznikov, Leah R.; Meyerholz, David K.; Adam, Ryan J.; Abou Alaiwa, Mahmoud; Jaffer, Omar; Michalski, Andrew S.; Powers, Linda S.; Price, Margaret P.; Stoltz, David A.; Welsh, Michael J.

2016-01-01

Neurons innervating the airways contribute to airway hyperreactivity (AHR), a hallmark feature of asthma. Several observations suggested that acid-sensing ion channels (ASICs), neuronal cation channels activated by protons, might contribute to AHR. For example, ASICs are found in vagal sensory neurons that innervate airways, and asthmatic airways can become acidic. Moreover, airway acidification activates ASIC currents and depolarizes neurons innervating airways. We found ASIC1a protein in vagal ganglia neurons, but not airway epithelium or smooth muscle. We induced AHR by sensitizing mice to ovalbumin and found that ASIC1a-/- mice failed to exhibit AHR despite a robust inflammatory response. Loss of ASIC1a also decreased bronchoalveolar lavage fluid levels of substance P, a sensory neuropeptide secreted from vagal sensory neurons that contributes to AHR. These findings suggest that ASIC1a is an important mediator of AHR and raise the possibility that inhibiting ASIC channels might be beneficial in asthma. PMID:27820848

Role of Polyamines in Asthma Pathophysiology

PubMed Central

2018-01-01

Asthma is a complex disease of airways, where the interactions of immune and structural cells result in disease outcomes with airway remodeling and airway hyper-responsiveness. Polyamines, which are small-sized, natural super-cations, interact with negatively charged intracellular macromolecules, and altered levels of polyamines and their interactions have been associated with different pathological conditions including asthma. Elevated levels of polyamines have been reported in the circulation of asthmatic patients as well as in the lungs of a murine model of asthma. In various studies, polyamines were found to potentiate the pathogenic potential of inflammatory cells, such as mast cells and granulocytes (eosinophils and neutrophils), by either inducing the release of their pro-inflammatory mediators or prolonging their life span. Additionally, polyamines were crucial in the differentiation and alternative activation of macrophages, which play an important role in asthma pathology. Importantly, polyamines cause airway smooth muscle contraction and thus airway hyper-responsiveness, which is the key feature in asthma pathophysiology. High levels of polyamines in asthma and their active cellular and macromolecular interactions indicate the importance of the polyamine pathway in asthma pathogenesis; therefore, modulation of polyamine levels could be a suitable approach in acute and severe asthma management. This review summarizes the possible roles of polyamines in different pathophysiological features of asthma. PMID:29316647

Atopic asthmatic immune phenotypes associated with airway microbiota and airway obstruction.

PubMed

Turturice, Benjamin A; McGee, Halvor S; Oliver, Brian; Baraket, Melissa; Nguyen, Brian T; Ascoli, Christian; Ranjan, Ravi; Rani, Asha; Perkins, David L; Finn, Patricia W

2017-01-01

Differences in asthma severity may be related to inflammation in the airways. The lower airway microbiota has been associated with clinical features such as airway obstruction, symptom control, and response to corticosteroids. To assess the relationship between local airway inflammation, severity of disease, and the lower airway microbiota in atopic asthmatics. A cohort of young adult, atopic asthmatics with intermittent or mild/moderate persistent symptoms (n = 13) were assessed via bronchoscopy, lavage, and spirometry. These individuals were compared to age matched non-asthmatic controls (n = 6) and to themselves after six weeks of treatment with fluticasone propionate (FP). Inflammation of the airways was assessed via a cytokine and chemokine panel. Lower airway microbiota composition was determined by metagenomic shotgun sequencing. Unsupervised clustering of cytokines and chemokines prior to treatment with FP identified two asthmatic phenotypes (AP), termed AP1 and AP2, with distinct bronchoalveolar lavage inflammatory profiles. AP2 was associated with more obstruction, compared to AP1. After treatment with FP reduced MIP-1β and TNF-α and increased IL-2 was observed. A module of highly correlated cytokines that include MIP-1β and TNF-α was identified that negatively correlated with pulmonary function. Independently, IL-2 was positively correlated with pulmonary function. The airway microbiome composition correlated with asthmatic phenotypes. AP2, prior to FP treatment, was enriched with Streptococcus pneumoniae. Unique associations between IL-2 or the cytokine module and the microbiota composition of the airways were observed in asthmatics subjects prior to treatment but not after or in controls. The underlying inflammation in atopic asthma is related to the composition of microbiota and is associated with severity of airway obstruction. Treatment with inhaled corticosteroids was associated with changes in the airway inflammatory response to microbiota.

Inhibition of airway surface fluid absorption by cholinergic stimulation

PubMed Central

Joo, Nam Soo; Krouse, Mauri E.; Choi, Jae Young; Cho, Hyung-Ju; Wine, Jeffrey J.

2016-01-01

In upper airways airway surface liquid (ASL) depth and clearance rates are both increased by fluid secretion. Secretion is opposed by fluid absorption, mainly via the epithelial sodium channel, ENaC. In static systems, increased fluid depth activates ENaC and decreased depth inhibits it, suggesting that secretion indirectly activates ENaC to reduce ASL depth. We propose an alternate mechanism in which cholinergic input, which causes copious airway gland secretion, also inhibits ENaC-mediated absorption. The conjoint action accelerates clearance, and the increased transport of mucus out of the airways restores ASL depth while cleansing the airways. We were intrigued by early reports of cholinergic inhibition of absorption by airways in some species. To reinvestigate this phenomenon, we studied inward short-circuit currents (Isc) in tracheal mucosa from human, sheep, pig, ferret, and rabbit and in two types of cultured cells. Basal Isc was inhibited 20–70% by the ENaC inhibitor, benzamil. Long-lasting inhibition of ENaC-dependent Isc was also produced by basolateral carbachol in all preparations except rabbit and the H441 cell line. Atropine inhibition produced a slow recovery or prevented inhibition if added before carbachol. The mechanism for inhibition was not determined and is most likely multi-factorial. However, its physiological significance is expected to be increased mucus clearance rates in cholinergically stimulated airways. PMID:26846701

Degrees of reality: airway anatomy of high-fidelity human patient simulators and airway trainers.

PubMed

Schebesta, Karl; Hüpfl, Michael; Rössler, Bernhard; Ringl, Helmut; Müller, Michael P; Kimberger, Oliver

2012-06-01

Human patient simulators and airway training manikins are widely used to train airway management skills to medical professionals. Furthermore, these patient simulators are employed as standardized "patients" to evaluate airway devices. However, little is known about how realistic these patient simulators and airway-training manikins really are. This trial aimed to evaluate the upper airway anatomy of four high-fidelity patient simulators and two airway trainers in comparison with actual patients by means of radiographic measurements. The volume of the pharyngeal airspace was the primary outcome parameter. Computed tomography scans of 20 adult trauma patients without head or neck injuries were compared with computed tomography scans of four high-fidelity patient simulators and two airway trainers. By using 14 predefined distances, two cross-sectional areas and three volume parameters of the upper airway, the manikins' similarity to a human patient was assessed. The pharyngeal airspace of all manikins differed significantly from the patients' pharyngeal airspace. The HPS Human Patient Simulator (METI®, Sarasota, FL) was the most realistic high-fidelity patient simulator (6/19 [32%] of all parameters were within the 95% CI of human airway measurements). The airway anatomy of four high-fidelity patient simulators and two airway trainers does not reflect the upper airway anatomy of actual patients. This finding may impact airway training and confound comparative airway device studies.

Expression and coupling of neurokinin receptor subtypes to inositol phosphate and calcium signaling pathways in human airway smooth muscle cells.

PubMed

Mizuta, Kentaro; Gallos, George; Zhu, Defen; Mizuta, Fumiko; Goubaeva, Farida; Xu, Dingbang; Panettieri, Reynold A; Yang, Jay; Emala, Charles W

2008-03-01

Neuropeptide tachykinins (substance P, neurokinin A, and neurokinin B) are present in peripheral terminals of sensory nerve fibers within the respiratory tract and cause airway contractile responses and hyperresponsiveness in humans and most mammalian species. Three subtypes of neurokinin receptors (NK1R, NK2R, and NK3R) classically couple to Gq protein-mediated inositol 1,4,5-trisphosphate (IP3) synthesis and liberation of intracellular Ca2+, which initiates contraction, but their expression and calcium signaling mechanisms are incompletely understood in airway smooth muscle. All three subtypes were identified in native and cultured human airway smooth muscle (HASM) and were subsequently overexpressed in HASM cells using a human immunodeficiency virus-1-based lentivirus transduction system. Specific NKR agonists {NK1R, [Sar9,Met(O2)11]-substance P; NK2R, [beta-Ala8]-neurokinin A(4-10); NK3R, senktide} stimulated inositol phosphate synthesis and increased intracellular Ca2+ concentration ([Ca2+]i) in native HASM cells and in HASM cells transfected with each NKR subtype. These effects were blocked by NKR-selective antagonists (NK1R, L-732138; NK2R, GR-159897; NK3R, SB-222200). The initial transient and sustained phases of increased [Ca2+]i were predominantly inhibited by the IP3 receptor antagonist 2-aminoethoxydiphenyl borate (2-APB) or the store-operated Ca2+ channel antagonist SKF-96365, respectively. These results show that all three subtypes of NKRs are expressed in native HASM cells and that IP3 levels are the primary mediators of NKR-stimulated initial [Ca2+]i increases, whereas store-operated Ca2+ channels mediate the sustained phase of the [Ca2+]i increase.

Alleviation of Multiple Asthmatic Pathologic Features with Orally Available and Subtype Selective GABAA Receptor Modulators.

