elastin and Asthma

Extracellular matrix is generally increased in asthma, causing thickening of the airways which may either increase or decrease airway responsiveness, depending on the mechanical requirements of the deposited matrix. However, in vitro studies have shown that the altered extracellular matrix produced by asthmatic airway smooth muscle cells is able to induce increased proliferation of non-asthmatic smooth muscle cells, which is a process believed to contribute to airway hyper-responsiveness in asthma. Elastin is an extracellular matrix protein that is altered in asthmatic airways, but there has been no systematic investigation of the functional effect of these changes. This review reveals divergent reports of the state of elastin in the airway wall in asthma. In some layers of the airway it has been described as increased, decreased and/or fragmented, or unchanged. There is also considerable evidence for an imbalance of matrix metalloproteinases, which degrade elastin, and their respective inhibitors the tissue inhibitors of metalloproteinases, which collectively help to explain observations of both increased elastin and elastin fragments. A loss of lung elastic recoil in asthma suggests a mechanical role for disordered elastin in the aetiology of the disease, but extensive studies of elastin in other tissues show that elastin fragments elicit cellular effects such as increased proliferation and inflammation. This review summarises the current understanding of the role of elastin in the asthmatic airway.

Topics: Animals; Asthma; Bronchial Hyperreactivity; Cell Proliferation; Elastin; Extracellular Matrix; Humans; Inflammation; Matrix Metalloproteinases; Myocytes, Smooth Muscle

Structural changes in the airway walls involving extracellular matrix remodelling are prominent features of asthma. These changes are probably driven by mediators released as a consequence of chronic allergic inflammation. It is clear that changes in the extracellular matrix have the capacity to influence airway function in asthma. However, it is not clear how each of the many changes that occur in the airway wall contribute to altered airway function in asthma. Collagen deposition in the subepithelial matrix, and hyaluronan and versican deposition around and internal to the smooth muscle would be expected to oppose the effect of smooth muscle contraction. Conversely, geometric considerations would result in exaggerated airway narrowing for a given degree of smooth muscle shortening, as the airway wall is thickened by the deposition of these molecules internal to the smooth muscle. Elastin and cartilage reorganization and degradation in the airway walls would be expected to result in decreased airway wall stiffness and increased airway narrowing for a given amount of force generated by the smooth muscle. Degradation of matrix associated with the smooth muscle may both decrease the stiffness of the parallel elastic component and uncouple smooth muscle from the load provided by lung recoil, allowing exaggerated smooth muscle shortening. Increase in muscle mass may be associated with an increase, a decrease or no change in smooth muscle contractility. If an increase in muscle mass was associated with preservation of its contractile capacity modelling studies suggest that it could be the most important contributor to exaggerated airway narrowing. Modelling studies also suggest that the pattern of mucosal folding during smooth muscle contraction may be an important determinant of airway narrowing. The greater the number of folds, and the stiffer the subepithelial collagenous layer the more resistant the airway will be to narrowing.

Topics: Asthma; Collagen; Elastin; Epithelial Cells; Humans; Trachea

In this review article, the effects of old age on lung structure and function are discussed. Changes in lung morphology and biochemistry are correlated with changes in lung mechanics and gas exchange, as well as with the respiratory system's adaptability to the stresses of exercise and sleep. The effects of aging on the lungs' defense mechanisms are related to pulmonary diseases of the elderly.

Topics: Adaptation, Physiological; Aging; Animals; Asthma; Carcinoma, Bronchogenic; Closing Volume; Collagen; Diaphragm; Elastin; Humans; Lung; Lung Neoplasms; Maximal Expiratory Flow-Volume Curves; Nucleic Acids; Pneumonia; Proteins; Proteoglycans; Pulmonary Circulation; Pulmonary Diffusing Capacity; Pulmonary Gas Exchange; Residual Volume; Respiration; Total Lung Capacity; Tuberculosis, Pulmonary; Vital Capacity

Topics: Asthma; Cross-Sectional Studies; Elastin; Humans; Lung; Pulmonary Disease, Chronic Obstructive; X-Ray Microtomography

