Mechanisms of Airway Remodeling
TL;DR: Airway remodeling is often considered the result of longstanding airway inflammation, but it may be present to an equivalent degree in the airways of children with asthma, raising the necessity for early and specific therapeutic interventions.
About: This article is published in Chest.The article was published on 2013-09-01. It has received 260 citations till now. The article focuses on the topics: Airway.
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TL;DR: The current understanding of the core functions of TGF-β1 in promoting collagen accumulation, parallel pathways that promote physiological repair, and pathological triggers that tip the balance toward progressive fibrosis are examined.
Abstract: Activation of TGF-β1 initiates a program of temporary collagen accumulation important to wound repair in many organs. However, the outcome of temporary extracellular matrix strengthening all too frequently morphs into progressive fibrosis, contributing to morbidity and mortality worldwide. To avoid this maladaptive outcome, TGF-β1 signaling is regulated at numerous levels and intimately connected to feedback signals that limit accumulation. Here, we examine the current understanding of the core functions of TGF-β1 in promoting collagen accumulation, parallel pathways that promote physiological repair, and pathological triggers that tip the balance toward progressive fibrosis. Implicit in better understanding of these processes is the identification of therapeutic opportunities that will need to be further advanced to limit or reverse organ fibrosis.
360 citations
TL;DR: Mitochondrial dysfunction in patients with COPD is associated with excessive mitochondrial ROS levels, which contribute to enhanced inflammation and cell hyperproliferation.
Abstract: 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 hyperproliferation. Targeting mitochondrial ROS represents a promising therapeutic approach in patients with COPD.
320 citations
Cites background from "Mechanisms of Airway Remodeling"
...The airways in patients with COPD are remodeled with a thickened epithelium, lamina propria, and adventitia, with ASM hyperplasia and hypertrophy and deposition of collagen that might all contribute to the development of AHR.(27,28) In the ozone model AHR is associated with the presence of increased isometric contractile responsiveness of the airways to acetylcholine,(29) which was due to an increased activation of the p38 mitogenactivated protein kinase....
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...In addition, these ozone-induced processes were reversed by inhibition of mitochondrial ROS with the mitochondria-targeted antioxidant MitoQ, which was accompanied by reversal of ozone-induced lung inflammation and AHR....
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...Reversal of mitochondrial dysfunction by the mitochondria-targeted antioxidant MitoQ reduced inflammation and AHR....
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...The airways in patients with COPD are remodeled with a thickened epithelium, lamina propria, and adventitia, with ASM hyperplasia and hypertrophy and deposition of collagen that might all contribute to the development of AHR.27,28 In the ozone model AHR is associated with the presence of increased isometric contractile responsiveness of the airways to acetylcholine,29 which was due to an increased activation of the p38 mitogenactivated protein kinase....
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...The concentration of acetylcholine required to increase RL by 100% from baseline was calculated (PC100), and the concentration of acetylcholine that increased lung resistance by 100% (2logPC100) was taken as a measure of AHR.20,21 BAL samples and cytospin preparations were obtained and analyzed, as previously described.20,21 Keratinocyte-derived cytokine (KC), IL-6, and GM-CSF levels in BAL fluid were measured with commercial ELISA kits (R&D Systems Europe Ltd, Abingdon, United Kingdom)....
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TL;DR: Current knowledge of the role of neutrophils in asthma is reviewed and future avenues of research in this field are highlighted to help delineate different subtypes of asthma.
286 citations
TL;DR: The inflammatory and cellular mechanisms of asthma and COPD are compared and the differences in inflammatory cells and profile of inflammatory mediators are highlighted to better understand the underlying cellular and molecular mechanisms in order to develop new treatments in areas of unmet need.
Abstract: Asthma and chronic obstructive pulmonary disease (COPD) both cause airway obstruction and are associated with chronic inflammation of the airways. However, the nature and sites of the inflammation differ between these diseases, resulting in different pathology, clinical manifestations and response to therapy. In this review, the inflammatory and cellular mechanisms of asthma and COPD are compared and the differences in inflammatory cells and profile of inflammatory mediators are highlighted. These differences account for the differences in clinical manifestations of asthma and COPD and their response to therapy. Although asthma and COPD are usually distinct, there are some patients who show an overlap of features, which may be explained by the coincidence of two common diseases or distinct phenotypes of each disease. It is important to better understand the underlying cellular and molecular mechanisms of asthma and COPD in order to develop new treatments in areas of unmet need, such as severe asthma, curative therapy for asthma and effective anti-inflammatory treatments for COPD.