PubMed

Forkuo, Gloria S; Nieman, Amanda N; Yuan, Nina Y; Kodali, Revathi; Yu, Olivia B; Zahn, Nicolas M; Jahan, Rajwana; Li, Guanguan; Stephen, Michael Rajesh; Guthrie, Margaret L; Poe, Michael M; Hartzler, Benjamin D; Harris, Ted W; Yocum, Gene T; Emala, Charles W; Steeber, Douglas A; Stafford, Douglas C; Cook, James M; Arnold, Leggy A

2017-06-05

We describe pharmacokinetic and pharmacodynamic properties of two novel oral drug candidates for asthma. Phenolic α 4 β 3 γ 2 GABA A R selective compound 1 and acidic α 5 β 3 γ 2 selective GABA A R positive allosteric modulator compound 2 relaxed airway smooth muscle ex vivo and attenuated airway hyperresponsiveness (AHR) in a murine model of asthma. Importantly, compound 2 relaxed acetylcholine contracted human tracheal airway smooth muscle strips. Oral treatment of compounds 1 and 2 decreased eosinophils in bronchoalveolar lavage fluid in ovalbumin sensitized and challenged mice, thus exhibiting anti-inflammatory properties. Additionally, compound 1 reduced the number of lung CD4 + T lymphocytes and directly modulated their transmembrane currents by acting on GABA A Rs. Excellent pharmacokinetic properties were observed, including long plasma half-life (up to 15 h), oral availability, and extremely low brain distribution. In conclusion, we report the selective targeting of GABA A Rs expressed outside the brain and demonstrate reduction of AHR and airway inflammation with two novel orally available GABA A R ligands.

Inhaled ENaC antisense oligonucleotide ameliorates cystic fibrosis-like lung disease in mice.

PubMed

Crosby, Jeff R; Zhao, Chenguang; Jiang, Chong; Bai, Dong; Katz, Melanie; Greenlee, Sarah; Kawabe, Hiroshi; McCaleb, Michael; Rotin, Daniela; Guo, Shuling; Monia, Brett P

2017-11-01

Epithelial sodium channel (ENaC, Scnn1) hyperactivity in the lung leads to airway surface dehydration and mucus accumulation in cystic fibrosis (CF) patients and in mice with CF-like lung disease. We identified several potent ENaC specific antisense oligonucleotides (ASOs) and tested them by inhalation in mouse models of CF-like lung disease. The inhaled ASOs distributed into lung airway epithelial cells and decreased ENaC expression by inducing RNase H1-dependent degradation of the targeted Scnn1a mRNA. Aerosol delivered ENaC ASO down-regulated mucus marker expression and ameliorated goblet cell metaplasia, inflammation, and airway hyper-responsiveness. Lack of systemic activity of ASOs delivered via the aerosol route ensures the safety of this approach. Our results demonstrate that antisense inhibition of ENaC in airway epithelial cells could be an effective and safe approach for the prevention and reversal of lung symptoms in CF and potentially other inflammatory diseases of the lung. Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Incomplete Spontaneous Recovery from Airway Obstruction During Inhaled Anesthesia Induction: A Computational Simulation.

PubMed

Kuo, Alexander S; Vijjeswarapu, Mary A; Philip, James H

2016-03-01

Inhaled induction with spontaneous respiration is a technique used for difficult airways. One of the proposed advantages is if airway patency is lost, the anesthetic agent will spontaneously redistribute until anesthetic depth is reduced and airway patency can be recovered. There are little and conflicting clinical or experimental data regarding the kinetics of this anesthetic technique. We used computer simulation to investigate this situation. We used GasMan, a computer simulation of inhaled anesthetic kinetics. For each simulation, alveolar ventilation was initiated with a set anesthetic induction concentration. When the vessel-rich group level reached the simulation specified airway obstruction threshold, alveolar ventilation was set at 0 to simulate complete airway obstruction. The time until the vessel-rich group anesthetic level decreased below the airway obstruction threshold was designated time to spontaneous recovery. We varied the parameters for each simulation, exploring the use of sevoflurane and halothane, airway obstruction threshold from 0.5 to 2 minimum alveolar concentration (MAC), anesthetic induction concentration 2 to 4 MAC sevoflurane and 4 to 6 MAC halothane, cardiac output 2.5 to 10 L/min, functional residual capacity 1.5 to 3.5 L, and relative vessel-rich group perfusion 67% to 85%. In each simulation, there were 3 general phases: anesthetic wash-in, obstruction and overshoot, and then slow redistribution. During the first 2 phases, there was a large gradient between the alveolar and vessel-rich group. Alveolar do not reflect vessel-rich group anesthetic levels until the late third phase. Time to spontaneous recovery varied between 35 and 749 seconds for sevoflurane and 13 and 222 seconds for halothane depending on the simulation parameters. Halothane had a faster time to spontaneous recovery because of the lower alveolar gradient and less overshoot of the vessel-rich group, not faster redistribution. Higher airway obstruction thresholds

Parasympathetic Control of Airway Submucosal Glands: Central Reflexes and the Airway Intrinsic Nervous System

PubMed Central

Wine, Jeffrey J.

2007-01-01

Airway submucosal glands produce the mucus that lines the upper airways to protect them against insults. This review summarizes evidence for two forms of gland secretion, and hypothesizes that each is mediated by different but partially overlapping neural pathways. Airway innate defense comprises low level gland secretion, mucociliary clearance and surveillance by airway-resident phagocytes to keep the airways sterile in spite of nearly continuous inhalation of low levels of pathogens. Gland secretion serving innate defense is hypothesized to be under the control of intrinsic (peripheral) airway neurons and local reflexes, and these may depend disproportionately on non-cholinergic mechanisms, with most secretion being produced by VIP and tachykinins. In the genetic disease cystic fibrosis, airway glands no longer secrete in response to VIP alone and fail to show the synergy between VIP, tachykinins and ACh that is observed in normal glands. The consequent crippling of the submucosal gland contribution to innate defense may be one reason that cystic fibrosis airways are infected by mucus-resident bacteria and fungi that are routinely cleared from normal airways. By contrast, the acute (emergency) airway defense reflex is centrally mediated by vagal pathways, is primarily cholinergic, and stimulates copious volumes of gland mucus in response to acute, intense challenges to the airways, such as those produced by very vigorous exercise or aspiration of foreign material. In cystic fibrosis, the acute airway defense reflex can still stimulate the glands to secrete large amounts of mucus, although its properties are altered. Importantly, treatments that recruit components of the acute reflex, such as inhalation of hypertonic saline, are beneficial in treating cystic fibrosis airway disease. The situation for recipients of lung transplants is the reverse; transplanted airways retain the airway intrinsic nervous system but lose centrally mediated reflexes. The consequences

Effect of Continuous Positive Airway Pressure on Airway Reactivity in Asthma. A Randomized, Sham-controlled Clinical Trial

PubMed Central

Sugar, Elizabeth A.; Brown, Robert H.; Drye, Lea T.; Irvin, Charles G.; Schwartz, Alan R.; Tepper, Robert S.; Wise, Robert A.; Yasin, Razan Z.; Busk, Michael F.

2016-01-01

Rationale: Studies have demonstrated that application of stress suppresses airway smooth muscle contractility. In animal models of asthma, continuous positive airway pressure (CPAP) reduced airway reactivity. Short-term studies of CPAP in patients with asthma showed reductions in airway reactivity. Objectives: To evaluate whether nocturnal CPAP decreased the provocative concentration of methacholine to reduce FEV1 by 20% (PC20). Methods: One hundred ninety-four individuals with asthma were randomized (1:1:1) to use CPAP with warmed, filtered, humidified air at night at pressures either less than 1 cm H2O (sham) or at 5 cm H2O or 10 cm H2O. The primary outcome was change in PC20 after 12 weeks. Measurements and Main Results: Adherence to CPAP was low in all groups. Regardless, all groups had a significant improvement in PC20, with 12 weeks/baseline PC20 ratios of 2.12, 1.73, and 1.78 for the sham, 5 cm H2O, and 10 cm H2O groups, respectively, and no significant differences between the active and sham groups. Changes in FEV1 and exhaled nitric oxide were minimal in all groups. The sham group had larger improvements in most patient-reported outcomes measuring asthma symptoms and quality of life, as well as sinus symptoms, than the 5 cm H2O group. The 10 cm H2O group showed similar but less consistent improvements in scores, which were not different from improvements in the sham group. Conclusions: Adherence to nocturnal CPAP was low. There was no evidence to support positive pressure as being effective for reducing airway reactivity in people with well-controlled asthma. Regardless, airway reactivity was improved in all groups, which may represent an effect of participating in a study and/or an effect of warm, humid, filtered air on airway reactivity. Clinical trial registered with www.clinicaltrials.gov (NCT01629823). PMID:27398992

Bronchial hyperresponsiveness in women with chronic obstructive pulmonary disease related to wood smoke

PubMed Central

González-García, Mauricio; Torres-Duque, Carlos A; Bustos, Adriana; Jaramillo, Claudia; Maldonado, Darío

2012-01-01

Purpose Chronic obstructive pulmonary disease (COPD) related to wood smoke exposure is characterized by important inflammation of the central and peripheral airways without significant emphysema. The objective of this study is to describe the bronchial hyperresponsiveness (BHR) level in women with COPD related to wood smoke exposure and to compare it with the BHR in women with COPD related to tobacco smoking. Materials and methods Two groups of women with stable COPD were studied: (1) wood smoke exposed (WS-COPD); and (2) tobacco smoke exposed (TS-COPD). A methacholine challenge test (MCT) was performed in all patients according to American Thoracic Society criteria. BHR levels were compared using the methacholine concentration, which caused a 20% fall in the FEV1 (PC20). Results Thirty-one patients, 19 with WS-COPD and 12 with TS-COPD, were included. There were no significant differences between the groups in baseline FVC, FEV1, IC, FEF25–75, and FEF25–75/FVC. All 31 patients had a positive MCT (PC20 < 16 mg/mL) and the fall in the FEV1 and IC was similar in both groups. The severity of BHR was significantly higher in the WS-COPD patients (PC20: 0.39 mg/mL) than in the TS-COPD patients (PC20: 1.24 mg/mL) (P = 0.028). The presence of cough, phlegm, and dyspnea during the test were similar in both groups. Conclusion We found moderate to severe BHR in women with WS-COPD, which was more severe than in the TS-COPD women with similar age and airflow obstruction. This paper suggests that the structural and inflammatory changes induced by the chronic exposure to wood smoke, described in other studies, can explain the differences with TS-COPD patients. Future studies may clarify our understanding of the impact of BHR on COPD physiopathology, phenotypes, and treatment strategies. PMID:22791990

The effects of inhaled corticosteroids on intrinsic responsiveness and histology of airways from infant monkeys exposed to house dust mite allergen and ozone

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

Joad, Jesse P.; Kott, Kayleen S.; Bric, John M.