Airway remodelling, which may include goblet cell hyperplasia / hypertrophy, changes in epithelial integrity, accumulation of extracellular matrix components, smooth muscle hypertrophy and thickening of the lamina reticularis, is a feature of severe asthma and contributes to the clinical phenotype.. Within the U-BIOPRED severe asthma study, we have assessed histological elements of airway remodelling and their relationship to computed tomography (CT) measures of proximal airway dimensions.. Bronchial biopsies were collected from two severe asthma groups, one non-smoker (SAn, n = 28) and one current/ex-smoker (SAs/ex, n = 13), and a mild-moderate asthma group (MMA, n = 28) classified and treated according to GINA guidelines, plus a healthy control group (HC, n = 33). Movat's pentachrome technique was used to identify mucin, elastin and total collagen in these biopsies. The number of goblet cells (mucin+) was counted as a percentage of the total number of epithelial cells and the percentage mucin epithelial area measured. The percentage area of elastic fibres and total collagen within the submucosa was also measured, and the morphology of the elastic fibres classified. Participants in the asthma groups also had a CT scan to assess large airway morphometry.. The submucosal tissue elastin percentage was higher in both severe asthma groups (16.1% SAn, 18.9% SAs/ex) compared with the HC (9.7%) but did not differ between asthma groups. There was a positive relationship between elastin and airway wall area measured by CT (n = 18-20, rho=0.544, p = 0.024), which also related to an increase in elastic fibres with a thickened lamellar morphological appearance. Mucin epithelial area and total collagen were not different between the four groups. Due to small numbers of suitable CT scans, it was not feasible to compare airway morphometry between the asthma groups.. These findings identify a link between extent of elastin deposition and airway wall thickening in severe asthma.

Topics: Adult; Airway Remodeling; Asthma; Biopsy; Bronchi; Bronchoscopy; Case-Control Studies; Collagen; Elastin; Female; Goblet Cells; Humans; Hyperplasia; Male; Middle Aged; Mucins; Tomography, X-Ray Computed

Topics: Adolescent; Adult; Airway Remodeling; Asthma; Child; Collagen Type I; Decorin; Elastin; Extracellular Matrix; Female; Fibrillar Collagens; Fibroblasts; Humans; In Vitro Techniques; Lung; Male; Microscopy, Electron, Transmission; Nonlinear Optical Microscopy; Young Adult

Elastin synthesis and degradation in the airway and lung parenchyma contribute to airway mechanics, including airway patency and elastic recoil. IL-13 mediates many features of asthma pathobiology, including airway remodeling, but the effects of IL-13 on elastin architecture in the airway wall are not known. We hypothesized that IL-13 modulates elastin expression in airway fibroblasts from subjects with allergic asthma. Twenty-five subjects with mild asthma (FEV1, 89 ± 3% predicted) and 30 normal control subjects (FEV1, 102 ± 2% predicted) underwent bronchoscopy with endobronchial biopsy. Elastic fibers were visualized in airway biopsy specimens using Weigert's resorcin-fuchsin elastic stain. Airway fibroblasts were exposed to IL-13; a pan-matrix metalloproteinase (MMP) inhibitor (GM6001); specific inhibitors to MMP-1, -2, -3, and -8; and combinations of IL-13 with MMP inhibitors in separate conditions in serum-free media for 48 hours. Elastin (ELN) expression as well as MMP secretion and activity were quantified. Results of this study show that elastic fiber staining of airway biopsy tissue was significantly associated with methacholine PC20 (i.e., the provocative concentration of methacholine resulting in a 20% fall in FEV1 levels) in patients with asthma. IL-13 significantly suppressed ELN expression in asthmatic airway fibroblasts as compared with normal control fibroblasts. The effect of IL-13 on ELN expression was significantly correlated with postbronchodilator FEV1/FVC in patients with asthma. MMP inhibition significantly stimulated ELN expression in patients with asthma as compared with normal control subjects. Specific inhibition of MMP-1 and MMP-2, but not MMP-3 or MMP-8, reversed the IL-13-induced suppression of ELN expression. In asthma, MMP-1 and MMP-2 mediate IL-13-induced suppression of ELN expression in airway fibroblasts.

Topics: Adult; Airway Remodeling; Asthma; Bronchial Provocation Tests; Case-Control Studies; Colorado; Down-Regulation; Elastic Tissue; Elastin; Female; Fibroblasts; Forced Expiratory Volume; Humans; Interleukin-13; Lung; Male; Matrix Metalloproteinase 1; Matrix Metalloproteinase 2; Matrix Metalloproteinase Inhibitors; North Carolina; Severity of Illness Index; Signal Transduction; Vital Capacity