286 citations
TL;DR: This review will address a few major aspects: what are reliable quantitative approaches to assess airway remodeling, and are there any indications supporting the notion that airways remodeling can occur as a primary event, i.e., before any inflammatory process was initiated?
Abstract: Airway remodeling is generally quite broadly defined as any change in composition, distribution, thickness, mass or volume and/or number of structural components observed in the airway wall of patients relative to healthy individuals. However, two types of airway remodeling should be distinguished more clearly: (1) physiological airway remodeling, which encompasses structural changes that occur regularly during normal lung development and growth leading to a normal mature airway wall or as an acute and transient response to injury and/or inflammation, which ultimately results in restoration of a normal airway structures; and (2) pathological airway remodeling, which comprises those structural alterations that occur as a result of either disturbed lung development or as a response to chronic injury and/or inflammation leading to persistently altered airway wall structures and function. This review will address a few major aspects: (1) what are reliable quantitative approaches to assess airway remodeling? (2) Are there any indications supporting the notion that airway remodeling can occur as a primary event, i.e., before any inflammatory process was initiated? (3) What is known about airway remodeling being a secondary event to inflammation? And (4), what can we learn from the different animal models ranging from invertebrate to primate models in the study of airway remodeling? Future studies are required addressing particularly pheno-/endotype-specific aspects of airway remodeling using both endotype-specific animal models and “endotyped” human asthmatics. Hopefully, novel in vivo imaging techniques will be further advanced to allow monitoring development, growth and inflammation of the airways already at a very early stage in life.
271 citations
Cites background from "Mechanisms of Airway Remodeling"
...…airway remodeling quite broadly as any change in composition, distribution, thickness, mass or volume and/or number of structural components observed in the airway wall of patients relative to the airway wall of normal healthy individuals (Bergeron et al. 2009; Bai 2010; Hirota and Martin 2013)....
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...The observation of an inflammatory infiltrate characterized by eosinophilic granulocytes and CD4 Th cells in the airways of (probably Th2-high) asthmatics (Saetta and Turato 2001), sometimes being the result of a longstanding inflammatory process, was suggested as a conditio sine qua non of the definition of airway remodeling in asthma (Hirota and Martin 2013)....
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...Direct injury to the airway epithelium induced by various triggers has long been widely accepted as a very early, may be the initial, step in asthma pathogenesis (AlMuhsen et al. 2011; Hirota and Martin 2013; Holt et al. 2014)....
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...…granulocytes and CD4+ Th cells in the airways of (probably Th2-high) asthmatics (Saetta and Turato 2001), sometimes being the result of a longstanding inflammatory process, was suggested as a conditio sine qua non of the definition of airway remodeling in asthma (Hirota and Martin 2013)....
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References
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TL;DR: The results of this study suggest that eosinophils have a role as important effector cells in the pathogenesis of severe exacerbations of asthma in this patient population.
Abstract: BACKGROUND: Exacerbations of asthma are associated with substantial morbidity and mortality and with considerable use of health care resources. Preventing exacerbations remains an important goal of therapy. There is evidence that eosinophilic inflammation of the airway is associated with the risk of exacerbations. METHODS: We conducted a randomized, double-blind, placebo-controlled, parallel-group study of 61 subjects who had refractory eosinophilic asthma and a history of recurrent severe exacerbations. Subjects received infusions of either mepolizumab, an anti-interleukin-5 monoclonal antibody (29 subjects), or placebo (32) at monthly intervals for 1 year. The primary outcome measure was the number of severe exacerbations per subject during the 50-week treatment phase. Secondary outcomes included a change in asthma symptoms, scores on the Asthma Quality of Life Questionnaire (AQLQ, in which scores range from 1 to 7, with lower values indicating more severe impairment and a change of 0.5 unit considered to be clinically important), forced expiratory volume in 1 second (FEV(1)) after use of a bronchodilator, airway hyperresponsiveness, and eosinophil counts in the blood and sputum. RESULTS: Mepolizumab was associated with significantly fewer severe exacerbations than placebo over the course of 50 weeks (2.0 vs. 3.4 mean exacerbations per subject; relative risk, 0.57; 95% confidence interval [CI], 0.32 to 0.92; P=0.02) and with a significant improvement in the score on the AQLQ (mean increase from baseline, 0.55 vs. 0.19; mean difference between groups, 0.35; 95% CI, 0.08 to 0.62; P=0.02). Mepolizumab significantly lowered eosinophil counts in the blood (P<0.001) and sputum (P=0.002). There were no significant differences between the groups with respect to symptoms, FEV(1) after bronchodilator use, or airway hyperresponsiveness. The only serious adverse events reported were hospitalizations for acute severe asthma. CONCLUSIONS: Mepolizumab therapy reduces exacerbations and improves AQLQ scores in patients with refractory eosinophilic asthma. The results of our study suggest that eosinophils have a role as important effector cells in the pathogenesis of severe exacerbations of asthma in this patient population. (Current Controlled Trials number, ISRCTN75169762.)