2008-01-15

Inhaled corticosteroids (ICS) are recommended to treat infants with asthma, some with intermittent asthma. We previously showed that exposing infant monkeys to allergen/ozone resulted in asthma-like characteristics of their airways. We evaluated the effects of ICS on histology and intrinsic responsiveness of allergen/ozone-exposed and normal infant primate airways. Infant monkeys were exposed by inhalation to (1) filtered air and saline, (2) house dust mite allergen (HDMA) + ozone and saline, (3) filtered air and ICS (budesonide) or (4) HDMA + ozone and ICS. Allergen/ozone exposures started at 1 month and ICS at 3 months of age. At 6 months ofmore » age, methacholine-induced changes in luminal area of airways in proximal and distal lung slices were determined using videomicrometry, followed by histology of the same slices. Proximal airway responsiveness was increased by allergen/ozone and by ICS. Eosinophil profiles were increased by allergen/ozone in both proximal and distal airways, an effect that was decreased by ICS in distal airways. In both allergen/ozone- and air-exposed monkeys, ICS increased the number of alveolar attachments in distal airways, decreased mucin in proximal airways and decreased epithelial volume in both airways. ICS increased smooth muscle in air-exposed animals while decreasing it in allergen/ozone-exposed animals in both airways. In proximal airways, there was a small but significant positive correlation between smooth muscle and airway responsiveness, as well as between alveolar attachments and responsiveness. ICS change morphology and function in normal airways as well as allergen/ozone-exposed airways, suggesting that they should be reserved for infants with active symptoms.« less

Guinea pig models of asthma.

PubMed

McGovern, Alice E; Mazzone, Stuart B

2014-12-01

Described in this unit are methods for establishing guinea pig models of asthma. Sufficient detail is provided to enable investigators to study bronchoconstriction, cough, airway hyperresponsiveness, inflammation, and remodeling. Copyright © 2014 John Wiley & Sons, Inc.

Classification of pulmonary airway disease based on mucosal color analysis

NASA Astrophysics Data System (ADS)

Suter, Melissa; Reinhardt, Joseph M.; Riker, David; Ferguson, John Scott; McLennan, Geoffrey

2005-04-01

Airway mucosal color changes occur in response to the development of bronchial diseases including lung cancer, cystic fibrosis, chronic bronchitis, emphysema and asthma. These associated changes are often visualized using standard macro-optical bronchoscopy techniques. A limitation to this form of assessment is that the subtle changes that indicate early stages in disease development may often be missed as a result of this highly subjective assessment, especially in inexperienced bronchoscopists. Tri-chromatic CCD chip bronchoscopes allow for digital color analysis of the pulmonary airway mucosa. This form of analysis may facilitate a greater understanding of airway disease response. A 2-step image classification approach is employed: the first step is to distinguish between healthy and diseased bronchoscope images and the second is to classify the detected abnormal images into 1 of 4 possible disease categories. A database of airway mucosal color constructed from healthy human volunteers is used as a standard against which statistical comparisons are made from mucosa with known apparent airway abnormalities. This approach demonstrates great promise as an effective detection and diagnosis tool to highlight potentially abnormal airway mucosa identifying a region possibly suited to further analysis via airway forceps biopsy, or newly developed micro-optical biopsy strategies. Following the identification of abnormal airway images a neural network is used to distinguish between the different disease classes. We have shown that classification of potentially diseased airway mucosa is possible through comparative color analysis of digital bronchoscope images. The combination of the two strategies appears to increase the classification accuracy in addition to greatly decreasing the computational time.

K/sup +/-induced alterations in airway muscle responsiveness to electrical field stimulation

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

Murlas, C.; Ehring, G.; Suszkiw, J.

1986-07-01

The authors investigated possible pre- and postsynaptic effects of K/sup +/-induced depolarization on ferret tracheal smooth muscle (TSM) responsiveness to cholinergic stimulation. To assess electromechanical activity, cell membrane potential (E/sub m/) and tension (T/sub m/) were simultaneously recorded in buffer containing 6, 12, 18, or 24 mM K/sup +/ before and after electrical field stimulation (EFS) or exogenous acetylcholine (ACh). In 6 mM K/sup +/ E/sub m/ was -58.1 +/- 1.0 m V (mean +/- SE). In 12 mM K/sup +/, E/sub m/ was depolarized to -52.3 +/- 0.9 mV, basal T/sub m/ did not change, and both excitatory junctionalmore » potentials and contractile responses to EFS at short stimulus duration were larger than in 6 mM K/sup +/. No such potentiation occurred at a higher K/sup +/, although resting E/sub m/ and T/sub m/ increased progressively above 12 mM K/sup +/. The sensitivity of ferret TSM to exogenous ACh appeared unaffected by K/sup +/. To determine whether the hyperresponsiveness in 12 mM K/sup +/ was due, in part, to augmented ACh release from intramural airway nerves, experiments were done using TSM preparations incubated with (/sup 3/H)choline to measure (/sup 3/H)ACh release at rest and during EFS. Although resting (/sup 3/H)ACh release increased progressively in higher K/sup +/, release evoked by EFS was maximal in 12 mM K/sup +/ and declined in higher concentrations. They conclude that small elevations in the extracellular K/sup +/ concentration augment responsiveness of the airways, by increasing the release of ACh both at rest and during EFS from intramural cholinergic nerve terminals. Larger increases in K/sup +/ appear to be inhibitory, possibly due to voltage-dependent effects that occur both pre- and postsynaptically.« less

Suppressive effects of ginsan on the development of allergic reaction in murine asthmatic model.

PubMed

Lim, You-Jin; Na, Hee-Sam; Yun, Yeon-Sook; Choi, Inseon S; Oh, Jong-Suk; Rhee, Joon-Haeng; Cho, Bok-Hee; Lee, Hyun-Chul

2009-01-01

Asthma is a major health problem worldwide, and the morbidity and mortality caused by asthma are on the rise. Corticosteroid therapies for asthma treatment frequently induce many side effects. Therefore, the development of new medicines that have both high efficacy and fewer side effects has been a scientific challenge. Here we tested the effect of ginsan, a polysaccharide derived from Panax ginseng, against allergic reaction in an ovalbumin (OVA)-induced murine asthmatic model in comparison with dexamethasone, and investigated its underlying mechanism. To induce murine asthma, mice were sensitized and challenged with OVA. Ginsan or dexamethasone was administered by injection 3 times a week. Airway hyperresponsiveness, airway inflammation and lung pathology were assessed in order to evaluate the effect of ginsan against asthma. Ginsan treatment reduced airway hyperresponsiveness, remodeling and eosinophilia. These effects of ginsan were equivalent to those of dexamethasone. Ginsan treatment decreased the IL-5 level in the supernatant of cultured splenocytes, while IFN-gamma and serum IgE were not altered. To elucidate the mechanism of ginsan, expression of inflammation-related genes were screened. Interestingly, ginsan treatment upregulated cyclooxygenase (COX)-1 and COX-2 mRNA, and expression of their proteins in the lung were also increased. PGE(2) in the bronchoalveolar lavage fluid was also increased by the ginsan treatment. Lastly, ginsan inhibited the allergic reaction aggravated by COX inhibitor (indomethacin). Ginsan has anti-asthmatic effects, which seem to be partially mediated by enhancing the synthesis of COX gene products. Copyright 2009 S. Karger AG, Basel.

Parasympathetic control of airway submucosal glands: central reflexes and the airway intrinsic nervous system.

PubMed

Wine, Jeffrey J

2007-04-30

Airway submucosal glands produce the mucus that lines the upper airways to protect them against insults. This review summarizes evidence for two forms of gland secretion, and hypothesizes that each is mediated by different but partially overlapping neural pathways. Airway innate defense comprises low level gland secretion, mucociliary clearance and surveillance by airway-resident phagocytes to keep the airways sterile in spite of nearly continuous inhalation of low levels of pathogens. Gland secretion serving innate defense is hypothesized to be under the control of intrinsic (peripheral) airway neurons and local reflexes, and these may depend disproportionately on non-cholinergic mechanisms, with most secretion being produced by VIP and tachykinins. In the genetic disease cystic fibrosis, airway glands no longer secrete in response to VIP alone and fail to show the synergy between VIP, tachykinins and ACh that is observed in normal glands. The consequent crippling of the submucosal gland contribution to innate defense may be one reason that cystic fibrosis airways are infected by mucus-resident bacteria and fungi that are routinely cleared from normal airways. By contrast, the acute (emergency) airway defense reflex is centrally mediated by vagal pathways, is primarily cholinergic, and stimulates copious volumes of gland mucus in response to acute, intense challenges to the airways, such as those produced by very vigorous exercise or aspiration of foreign material. In cystic fibrosis, the acute airway defense reflex can still stimulate the glands to secrete large amounts of mucus, although its properties are altered. Importantly, treatments that recruit components of the acute reflex, such as inhalation of hypertonic saline, are beneficial in treating cystic fibrosis airway disease. The situation for recipients of lung transplants is the reverse; transplanted airways retain the airway intrinsic nervous system but lose centrally mediated reflexes. The consequences

Enhanced basophil histamine release and neutrophil chemotactic activity predispose grain dust-induced airway obstruction.

PubMed

Park, H; Jung, K; Kang, K; Nahm, D; Cho, S; Kim, Y

1999-04-01

The pathogenic mechanism of grain dust (GD)-induced occupational asthma (OA) remains unclear. To understand further the mechanism of GD-induced OA. Fifteen employees working in a same GD industry, complaining of work-related respiratory symptoms, were enrolled and were divided into two groups according to the GD-bronchoprovocation test (BPT) result: six positive responders were grouped as group III, nine negative responders as group II and five healthy controls as group I. Serum GD-specific immunoglobulin (Ig)E (sIgE), specific IgG (sIgG) and specific IgG4 (sIgG4) antibodies were detected by enzyme-linked immunosorbent assay. Basophil histamine release was measured by the autofluorometric method, and changes of serum neutrophil chemotactic activity were observed by the Boyden chamber method. For clinical parameters such as degree of airway hyperresponsiveness to methacholine, duration of respiratory symptoms, exposure duration, and prevalences of serum sIgE, sIgG and sIgG4 antibodies, there were no significant differences between group II and III (P > 0.05, respectively). Serum neutrophil chemotactic activity increased significantly at 30 min and decreased at 240 min after the GD-BPT in group III subjects (P < 0.05, respectively), while no significant changes were noted in group II subjects (P > 0.05). Basophil histamine release induced by GD was significantly higher in group III than those of group I or group II (P < 0.05, respectively), while minimal release of anti-IgG4 antibodies was noted in all three groups. These results suggest that enhanced basophil histamine release and serum neutrophil chemotactic activity might contribute to the development of GD-induced occupational asthma.