The peripheral lung parenchyma has been studied as a component of the asthmatic inflammatory response. During induced constriction, tissue resistance increases in different asthma models. Approximately 60% of the asthmatic patients show early and late responses. The late response is characterized by more severe airway obstruction. In the present study, we evaluated lung parenchymal strips mechanics in ovalbumin-sensitized guinea pigs, trying to reproduce both early and late inflammatory responses. Oscillatory mechanics of lung strips were performed in a control group (C), in an early response group (ER), and in two late response groups: 17 h (L1) and 72 h (L2) after the last ovalbumin challenge. Measurements of resistance and elastance were obtained before and after ovalbumin challenge in C and ER groups and before and after acetylcholine challenge in all groups. Using morphometry, we assessed the density of eosinophils and smooth muscle cells, as well as collagen and elastin content in lung strips. The baseline and postagonist values of resistance and elastance were increased in ER, L1, and L2 groups compared with C (P < or = 0.001). The morphometric analysis showed an increase in alveolar eosinophil density in ER and L2 groups compared with C (P < 0.05). There was a significant correlation between eosinophil density in parenchymal strips of C, L1, and L2 groups and values of resistance and elastance postacetylcholine (r = 0.71, P = 0.001 and r = 0.74, P < 0.001, respectively). The results show that the lung parenchyma is involved in the late response, and the constriction response in this phase is related to the eosinophilic inflammation.

Topics: Animals; Antibody Formation; Antigens; Asthma; Bronchoconstriction; Cell Count; Collagen; Elastin; Eosinophils; Guinea Pigs; Lung; Male; Ovalbumin; Reaction Time; Respiratory Hypersensitivity; Time Factors

This study tested the hypotheses that chronic allergic inflammation induces not only bronchial but also lung parenchyma remodeling, and that these histologic changes are associated with concurrent changes in respiratory mechanics. For this purpose, airway and lung parenchyma remodeling were evaluated by quantitative analysis of collagen and elastin, immunohistochemistry (smooth-muscle actin expression, eosinophil, and dendritic cell densities), and electron microscopy. In vivo (airway resistance, viscoelastic pressure, and static elastance) and in vitro (tissue elastance, resistance, and hysteresivity) respiratory mechanics were also analyzed. BALB/c mice were sensitized with ovalbumin and exposed to repeated ovalbumin challenges. A marked eosinophilic infiltration was seen in lung parenchyma and in large and distal airways. Neutrophils, lymphocytes, and dendritic cells also infiltrated the lungs. There was subepithelial fibrosis, myocyte hypertrophy and hyperplasia, elastic fiber fragmentation, and increased numbers of myofibroblasts in airways and lung parenchyma. Collagen fiber content was increased in the alveolar walls. The volume proportion of smooth muscle-specific actin was augmented in distal airways and alveolar duct walls. Airway resistance, viscoelastic pressure, static elastance, and tissue elastance and resistance were significantly increased. In conclusion, prolonged allergen exposure induced remodeling not only of the airway wall but also of the lung parenchyma, leading to in vivo and in vitro mechanical changes.

Topics: Actins; Airway Resistance; Animals; Asthma; Bronchi; Collagen; Disease Models, Animal; Elastin; Hyperplasia; Hypertrophy; In Vitro Techniques; Lung; Mice; Mice, Inbred BALB C; Microscopy, Electron; Muscle, Smooth; Pulmonary Alveoli; Pulmonary Eosinophilia; Pulmonary Fibrosis; Respiratory Hypersensitivity; Respiratory Mechanics

The production of the inflammatory cytokine interleukin (IL)-1 is increased in lungs of patients with chronic obstructive pulmonary disease (COPD) or asthma. To characterize the in vivo actions of IL-1 in the lung, transgenic mice were generated in which human IL-1beta was expressed in the lung epithelium with a doxycycline-inducible system controlled by the rat Clara cell secretory protein (CCSP) promoter. Induction of IL-1beta expression in the lungs of adult mice caused pulmonary inflammation characterized by neutrophil and macrophage infiltrates. IL-1beta caused distal airspace enlargement, consistent with emphysema. IL-1beta caused disruption of elastin fibers in alveolar septa and fibrosis in airway walls and in the pleura. IL-1beta increased the thickness of conducting airways, enhanced mucin production, and caused lymphocytic aggregates in the airways. Decreased immunostaining for the winged helix transcription factor FOXA2 was associated with goblet cell hyperplasia in IL-1beta-expressing mice. The production of the neutrophil attractant CXC chemokines KC (CXCL1) and MIP-2 (CXCL2), and of matrix metalloproteases MMP-9 and MMP-12, was increased by IL-1beta. Chronic production of IL-1beta in respiratory epithelial cells of adult mice causes lung inflammation, enlargement of distal airspaces, mucus metaplasia, and airway fibrosis in the adult mouse.