1,674 citations
TL;DR: A treatment strategy directed at normalisation of the induced sputum eosinophil count reduces asthma exacerbations and admissions without the need for additional anti-inflammatory treatment.
1,669 citations
TL;DR: The results suggest that two distinct pathologic, physiologic, and clinical subtypes of severe asthma exist, with implications for further research and treatment.
Abstract: The mechanisms associated with the development of severe, corticosteroid (CS)-dependent asthma are poorly understood, but likely heterogenous. It was hypothesized that severe asthma could be divided pathologically into two inflammatory groups based on the presence or absence of eosinophils, and that the inflammatory subtype would be associated with distinct structural, physiologic, and clinical characteristics. Thirty-four severe, refractory CS-dependent asthmatics were evaluated with endobronchial biopsy, pulmonary function, allergy testing, and clinical history. Milder asthmatic and normal control subjects were also evaluated. Tissue cell types and subbasement membrane (SBM) thickness were evaluated immunohistochemically. Fourteen severe asthmatics [eosinophil ( 2 )] had nearly absent eosinophils ( , 2 SD from the normal mean). The remaining 20 severe asthmatics were categorized as eosinophil ( 1 ). Eosinophil ( 1 ) severe asthmatics had associated increases (p , 0.05) in lymphocytes (CD3 1 , CD4 1 , CD8 1 ), mast cells, and macrophages. Neutrophils were increased in severe asthmatics and not different between the groups. The SBM was significantly thicker in eosinophil ( 1 ) severe asthmatics than eosinophil ( 2 ) severe asthmatics and correlated with eosinophil numbers (r 5 0.50). Despite the absence of eosinophils and the thinner SBM, the FEV 1 was marginally lower in eosinophil ( 2 ) asthmatics (p 5 0.05) with no difference in bronchodilator response. The eosinophil ( 1 ) group (with a thicker SBM) had more intubations than the eosinophil ( 2 ) group (p 5 0.0004). Interestingly, this group also had a decreased FVC/slow vital capacity (SVC). These results suggest that two distinct pathologic, physiologic, and clinical subtypes of severe asthma exist, with implications for further research and treatment. Wenzel SE, Schwartz LB, Langmack EL, Halliday JL, Trudeau JB, Gibbs RL, Chu HW. Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. AM J RESPIR CRIT CARE MED 1999;160:1001‐1008.
1,186 citations
TL;DR: Results show that narrowing and disappearance of small conducting airways before the onset of emphysematous destruction can explain the increased peripheral airway resistance reported in COPD.
Abstract: Background The major sites of obstruction in chronic obstructive pulmonary disease (COPD) are small airways (<2 mm in diameter). We wanted to determine whether there was a relationship between small-airway obstruction and emphysematous destruction in COPD. Methods We used multidetector computed tomography (CT) to compare the number of airways measuring 2.0 to 2.5 mm in 78 patients who had various stages of COPD, as judged by scoring on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) scale, in isolated lungs removed from patients with COPD who underwent lung transplantation, and in donor (control) lungs. MicroCT was used to measure the extent of emphysema (mean linear intercept), the number of terminal bronchioles per milliliter of lung volume, and the minimum diameters and cross-sectional areas of terminal bronchioles. Results On multidetector CT, in samples from patients with COPD, as compared with control samples, the number of airways measuring 2.0 to 2.5 mm in diameter was reduced in...
920 citations
TL;DR: Pulmonary-function tests showed abnormalities at a time when the pathologic changes were still potentially reversible and when other tests were not appreciably changed, and increase in disease in small airways correlated with deterioration in lung function.
Abstract: To examine the relation between small-airways abnormalities and specific lung functions, we performed pulmonary-function tests in 36 patients, of whom two were nonsmokers, one to three days before open-lung biopsy for localized pulmonary lesions. The primary lesion in the small airways was a progressive inflammatory reaction leading to fibrosis with connective-tissue deposition in the airway walls. Increase in disease in small airways correlated with deterioration in lung function. Lesions could be reliably detected (P<0.05) by tests for closing capacity, the volume at which air and helium flow were equal (a test of airway caliber and elastic recoil), and the slope of phase III of the single-breath washout curve (which tests evenness of ventilation). These tests showed abnormalities at a time when the pathologic changes were still potentially reversible and when other tests were not appreciably changed. (N Engl J Med 298:1277–1281, 1977)
806 citations