Reduction of eotaxin production and eosinophil recruitment by pulmonary autologous macrophage transfer in a cockroach allergen-induced asthma model.

PubMed

Beal, Dominic R; Stepien, David M; Natarajan, Sudha; Kim, Jiyoun; Remick, Daniel G

2013-12-01

We sought to investigate the effects of cockroach allergen (CRA) exposure on the lung macrophage population to determine how different macrophage phenotypes influence exacerbation of disease. CRA exposure caused significantly reduced expression of CD86 on lung macrophages. These effects were not systemic, as peritoneal macrophage CD86 expression was not altered. To investigate whether naïve macrophages could reduce asthma-like pulmonary inflammation, autologous peritoneal macrophages were instilled into the airways 24 h before the final CRA challenge. Pulmonary inflammation was assessed by measurement of airway hyperresponsiveness, mucin production, inflammatory cell recruitment, and cytokine production. Cell transfer did not have significant effects in control mice, nor did it affect pulmonary mucin production or airway hyperresponsiveness in control or CRA-exposed mice. However, there was significant reduction in the number of eosinophils recovered in the bronchoalveolar lavage (BAL) (5.8 × 10⁵ vs. 0.88 × 10⁵), and total cell recruitment to the airways of CRA-exposed mice was markedly reduced (1.1 × 10⁶ vs. 0.57 × 10⁶). The reduced eosinophil recruitment was reflected by substantially lower levels of eosinophil peroxidase in the lung and significantly lower concentrations of eotaxins in BAL (eotaxin 1: 3 pg/ml vs. undetectable; eotaxin 2: 2,383 vs. 131 pg/ml) and lung homogenate (eotaxin 1: 1,043 vs. 218 pg/ml; eotaxin 2: 10 vs. 1.5 ng/ml). We conclude that CRA decreases lung macrophage CD86 expression. Furthermore, supplementation of the lung cell population with peritoneal macrophages inhibits eosinophil recruitment, achieved through reduction of eotaxin production. These data demonstrate that transfer of naïve macrophages will reduce some aspects of asthma-like pulmonary inflammation in response to CRA.

Host-microbe interactions in distal airways: relevance to chronic airway diseases.

PubMed

Martin, Clémence; Burgel, Pierre-Régis; Lepage, Patricia; Andréjak, Claire; de Blic, Jacques; Bourdin, Arnaud; Brouard, Jacques; Chanez, Pascal; Dalphin, Jean-Charles; Deslée, Gaetan; Deschildre, Antoine; Gosset, Philippe; Touqui, Lhousseine; Dusser, Daniel

2015-03-01

This article is the summary of a workshop, which took place in November 2013, on the roles of microorganisms in chronic respiratory diseases. Until recently, it was assumed that lower airways were sterile in healthy individuals. However, it has long been acknowledged that microorganisms could be identified in distal airway secretions from patients with various respiratory diseases, including cystic fibrosis (CF) and non-CF bronchiectasis, chronic obstructive pulmonary disease, asthma and other chronic airway diseases (e.g. post-transplantation bronchiolitis obliterans). These microorganisms were sometimes considered as infectious agents that triggered host immune responses and contributed to disease onset and/or progression; alternatively, microorganisms were often considered as colonisers, which were considered unlikely to play roles in disease pathophysiology. These concepts were developed at a time when the identification of microorganisms relied on culture-based methods. Importantly, the majority of microorganisms cannot be cultured using conventional methods, and the use of novel culture-independent methods that rely on the identification of microorganism genomes has revealed that healthy distal airways display a complex flora called the airway microbiota. The present article reviews some aspects of current literature on host-microbe (mostly bacteria and viruses) interactions in healthy and diseased airways, with a special focus on distal airways. Copyright ©ERS 2015.

The New Perilaryngeal Airway (CobraPLA™)1 Is as Efficient as the Laryngeal Mask Airway (LMA™)2, But Provides Better Airway Sealing Pressures

PubMed Central

Akça, Ozan; Wadhwa, Anupama; Sengupta, Papiya; Durrani, Jaleel; Hanni, Keith; Wenke, Mary; Yücel, Yüksel; Lenhardt, Rainer; Doufas, Anthony G.; Sessler, Daniel I.

2006-01-01

The Laryngeal Mask Airway (LMA) is a frequently-used efficient airway device, yet it sometimes seals poorly, thus reducing the efficacy of positive-pressure ventilation. The Perilaryngeal Airway (CobraPLA) is a novel airway device with a larger pharyngeal cuff (when inflated). We tested the hypothesis that the CobraPLA was superior to LMA with regard to insertion time and airway sealing pressure and comparable to LMA in airway adequacy and recovery characteristics. After midazolam and fentanyl, 81 ASA I-II outpatients having elective surgery were randomized to receive an LMA or CobraPLA. Anesthesia was induced with propofol (2.5 mg/kg, IV), and the airway inserted. We measured 1) insertion time; 2) adequacy of the airway (no leak at 15-cm-H2O peak pressure or tidal volume of 5 ml/kg); 3) airway sealing pressure; 4) number of repositioning attempts; and 5) sealing quality (no leak at tidal volume of 8 ml/kg). At the end of surgery, gastric insufflation, postoperative sore throat, dysphonia, and dysphagia were evaluated. Data were compared with unpaired t-tests, chi-square tests, or Fisher’s Exact tests; P<0.05 was significant. Patient characteristics, insertion times, airway adequacy, number of repositioning attempts, and recovery were similar in each group. Airway sealing pressure was significantly greater with CobraPLA (23±6 cm H2O) than LMA (18±5 cm H2O, P<0.001). The CobraPLA has insertion characteristics similar to LMA, but better airway sealing capabilities. PMID:15281543

Airway surface mycosis in chronic TH2-associated airway disease.

PubMed

Porter, Paul C; Lim, Dae Jun; Maskatia, Zahida Khan; Mak, Garbo; Tsai, Chu-Lin; Citardi, Martin J; Fakhri, Samer; Shaw, Joanne L; Fothergil, Annette; Kheradmand, Farrah; Corry, David B; Luong, Amber

2014-08-01

Environmental fungi have been linked to TH2 cell-related airway inflammation and the TH2-associated chronic airway diseases asthma, chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP), and allergic fungal rhinosinusitis (AFRS), but whether these organisms participate directly or indirectly in disease pathology remains unknown. To determine the frequency of fungus isolation and fungus-specific immunity in patients with TH2-associated and non-TH2-associated airway disease. Sinus lavage fluid and blood were collected from sinus surgery patients (n = 118) including patients with CRSwNP, patients with CRS without nasal polyps, patients with AFRS, and non-CRS/nonasthmatic control patients. Asthma status was determined from medical history. Sinus lavage fluids were cultured and directly examined for evidence of viable fungi. PBMCs were restimulated with fungal antigens in an enzyme-linked immunocell spot assay to determine total memory fungus-specific IL-4-secreting cells. These data were compared with fungus-specific IgE levels measured from plasma by ELISA. Filamentous fungi were significantly more commonly cultured in patients with TH2-associated airway disease (asthma, CRSwNP, or AFRS: n = 68) than in control patients with non-TH2-associated disease (n = 31): 74% vs 16%, respectively (P < .001). Both fungus-specific IL-4 enzyme-linked immunocell spot (n = 48) and specific IgE (n = 70) data correlated with TH2-associated diseases (sensitivity 73% and specificity 100% vs 50% and 77%, respectively). The frequent isolation of fungi growing directly within the airways accompanied by specific immunity to these organisms only in patients with TH2-associated chronic airway diseases suggests that fungi participate directly in the pathogenesis of these conditions. Efforts to eradicate airway fungi from the airways should be considered in selected patients. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

The Effect of Lung Stretch during Sleep on Airway Mechanics in Overweight and Obese Asthma

PubMed Central

Campana, L.M.; Malhotra, A.; Suki, B.; Hess, L.; Israel, E.; Smales, E.; DeYoung, P.; Owens, R.L.

2012-01-01

Both obesity and sleep reduce lung volume and limit deep breaths, possibly contributing to asthma. We hypothesize that increasing lung volume dynamically during sleep would reduce airway resistance in asthma. Asthma (n=10) and control (n=10) subjects were studied during sleep at baseline and with increased lung volume via bi-level positive airway pressure (BPAP). Using forced oscillations, respiratory system resistance (Rrs) and reactance (Xrs) were measured during sleep and Rrs was partitioned to upper and lower airway resistance (Rup, Rlow) using an epiglottic pressure catheter. Rrs and Rup increased with sleep (p<0.01) and Xrs was decreased in REM (p=0.02) as compared to wake. Rrs, Rup, and Rlow, were larger (p<0.01) and Xrs was decreased (p<0.02) in asthma. On BPAP, Rrs and Rup were decreased (p<0.001) and Xrs increased (p<0.01), but Rlow was unchanged. High Rup was observed in asthma, which reduced with BPAP. We conclude that the upper airway is a major component of Rrs and larger lung volume changes may be required to alter Rlow. PMID:23041446

Expression and coupling of neurokinin receptor subtypes to inositol phosphate and calcium signaling pathways in human airway smooth muscle cells

PubMed Central

Mizuta, Kentaro; Gallos, George; Zhu, Defen; Mizuta, Fumiko; Goubaeva, Farida; Xu, Dingbang; Panettieri, Reynold A.; Yang, Jay; Emala, Charles W.