Topics: Animals; Asthma; Base Sequence; Bronchoalveolar Lavage Fluid; Chemokines, CXC; Collagen; Disease Models, Animal; DNA, Complementary; Elastin; Gene Expression; Humans; Inflammation; Interleukin-1; Lymphocytes; Matrix Metalloproteinases; Mice; Mice, Transgenic; Organ Size; Organ Specificity; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Respiratory System; RNA, Messenger; Tumor Necrosis Factor-alpha

Matrix metalloproteinase-9 (MMP-9) is capable of degrading elastin, whereas tissue inhibitor of metalloproteinase-1 (TIMP-1) can inhibit MMP-9 activity. We observed reduced airway tissue elastin volume density in six subjects with nocturnal asthma (NA) as compared with seven subjects with nonnocturnal asthma (NNA) and seven normal controls (NL) when endobronchial biopsies were evaluated morphometrically at 4:00 PM and 4:00 AM.. We hypothesized that increased metalloproteinases and decreased tissue inhibitors of metalloproteinases in the airways of subjects with NA may be responsible for reduced elastin volume density.. Ten additional subjects with NA, 10 subjects with NNA, and 7 normal control subjects underwent bronchoscopy with bronchoalveolar lavage at 4:00 PM and 4:00 AM. Levels of MMP-2, MMP-9, TIMP-1, and TIMP-2 were determined in bronchoalveolar lavage by enzyme-linked immunosorbent assay.. There was a fourfold circadian increase in bronchoalveolar lavage levels of MMP-9, and there was a twofold increase in MMP-9:TIMP-1 ratio in NA subjects from 4:00 PM to 4:00 AM. There were no circadian changes in the NNA and NL subjects. At 4:00 AM, MMP-9 levels and the MMP-9:TIMP-1 ratio were highest in NA subjects. At 4:00 PM, no significant group differences were observed. The MMP-9 levels positively correlated with the overnight fall in forced expiratory volume in 1 second and the MMP-9/TIMP-1 ratio negatively correlated with the 4:00 AM % predicted forced expiratory volume in 1 second.. Our results from these two pilot studies suggest that increased MMP-9 and decreased TIMP-1 at night in NA may lead to reduced elastin density.

Topics: Adult; Asthma; Biopsy; Bronchi; Bronchoalveolar Lavage Fluid; Colorado; Elastin; Female; Forced Expiratory Volume; Humans; Male; Matrix Metalloproteinase 9; Respiratory Function Tests; Statistics as Topic; Time Factors; Tissue Inhibitor of Metalloproteinases

Elastic fibers required to maintain bronchial patency during ventilation may be damaged in asthma as a result of repair following inflammation or stretching during exacerbations. Fifteen normal subjects and 40 asthmatics of variable severity were studied. Bronchial biopsies were obtained from a subsegmental bronchus using a flexible bronchoscope. The elastic fibers were examined using orceine-eosine sustaining and/or immunohistochemistry with two monoclonal antibodies against elastin or transmission electron microscopy (six asthmatics and four control subjects). Orceine-eosine staining revealed that most normal subjects had normal fibers throughout the submucosa whereas of the 21 asthmatics analyzed only three had a normal superficial elastin network. In five patients, elastin had virtually disappeared. In the remaining patients, fibers appeared fragmented. The deeper layer of elastic fibers was abnormal in 17 asthmatics, fibers being patchy, tangled, and thickened. The fragmentation of the superficial network of elastic fibers shown in asthmatics was confirmed by immunohistochemistry. Electron microscopy studies suggested that the elastinolytic process and fragmentation of elastic fibers occurred in asthmatics. Elastinolysis occurs in the airways of asthmatics possibly as a result of repair elicited by chronic inflammation. Mechanical stretch induced by breathing and edema may lead to the fragmentation of fibers in asthmatic airways.

Topics: Adult; Antibodies, Monoclonal; Asthma; Biopsy; Bronchi; Bronchitis; Bronchoscopes; Case-Control Studies; Coloring Agents; Edema; Elastic Tissue; Elastin; Eosine Yellowish-(YS); Fluorescent Dyes; Humans; Immunohistochemistry; Microscopy, Electron; Middle Aged; Oxazines; Respiratory Mechanics

Topics: Adult; Aged; Animals; Asthma; Cell Count; Dogs; Elastin; Female; Humans; Lung; Lung Volume Measurements; Macrophages; Male; Middle Aged; Neutrophils; Protease Inhibitors; Pulmonary Emphysema; Smoking