2013-01-01

Neuropeptide tachykinins (substance P, neurokinin A, and neurokinin B) are present in peripheral terminals of sensory nerve fibers within the respiratory tract and cause airway contractile responses and hyperresponsiveness in humans and most mammalian species. Three subtypes of neurokinin receptors (NK1R, NK2R, and NK3R) classically couple to Gq protein-mediated inositol 1,4,5-trisphosphate (IP3) synthesis and liberation of intracellular Ca2+, which initiates contraction, but their expression and calcium signaling mechanisms are incompletely understood in airway smooth muscle. All three subtypes were identified in native and cultured human airway smooth muscle (HASM) and were subsequently overexpressed in HASM cells using a human immunodeficiency virus-1-based lentivirus transduction system. Specific NKR agonists {NK1R, [Sar9,Met(O2)11]-substance P; NK2R, [β-Ala8]-neurokinin A(4–10); NK3R, senktide} stimulated inositol phosphate synthesis and increased intracellular Ca2+ concentration ([Ca2+]i) in native HASM cells and in HASM cells transfected with each NKR subtype. These effects were blocked by NKR-selective antagonists (NK1R, L-732138; NK2R, GR-159897; NK3R, SB-222200). The initial transient and sustained phases of increased [Ca2+]i were predominantly inhibited by the IP3 receptor antagonist 2-aminoethoxydiphenyl borate (2-APB) or the store-operated Ca2+ channel antagonist SKF-96365, respectively. These results show that all three subtypes of NKRs are expressed in native HASM cells and that IP3 levels are the primary mediators of NKR-stimulated initial [Ca2+]i increases, whereas store-operated Ca2+ channels mediate the sustained phase of the [Ca2+]i increase. PMID:18203813

Difficult airway response team: a novel quality improvement program for managing hospital-wide airway emergencies.

PubMed

Mark, Lynette J; Herzer, Kurt R; Cover, Renee; Pandian, Vinciya; Bhatti, Nasir I; Berkow, Lauren C; Haut, Elliott R; Hillel, Alexander T; Miller, Christina R; Feller-Kopman, David J; Schiavi, Adam J; Xie, Yanjun J; Lim, Christine; Holzmueller, Christine; Ahmad, Mueen; Thomas, Pradeep; Flint, Paul W; Mirski, Marek A

2015-07-01

Difficult airway cases can quickly become emergencies, increasing the risk of life-threatening complications or death. Emergency airway management outside the operating room is particularly challenging. We developed a quality improvement program-the Difficult Airway Response Team (DART)-to improve emergency airway management outside the operating room. DART was implemented by a team of anesthesiologists, otolaryngologists, trauma surgeons, emergency medicine physicians, and risk managers in 2005 at The Johns Hopkins Hospital in Baltimore, Maryland. The DART program had 3 core components: operations, safety, and education. The operations component focused on developing a multidisciplinary difficult airway response team, standardizing the emergency response process, and deploying difficult airway equipment carts throughout the hospital. The safety component focused on real-time monitoring of DART activations and learning from past DART events to continuously improve system-level performance. This objective entailed monitoring the paging system, reporting difficult airway events and DART activations to a Web-based registry, and using in situ simulations to identify and mitigate defects in the emergency airway management process. The educational component included development of a multispecialty difficult airway curriculum encompassing case-based lectures, simulation, and team building/communication to ensure consistency of care. Educational materials were also developed for non-DART staff and patients to inform them about the needs of patients with difficult airways and ensure continuity of care with other providers after discharge. Between July 2008 and June 2013, DART managed 360 adult difficult airway events comprising 8% of all code activations. Predisposing patient factors included body mass index >40, history of head and neck tumor, prior difficult intubation, cervical spine injury, airway edema, airway bleeding, and previous or current tracheostomy. Twenty

Difficult Airway Response Team: A Novel Quality Improvement Program for Managing Hospital-Wide Airway Emergencies

PubMed Central

Mark, Lynette J.; Herzer, Kurt R.; Cover, Renee; Pandian, Vinciya; Bhatti, Nasir I.; Berkow, Lauren C.; Haut, Elliott R.; Hillel, Alexander T.; Miller, Christina R.; Feller-Kopman, David J.; Schiavi, Adam J.; Xie, Yanjun J.; Lim, Christine; Holzmueller, Christine; Ahmad, Mueen; Thomas, Pradeep; Flint, Paul W.; Mirski, Marek A.

2015-01-01

Background Difficult airway cases can quickly become emergencies, increasing the risk of life-threatening complications or death. Emergency airway management outside the operating room is particularly challenging. Methods We developed a quality improvement program—the Difficult Airway Response Team (DART)—to improve emergency airway management outside the operating room. DART was implemented by a team of anesthesiologists, otolaryngologists, trauma surgeons, emergency medicine physicians, and risk managers in 2005 at The Johns Hopkins Hospital in Baltimore, Maryland. The DART program had three core components: operations, safety, and education. The operations component focused on developing a multidisciplinary difficult airway response team, standardizing the emergency response process, and deploying difficult airway equipment carts throughout the hospital. The safety component focused on real-time monitoring of DART activations and learning from past DART events to continuously improve system-level performance. This objective entailed monitoring the paging system, reporting difficult airway events and DART activations to a web-based registry, and using in situ simulations to identify and mitigate defects in the emergency airway management process. The educational component included development of a multispecialty difficult airway curriculum encompassing case-based lectures, simulation, and team building/communication to ensure consistency of care. Educational materials were also developed for non-DART staff and patients to inform them about the needs of patients with difficult airways and ensure continuity of care with other providers after discharge. Results Between July 2008 and June 2013, DART managed 360 adult difficult airway events comprising 8% of all code activations. Predisposing patient factors included body mass index > 40, history of head and neck tumor, prior difficult intubation, cervical spine injury, airway edema, airway bleeding, and previous

Increased contralateral suppression of otoacoustic emissions indicates a hyperresponsive medial olivocochlear system in humans with tinnitus and hyperacusis

PubMed Central

Shera, Christopher A.; Melcher, Jennifer R.

2014-01-01

Atypical medial olivocochlear (MOC) feedback from brain stem to cochlea has been proposed to play a role in tinnitus, but even well-constructed tests of this idea have yielded inconsistent results. In the present study, it was hypothesized that low sound tolerance (mild to moderate hyperacusis), which can accompany tinnitus or occur on its own, might contribute to the inconsistency. Sound-level tolerance (SLT) was assessed in subjects (all men) with clinically normal or near-normal thresholds to form threshold-, age-, and sex-matched groups: 1) no tinnitus/high SLT, 2) no tinnitus/low SLT, 3) tinnitus/high SLT, and 4) tinnitus/low SLT. MOC function was measured from the ear canal as the change in magnitude of distortion-product otoacoustic emissions (DPOAE) elicited by broadband noise presented to the contralateral ear. The noise reduced DPOAE magnitude in all groups (“contralateral suppression”), but significantly more reduction occurred in groups with tinnitus and/or low SLT, indicating hyperresponsiveness of the MOC system compared with the group with no tinnitus/high SLT. The results suggest hyperresponsiveness of the interneurons of the MOC system residing in the cochlear nucleus and/or MOC neurons themselves. The present data, combined with previous human and animal data, indicate that neural pathways involving every major division of the cochlear nucleus manifest hyperactivity and/or hyperresponsiveness in tinnitus and/or low SLT. The overactivation may develop in each pathway separately. However, a more parsimonious hypothesis is that top-down neuromodulation is the driving force behind ubiquitous overactivation of the auditory brain stem and may correspond to attentional spotlighting on the auditory domain in tinnitus and hyperacusis. PMID:25231612

Effects of local nasal immunotherapy in allergic airway inflammation: Using urea denatured Dermatophagoides pteronyssinus

PubMed Central

Yu, Sheng-Jie; Liao, En-Chih; Tsai, Jaw-Ji

2015-01-01

Despite improvements in anti-allergy medication, the prevalence of allergic airway inflammation remains high, affecting up to 40% of the population worldwide. Allergen immunotherapy is effective for inducing tolerance but has the adverse effect of severe allergic reaction. This can be avoided by denaturing with urea. In this study, we demonstrated that the serum level of allergen-specific IgE in mice sensitized with native Dermatophagoides pteronyssinus (Der p) crude extract after receiving local nasal immunotherapy (LNIT) with urea-denatured Der p crude extract (DN-Dp) significantly decreased compared to that in the normal saline (NS) treatment group. Expressions of IL-4 were significantly reduced in lung tissues after treatment. Inflammation around the bronchial epithelium improved and airway hypersensitivity was down-regulated. LNIT with DN-Dp can down-regulate IL-1b, IL-6 and TNF-a expression and then decrease Der p-induced allergic airway inflammation. This therapeutic modality may be used as an alternative treatment for airway allergic diseases. PMID:25933184

KF19514, a phosphodieterase 4 and 1 inhibitor, inhibits PAF-induced lung inflammatory responses by inhaled administration in guinea pigs.

PubMed

Manabe, H; Akuta, K; Okamura, K; Ohmori, K

1997-12-01

Phosphodiesterase (PDE) 4 inhibitors are well known for their inhibitory effect on bronchoconstriction and inflammation and may be promising anti-asthma drugs. Platelet-activating factor (PAF) has been proposed as an inflammatory mediator to be relevant to asthma. It causes bronchoconstriction, airway microvascular leakage, inflammatory cell accumulation in the lung and hyperresponsiveness. In this study, we therefore have investigated the anti-asthmatic effects of the inhaled KF19514 [5-phenyl-3'-(3-pyridyl)methyl-3H-imidazo(4,5-c)(1,8) naphthyridin-4(5H)-one], a PDE 4 and 1 inhibitor, on PAF-induced lung inflammatory responses in guinea pigs. The inhaled KF19514 (0.0001-0.01%) significantly inhibited PAF-induced eosinophil and neutrophil accumulation into the airway and hyperresponsiveness in guinea pigs. The IC50 value of KF19514 against eosinophil accumulation was 14.8 microM (0.00063%). Moreover, the effect of KF19514 on the electrical field stimulation-induced bronchial contraction was examined using the main bronchi of guinea pigs in vitro. KF19514 inhibited both cholinergic and tachykininergic contraction and, in particular, produced a potent inhibitory effect on tachykininergic contraction (IC50 = 0.49 microM). The mechanism by which KF19514 inhibited the PAF-induced hyperresponsiveness may in part be the suppression of the tachykinin release. Based on these results, it was demonstrated that the inhaled KF19514 might have a significant potential effect on the inflammatory cell accumulation and hyperresponsiveness induced by PAF.

Laryngeal mask airway for airway control during percutaneous dilatational tracheostomy.

PubMed

Pratt, T; Bromilow, J

2011-11-01

Percutaneous dilatational tracheostomy is a common bedside procedure in critical care for patients requiring prolonged mechanical ventilation. The traditional technique requires withdrawal of the endotracheal tube to a proximal position to facilitate tracheostomy insertion, but this carries the risk of inadvertent extubation and does not prevent cuff rupture. Use of a supraglottic airway such as the laryngeal mask airway may avoid these risks and could provide a safe alternative to the endotracheal tube. We present an appraisal of the literature to date. We found reasonable evidence to show improved ventilation and bronchoscopic visualisation with the laryngeal mask airway, but this has not been translated into improved outcome. There is currently insufficient evidence to draw conclusions about the safety of the laryngeal mask airway during percutaneous dilatational tracheostomy.

Computed Tomographic Airway Morphology in Chronic Obstructive Pulmonary Disease. Remodeling or Innate Anatomy?

PubMed

Diaz, Alejandro A; Estépar, Raul San José; Washko, George R

2016-01-01

Computed tomographic measures of central airway morphology have been used in clinical, epidemiologic, and genetic investigation as an inference of the presence and severity of small-airway disease in smokers. Although several association studies have brought us to believe that these computed tomographic measures reflect airway remodeling, a careful review of such data and more recent evidence may reveal underappreciated complexity to these measures and limitations that prompt us to question that belief. This Perspective offers a review of seminal papers and alternative explanations of their data in the light of more recent evidence. The relationships between airway morphology and lung function are observed in subjects who never smoked, implying that native airway structure indeed contributes to lung function; computed tomographic measures of central airways such as wall area, lumen area, and total bronchial area are smaller in smokers with chronic obstructive pulmonary disease versus those without chronic obstructive pulmonary disease; and the airways are smaller as disease severity increases. The observations suggest that (1) native airway morphology likely contributes to the relationships between computed tomographic measures of airways and lung function; and (2) the presence of smaller airways in those with chronic obstructive pulmonary disease versus those without chronic obstructive pulmonary disease as well as their decrease with disease severity suggests that smokers with chronic obstructive pulmonary disease may simply have smaller airways to begin with, which put them at greater risk for the development of smoking-related disease.

Lung function requirements in flying duty the problem of bronchial hyperresponsiveness in military aircrew.

PubMed

Hartmann, C M; Steinhoff-Lankes, D; Maya-Pelzer, P

1999-09-09

Uncompromised lung function is essential for fitness to fly. Under hypobaric conditions there is an increased risk of hypoxemia. G-forces, positive pressure breathing and anti-G maneuvers cause physical stress to the lung tissue and altered pulmonary blood flow. Breathing with pure oxygen, dry cabin air and ozone can cause airway irritation. Chemically and physically by irritating agents may be present. Emergencies such as smoke in the cockpit or inhalation of tear gas can rapidly compromise the pulmonary system in susceptible persons. Sudden incapacitation may occur. Trapped gases may cause overinflation and lung rupture in rapid decompression. Applicants for military duty have to pass basic lung function tests routinely. Preselection of aircrew candidates tends to be even stricter. Asthma and obstructive lung disease are disqualifying. Trained aircrew with late onset of pulmonary problems can be waived under certain restrictions in many cases. Some national regulations exclude even applicants with allergies. Due to aeromedical experience we should always be aware of the latent unspecific bronchial hyperresponsiveness (BHR). BHR is one of the characteristics of asthma bronchiale. If BHR exists there is an increased risk of later development of asthma bronchiale, especially together with perennial allergies such as against house dust mite. Under certain conditions BHR can become symptomatic and aeromedically relevant. In some cases we saw an exacerbation under medication, mostly under beta-receptor-blockers. In one case even under betablocker-containing eye drops. In the Gulf War 1991 a number of allied military personnel had to be withdrawn because of bronchospastic symptoms. This can be explained among others by medication with physostigmine. Physostigmine is a systemically active cholinergic drug which is prophylactically used under threat of chemically warfare agents. In individuals with latent BHR physostigmine will lower the threshold for bronchial reactions

Associations of airway inflammation and responsiveness markers in non asthmatic subjects at start of apprenticeship

PubMed Central

2010-01-01

Background Bronchial Hyperresponsiveness (BHR) is considered a hallmark of asthma. Other methods are helpful in epidemiological respiratory health studies including Fractional Exhaled Nitric Oxide (FENO) and Eosinophils Percentage (EP) in nasal lavage fluid measuring markers for airway inflammation along with the Forced Oscillatory Technique measuring Airway resistance (AR). Can their outcomes discriminate profiles of respiratory health in healthy subjects starting apprenticeship in occupations with a risk of asthma? Methods Rhinoconjunctivitis, asthma-like symptoms, FEV1 and AR post-Methacholine Bronchial Challenge (MBC) test results, FENO measurements and EP were all investigated in apprentice bakers, pastry-makers and hairdressers not suffering from asthma. Multiple Correspondence Analysis (MCA) was simultaneously conducted in relation to these groups and this generated a synthetic partition (EI). Associations between groups of subjects based on BHR and EI respectively, as well as risk factors, symptoms and investigations were also assessed. Results Among the 441 apprentice subjects, 45 (10%) declared rhinoconjunctivitis-like symptoms, 18 (4%) declared asthma-like symptoms and 26 (6%) suffered from BHR. The mean increase in AR post-MBC test was 21% (sd = 20.8%). The median of FENO values was 12.6 ppb (2.6-132 range). Twenty-six subjects (6.7%) had EP exceeding 14%. BHR was associated with atopy (p < 0.01) and highest FENO values (p = 0.09). EI identified 39 subjects with eosinophilic inflammation (highest values of FENO and eosinophils), which was associated with BHR and atopy. Conclusions Are any of the identified markers predictive of increased inflammatory responsiveness or of development of symptoms caused by occupational exposures? Analysis of population follow-up will attempt to answer this question. PMID:20604945

Acute administration of ivacaftor to people with cystic fibrosis and a G551D-CFTR mutation reveals smooth muscle abnormalities

PubMed Central

Adam, Ryan J.; Hisert, Katherine B.; Dodd, Jonathan D.; Grogan, Brenda; Launspach, Janice L.; Barnes, Janel K.; Gallagher, Charles G.; Sieren, Jered P.; Gross, Thomas J.; Fischer, Anthony J.; Cavanaugh, Joseph E.; Hoffman, Eric A.; Singh, Pradeep K.; Welsh, Michael J.; McKone, Edward F.; Stoltz, David A.

2016-01-01

BACKGROUND. Airflow obstruction is common in cystic fibrosis (CF), yet the underlying pathogenesis remains incompletely understood. People with CF often exhibit airway hyperresponsiveness, CF transmembrane conductance regulator (CFTR) is present in airway smooth muscle (ASM), and ASM from newborn CF pigs has increased contractile tone, suggesting that loss of CFTR causes a primary defect in ASM function. We hypothesized that restoring CFTR activity would decrease smooth muscle tone in people with CF. METHODS. To increase or potentiate CFTR function, we administered ivacaftor to 12 adults with CF with the G551D-CFTR mutation; ivacaftor stimulates G551D-CFTR function. We studied people before and immediately after initiation of ivacaftor (48 hours) to minimize secondary consequences of CFTR restoration. We tested smooth muscle function by investigating spirometry, airway distensibility, and vascular tone. RESULTS. Ivacaftor rapidly restored CFTR function, indicated by reduced sweat chloride concentration. Airflow obstruction and air trapping also improved. Airway distensibility increased in airways less than 4.5 mm but not in larger-sized airways. To assess smooth muscle function in a tissue outside the lung, we measured vascular pulse wave velocity (PWV) and augmentation index, which both decreased following CFTR potentiation. Finally, change in distensibility of <4.5-mm airways correlated with changes in PWV. CONCLUSIONS. Acute CFTR potentiation provided a unique opportunity to investigate CFTR-dependent mechanisms of CF pathogenesis. The rapid effects of ivacaftor on airway distensibility and vascular tone suggest that CFTR dysfunction may directly cause increased smooth muscle tone in people with CF and that ivacaftor may relax smooth muscle. FUNDING. This work was funded in part from an unrestricted grant from the Vertex Investigator-Initiated Studies Program. PMID:27158673

Use of a Novel Airway Kit and Simulation in Resident Training on Emergent Pediatric Airways.

PubMed

Melzer, Jonathan M; Hamersley, Erin R S; Gallagher, Thomas Q

2017-06-01

Objective Development of a novel pediatric airway kit and implementation with simulation to improve resident response to emergencies with the goal of improving patient safety. Methods Prospective study with 9 otolaryngology residents (postgraduate years 1-5) from our tertiary care institution. Nine simulated pediatric emergency airway drills were carried out with the existing system and a novel portable airway kit. Response times and time to successful airway control were noted with both the extant airway system and the new handheld kit. Results were analyzed to ensure parametric data and compared with t tests. A Bonferroni adjustment indicated that an alpha of 0.025 was needed for significance. Results Use of the airway kit significantly reduced the mean time of resident arrival by 47% ( P = .013) and mean time of successful intubation by 50% ( P = .007). Survey data indicated 100% improved resident comfort with emergent airway scenarios with use of the kit. Discussion Times to response and meaningful intervention were significantly reduced with implementation of the handheld airway kit. Use of simulation training to implement the new kit improved residents' comfort and airway skills. This study describes an affordable novel mobile airway kit and demonstrates its ability to improve response times. Implications for Practice The low cost of this airway kit makes it a tenable option even for smaller hospitals. Simulation provides a safe and effective way to familiarize oneself with novel equipment, and, when possible, realistic emergent airway simulations should be used to improve provider performance.

Difficult airway management in a patient with a parapharyngeal tumor.

PubMed

Ji, Sung-Mi

2015-09-01

A 47-year-old man was referred to the operating room to treat a dentigenous cyst of the mandibular bone. Initial assessment of the airway was considered normal. However, after the induction of anesthesia, we could not intubate the patient due to severe distortion of the glottis. Fiberoptic bronchoscopy and video laryngoscopy were not effective. Intubation using a retrograde wire technique was successful. After the conclusion of surgery, the patient recovered without any complications. Subsequent magnetic resonance imaging of the patient's neck showed a 6 × 4 × 8.6 cm heterogeneous T2 hyperintense, T1 isointense well-enhancing mass in the prestyloid parapharyngeal space. The patient was scheduled for excision of the mass. We planned awake intubation with fiberoptic bronchoscopy. The procedure was successful and the patient recovered without complications. Anesthetic induction can decrease the muscle tone of the airway and increase airway distortion. Therefore, careful airway assessment is necessary.

Heightened bronchial hyperresponsiveness in the absence of heightened atopy in children with current wheezing and low income status.

PubMed

Mallol, J; Castro-Rodriguez, J A; Cortez, E; Aguirre, V; Aguilar, P; Barrueto, L

2008-02-01

Although global studies such as the International Study of Asthma and Allergies in Childhood (ISAAC) have provided valuable data on the prevalence of asthma in children in Latin America, there is little information on the relationship between asthma symptoms, pulmonary function, bronchial hyperresponsiveness (BHR) and atopy in the region. This study examined the relationship between self-reported wheezing in the past 12 months, pulmonary function, airway responsiveness and atopy in children from a low income population in a neighbourhood of Santiago, Chile. Two random samples (100 each) of children aged 13-14 years who participated in ISAAC phase I were selected according to whether or not they reported wheezing in the past 12 months. Spirometry, the methacholine bronchial challenge test and the prick test were performed in all individuals. Children who reported current wheezing had significantly higher BHR to methacholine compared with those without wheezing (71.6% vs 52.6%; p = 0.007) and no significant difference was found in forced expiratory volume in 1 s (116.7 (12.3)% vs 120.3 (14.5%); p = 0.11). The prevalence of atopy was not significantly different between those children who reported wheezing compared with those who did not (44.2% vs 42.3%; p = 0.89). Multiple regression analysis showed that only BHR to methacholine (OR 2.72, 95% CI 1.25 to 4.13; p = 0.01) and maternal asthma (OR 3.1, 95% CI 1.2 to 8.3, p = 0.03) were significant risk factors for current wheezing. Our results support previous findings suggesting that in adolescents from underprivileged populations, self-reported current wheezing is related to BHR but not to atopy.

Antiasthmatic Effects of Herbal Complex MA and Its Fermented Product MA128.

PubMed

Kim, Dong-Seon; Kim, Seung-Hyung; Kim, Bok-Kyu; Yang, Min Cheol; Ma, Jin Yeul

2012-01-01

This study was conducted to determine if oral administration of the novel herbal medicine, MA, and its Lactobacillus acidophilus fermented product, MA128, have therapeutic properties for the treatment of asthma. Asthma was induced in BALB/c mice by systemic sensitization to ovalbumin (OVA) followed by intratracheal, intraperitoneal, and aerosol allergen challenges. MA and MA128 were orally administered 6 times a week for 4 weeks. At 1 day after the last ovalbumin exposure, airway hyperresponsiveness was assessed and samples of bronchoalveolar lavage fluid, lung cells, and serum were collected for further analysis. We investigated the effect of MA and MA128 on airway hyperresponsiveness, pulmonary eosinophilic infiltration, various immune cell phenotypes, Th2 cytokine production, OVA-specific IgE production, and Th1/Th2 cytokine production in this mouse model of asthma. In BALB/c mice, we found that MA and MA128 treatment suppressed eosinophil infiltration into airways and blood, allergic airway inflammation and AHR by suppressing the production of IL-5, IL-13, IL-17, Eotaxin, and OVA-specific IgE, by upregulating the production of OVA-specific Th1 cytokine (IFN-γ), and by downregulating OVA-specific Th2 cytokine (IL-4) in the culture supernatant of spleen cells. The effectiveness of MA was increased by fermentation with Lactobacillus acidophilus.

Rhinovirus infection of allergen-sensitized and -challenged mice induces eotaxin release from functionally polarized macrophages.

PubMed

Nagarkar, Deepti R; Bowman, Emily R; Schneider, Dina; Wang, Qiong; Shim, Jee; Zhao, Ying; Linn, Marisa J; McHenry, Christina L; Gosangi, Babina; Bentley, J Kelley; Tsai, Wan C; Sajjan, Umadevi S; Lukacs, Nicholas W; Hershenson, Marc B

2010-08-15

Human rhinovirus is responsible for the majority of virus-induced asthma exacerbations. To determine the immunologic mechanisms underlying rhinovirus (RV)-induced asthma exacerbations, we combined mouse models of allergic airways disease and human rhinovirus infection. We inoculated OVA-sensitized and challenged BALB/c mice with rhinovirus serotype 1B, a minor group strain capable of infecting mouse cells. Compared with sham-infected, OVA-treated mice, virus-infected mice showed increased lung infiltration with neutrophils, eosinophils and macrophages, airway cholinergic hyperresponsiveness, and increased lung expression of cytokines including eotaxin-1/CCL11, IL-4, IL-13, and IFN-gamma. Administration of anti-eotaxin-1 attenuated rhinovirus-induced airway eosinophilia and responsiveness. Immunohistochemical analysis showed eotaxin-1 in the lung macrophages of virus-infected, OVA-treated mice, and confocal fluorescence microscopy revealed colocalization of rhinovirus, eotaxin-1, and IL-4 in CD68-positive cells. RV inoculation of lung macrophages from OVA-treated, but not PBS-treated, mice induced expression of eotaxin-1, IL-4, and IL-13 ex vivo. Macrophages from OVA-treated mice showed increased expression of arginase-1, Ym-1, Mgl-2, and IL-10, indicating a shift in macrophage activation status. Depletion of macrophages from OVA-sensitized and -challenged mice reduced eosinophilic inflammation and airways responsiveness following RV infection. We conclude that augmented airway eosinophilic inflammation and hyperresponsiveness in RV-infected mice with allergic airways disease is directed in part by eotaxin-1. Airway macrophages from mice with allergic airways disease demonstrate a change in activation state characterized in part by altered eotaxin and IL-4 production in response to RV infection. These data provide a new paradigm to explain RV-induced asthma exacerbations.

Efficacy of Surgical Airway Plasty for Benign Airway Stenosis.

PubMed

Tsukioka, Takuma; Takahama, Makoto; Nakajima, Ryu; Kimura, Michitaka; Inoue, Hidetoshi; Yamamoto, Ryoji

2016-01-01

Long-term patency is required during treatment for benign airway stenosis. This study investigated the effectiveness of surgical airway plasty for benign airway stenosis. Clinical courses of 20 patients, who were treated with surgical plasty for their benign airway stenosis, were retrospectively investigated. Causes of stenosis were tracheobronchial tuberculosis in 12 patients, post-intubation stenosis in five patients, malacia in two patients, and others in one patient. 28 interventional pulmonology procedures and 20 surgical plasty were performed. Five patients with post-intubation stenosis and four patients with tuberculous stenosis were treated with tracheoplasty. Eight patients with tuberculous stenosis were treated with bronchoplasty, and two patients with malacia were treated with stabilization of the membranous portion. Anastomotic stenosis was observed in four patients, and one to four additional treatments were required. Performance status, Hugh-Jones classification, and ventilatory functions were improved after surgical plasty. Outcomes were fair in patients with tuberculous stenosis and malacia. However, efficacy of surgical plasty for post-intubation stenosis was not observed. Surgical airway plasty may be an acceptable treatment for tuberculous stenosis. Patients with malacia recover well after surgical plasty. There may be untreated patients with malacia who have the potential to benefit from surgical plasty.

Efficacy of Surgical Airway Plasty for Benign Airway Stenosis

PubMed Central

Takahama, Makoto; Nakajima, Ryu; Kimura, Michitaka; Inoue, Hidetoshi; Yamamoto, Ryoji

2015-01-01

Background: Long-term patency is required during treatment for benign airway stenosis. This study investigated the effectiveness of surgical airway plasty for benign airway stenosis. Methods: Clinical courses of 20 patients, who were treated with surgical plasty for their benign airway stenosis, were retrospectively investigated. Results: Causes of stenosis were tracheobronchial tuberculosis in 12 patients, post-intubation stenosis in five patients, malacia in two patients, and others in one patient. 28 interventional pulmonology procedures and 20 surgical plasty were performed. Five patients with post-intubation stenosis and four patients with tuberculous stenosis were treated with tracheoplasty. Eight patients with tuberculous stenosis were treated with bronchoplasty, and two patients with malacia were treated with stabilization of the membranous portion. Anastomotic stenosis was observed in four patients, and one to four additional treatments were required. Performance status, Hugh–Jones classification, and ventilatory functions were improved after surgical plasty. Outcomes were fair in patients with tuberculous stenosis and malacia. However, efficacy of surgical plasty for post-intubation stenosis was not observed. Conclusion: Surgical airway plasty may be an acceptable treatment for tuberculous stenosis. Patients with malacia recover well after surgical plasty. There may be untreated patients with malacia who have the potential to benefit from surgical plasty. PMID:26567879

Arginase inhibition in airways from normal and nitric oxide synthase 2-knockout mice exposed to ovalbumin

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

Bratt, Jennifer M.; Franzi, Lisa M.; Linderholm, Angela L.

Arginase1 and nitric oxide synthase2 (NOS2) utilize L-arginine as a substrate, with both enzymes expressed at high levels in the asthmatic lung. Inhibition of arginase in ovalbumin-exposed C57BL/6 mice with the transition state inhibitor N{sup o}mega-hydroxy-nor-L-arginine (nor-NOHA) significantly increased total L-arginine content in the airway compartment. We hypothesized that such an increase in L-arginine content would increase the amount of nitric oxide (NO) being produced in the airways and thereby decrease airway hyperreactivity and eosinophilic influx. We further hypothesized that despite arginase inhibition, NOS2 knockout (NOS2-/-) mice would be unable to up-regulate NO production in response to allergen exposure andmore » would demonstrate higher amounts of airway hyperreactivity and eosinophilia under conditions of arginase inhibition than C57BL/6 animals. We found that administration of nor-NOHA significantly decreased airway hyperreactivity and eosinophilic airway inflammation in ovalbumin-exposed C57BL/6 mice, but these parameters were unchanged in ovalbumin-exposed NOS2-/- mice. Arginase1 protein content was increased in mice exposed to ovalbumin, an effect that was reversed upon nor-NOHA treatment in C57BL/6 mice. Arginase1 protein content in the airway compartment directly correlated with the degree of airway hyperreactivity in all treatment groups. NOS2-/- mice had significantly greater arginase1 and arginase2 concentrations compared to their respective C57BL/6 groups, indicating that inhibition of arginase may be dependent upon NOS2 expression. Arginase1 and 2 content were not affected by nor-NOHA administration in the NOS2-/- mice. We conclude that L-arginine metabolism plays an important role in the development of airway hyperreactivity and eosinophilic airway inflammation. Inhibition of arginase early in the allergic inflammatory response decreases the severity of the chronic inflammatory phenotype. These effects appear to be attributable to

Airway and Parenchymal Strains during Bronchoconstriction in the Precision Cut Lung Slice

PubMed Central

Hiorns, Jonathan E.; Bidan, Cécile M.; Jensen, Oliver E.; Gosens, Reinoud; Kistemaker, Loes E. M.; Fredberg, Jeffrey J.; Butler, Jim P.; Krishnan, Ramaswamy; Brook, Bindi S.

2016-01-01

The precision-cut lung slice (PCLS) is a powerful tool for studying airway reactivity, but biomechanical measurements to date have largely focused on changes in airway caliber. Here we describe an image processing tool that reveals the associated spatio-temporal changes in airway and parenchymal strains. Displacements of sub-regions within the PCLS are tracked in phase-contrast movies acquired after addition of contractile and relaxing drugs. From displacement maps, strains are determined across the entire PCLS or along user-specified directions. In a representative mouse PCLS challenged with 10−4M methacholine, as lumen area decreased, compressive circumferential strains were highest in the 50 μm closest to the airway lumen while expansive radial strains were highest in the region 50–100 μm from the lumen. However, at any given distance from the airway the strain distribution varied substantially in the vicinity of neighboring small airways and blood vessels. Upon challenge with the relaxant agonist chloroquine, although most strains disappeared, residual positive strains remained a long time after addition of chloroquine, predominantly in the radial direction. Taken together, these findings establish strain mapping as a new tool to elucidate local dynamic mechanical events within the constricting airway and its supporting parenchyma. PMID:27559314

Motile cilia of human airway epithelia contain hedgehog signaling components that mediate noncanonical hedgehog signaling.

PubMed

Mao, Suifang; Shah, Alok S; Moninger, Thomas O; Ostedgaard, Lynda S; Lu, Lin; Tang, Xiao Xiao; Thornell, Ian M; Reznikov, Leah R; Ernst, Sarah E; Karp, Philip H; Tan, Ping; Keshavjee, Shaf; Abou Alaiwa, Mahmoud H; Welsh, Michael J

2018-02-06

Differentiated airway epithelia produce sonic hedgehog (SHH), which is found in the thin layer of liquid covering the airway surface. Although previous studies showed that vertebrate HH signaling requires primary cilia, as airway epithelia mature, the cells lose primary cilia and produce hundreds of motile cilia. Thus, whether airway epithelia have apical receptors for SHH has remained unknown. We discovered that motile cilia on airway epithelial cells have HH signaling proteins, including patched and smoothened. These cilia also have proteins affecting cAMP-dependent signaling, including Gα i and adenylyl cyclase 5/6. Apical SHH decreases intracellular levels of cAMP, which reduces ciliary beat frequency and pH in airway surface liquid. These results suggest that apical SHH may mediate noncanonical HH signaling through motile cilia to dampen respiratory defenses at the contact point between the environment and the lung, perhaps counterbalancing processes that stimulate airway defenses. Copyright © 2018 the Author(s). Published by PNAS.

Effect of interleukin 13 on bronchial hyperresponsiveness and the bronchoprotective effect of beta-adrenergic bronchodilators and corticosteroids.

PubMed

Townley, Robert G; Gendapodi, Pradeep R; Qutna, Nidal; Evans, Joseph; Romero, Francisco A; Abel, Peter

2009-03-01

Fluticasone affects airway bronchial hyperresponsiveness (BHR) and enhances bronchodilation and bronchoprotection induced by beta-adrenergic agonists. Interleukin 13 (IL-13), however, induces BHR. To test the hypotheses that fluticasone inhibits BHR after either allergen sensitization or IL-13 administration and that fluticasone restores the bronchodilation and bronchoprotective effects of beta-agonists. The BHR to methacholine induced by IL-13 or ovalbumin was determined in BALB/c mice, and the provocation concentration of methacholine that caused an increase in enhanced pause in expiration of 200% (PC200) was calculated. We compared this response to methacholine in control mice with the response after treatment with IL-13 receptor alpha 2-IgGFc fusion protein (IL-13R alpha 2) (an IL-13 blocker), fluticasone, albuterol, salmeterol, fluticasone-albuterol, and fluticasone-salmeterol. IL-13R alpha 2 (PC200, 17.59) completely blocks the BHR-induced effects of IL-13 (PC200, 7.28; P < .005). After IL-13 therapy (PC200, 5.90; P < .005), 1 mg/mL of albuterol (PC200, 3.38; P = .33), fluticasone (PC200, 4.59; P = .40), or fluticasone plus 50 microg/mL of salmeterol (PC200, 5.59; P = .11) showed no significant bronchoprotection. In nonsensitized mice, fluticasone plus 0.25 microg/mL of salmeterol (PC200, 25.90; P < .005) showed significantly greater bronchoprotection than did salmeterol alone (PC200, 11.08; P = .26). Fluticasone plus 0.3 mg/mL of albuterol and fluticasone plus 1 mg/mL of albuterol were significantly more protective than was fluticasone or albuterol alone in ovalbumin-sensitized mice. The protective effects of fluticasone, beta-agonists, and fluticasone plus beta-agonists are significantly less in IL-13-treated mice than in nonsensitized or ovalbumin-sensitized mice.

Airway and serum adipokines after allergen and diesel exposure in a controlled human crossover study of atopic adults.

PubMed

Kramer, Marabeth M; Hirota, Jeremy A; Sood, Akshay; Teschke, Kay; Carlsten, Christopher

2017-04-01

Adipokines are mediators released from adipose tissue. These proteins are regarded as active elements of systemic and pulmonary inflammation, whose dysregulation can alter an individual's risk of developing allergic lung diseases. Despite this knowledge, adipokine responses to inhaled stimuli are poorly understood. We sought to measure serum and lung adiponectin, leptin, and resistin in an atopic adult study population following exposure to allergen and diesel exhaust (DE). Two types of lung samples including bronchoalveolar lavage (BAL) and bronchial wash (BW), and a time course of serum samples, were collected from the 18 subjects who participated in the randomized, double-blinded controlled human study. The two crossover exposure triads in this study were inhaled DE and filtered air each followed by instilled allergen or saline. Serum and lung adipokine responses to these exposures were quantified using enzyme-linked immunosorbent assay. Allergen significantly increased adiponectin and leptin in BAL, and adiponectin in the BW 48 hours after exposure. Serum leptin and resistin responses were not differentially affected by exposure, but varied over time. Coexposure with DE and allergen revealed significant correlations between the adiponectin/leptin ratio and FEV 1 changes and airway responsiveness measures. Changes in lung and serum adipokines in response to allergen exposure were identified in the context of a controlled exposure study. Coexposure identified a potentially protective role of adiponectin in the lung. This response was not observed in those with baseline airway hyper-responsiveness, or after allergen exposure alone. The clinical relevance of this potentially adaptive adipokine pattern warrants further study. Copyright © 2016 Elsevier Inc. All rights reserved.

Airway management in neuroanesthesiology.

PubMed

Aziz, Michael

2012-06-01

Airway management for neuroanesthesiology brings together some key principles that are shared throughout neuroanesthesiology. This article appropriately targets the cervical spine with associated injury and the challenges surrounding airway management. The primary focus of this article is on the unique airway management obstacles encountered with cervical spine injury or cervical spine surgery, and unique considerations regarding functional neurosurgery are addressed. Furthermore, topics related to difficult airway management for those with rheumatoid arthritis or pituitary surgery are reviewed. Copyright © 2012 Elsevier Inc. All rights reserved.

The effects of IL-5 on airway physiology and inflammation in rats.

PubMed

Nag, Sammy S; Xu, Li Jing; Hamid, Qutayba; Renzi, Paolo M

2003-03-01

There is evidence that the cytokine IL-5 is a prominent feature of airway inflammation in asthma. The aim of this study was to determine whether exogenous IL-5 could cause changes in lung physiology, the early and late airway response after antigen challenge, and airway inflammation in rats that do not have a propensity to develop these changes after sensitization and challenge. Intratracheal administration of IL-5 to ovalbumin sensitized Brown Norway SSN rats increased the airway responsiveness to methacholine (AHR) 20 hours after administration of IL-5 at the same time as an increase in neutrophils occurred in the lung lavage. This effect was dose dependent and was not caused by endotoxin. Concurrent intratracheal administration of 50 ng of anti-IL-5 monoclonal antibody with 10 microg of recombinant human IL-5 decreased the AHR and neutrophil influx. Pretreatment with 3 microg of IL-5 had no effect on the early and late airway response or on AHR after ovalbumin challenge. However, IL-5 increased lung re-sistance 20 hours after antigen challenge. Although total lung cells and differential counts did not differ significantly 8 hours after antigen challenge, the blood lymphocyte CD4/CD8 ratio decreased in IL-5 pretreated rats (P <.05). In addition, in situ hybridization showed a significant increase in cells within the airway wall expressing IL-4 and IL-5 mRNA in IL-5 treated/challenged rats compared to controls (P <.05). The intratracheal administration of IL-5 causes only part of the physiologic changes that are associated with asthma. Other factors are necessary to obtain the complete asthma phenotype.

The effect of severe acute respiratory syndrome (SARS) on emergency airway management.

PubMed

Wong, Evelyn; Ho, Khoy Kheng

2006-07-01

From early March 2003 to late May 2003, severe acute respiratory syndrome (SARS) was detected in Singapore. The increase in workload and new infection control procedures were thought to affect resuscitation and airway management. Our aim was to study the effects of wearing of personal protective equipment (PPE) and powered air-purifying respirator (PAPR) and the restriction in the number of resuscitation personnel on airway management during the SARS crisis. Data was collected prospectively through an ongoing emergency airway registry. The data was divided into three periods: (1) before PPE was instituted from 1 November 2002 to 31 March 2003; (2) during SARS (when PPE use was mandatory) from 1 April to 31 July 2003; (3) post-SARs (when PPE use was non-mandatory but encouraged) from 1 August to 31 March 2004. There was no change in patient demographics during the three periods. There were significant increases in the proportion of resuscitation cases and airway interventions during the SARS period compared to the pre-SARS period. The resident medical officer intubation rate decreased from 45.1% pre-SARS to 35.2% during SARS and 17.7% post-SARS. The complication rates were 10.5%, 9.9% and 9.4% in periods 1-3, respectively. Restriction in the number of healthcare staff attending to each patient may have influenced the department's decision to allow only the most confident or experienced personnel to manage the airway. The exposure of junior medical officers in emergency airway management during SARS and the immediate post-SARS period was decreased. This trend should be monitored further and intervention may be necessary should it continue to decline.