Celine Bergeron

Remodeling in Asthma

Airway remodeling refers to the structural changes that occur in both the large and the small airways of miscellaneous diseases, including asthma. In asthma, airway structural changes include subepithelial fibrosis, increased smooth muscle mass, enlargement of glands, neovascularization, and epithelial alterations. Although controversial, airway remodeling is commonly attributed to the underlying chronic inflammatory process. These remodeling changes contribute to thickening of airway walls and consequently lead to airway narrowing, bronchial hyperresponsiveness, airway edema, and mucous hypersecretion. Airway remodeling is associated with poorer clinical outcome among patients with asthma. Early diagnosis and prevention of airway remodeling has the potential to decrease disease severity, to improve control, and to prevent disease expression. In this article, we briefly provide an update on the characteristic features of airway remodeling observed in asthma and their clinical consequences.

Airway remodelling in asthma: from benchside to clinical practice.

Airway remodelling refers to the structural changes that occur in both large and small airways relevant to miscellaneous diseases including asthma. In asthma, airway structural changes include subepithelial fibrosis, increased smooth muscle mass, gland enlargement, neovascularization and epithelial alterations. Although controversial, airway remodelling is commonly attributed to an underlying chronic inflammatory process. These remodelling changes contribute to thickening of airway walls and, consequently, lead to airway narrowing, bronchial hyper-responsiveness, airway edema and mucous hypersecretion. Airway remodelling is associated with poor clinical outcomes among asthmatic patients. Early diagnosis and prevention of airway remodelling has the potential to decrease disease severity, improve control and prevent disease expression. The relationship between structural changes and clinical and functional abnormalities clearly deserves further investigation. The present review briefly describes the characteristic features of airway remodelling observed in asthma, its clinical consequences and relevance for physicians, and its modulation by therapeutic approaches used in the treatment of asthmatic patients.

Myosin, Transgelin, and Myosin Light Chain Kinase: Expression and Function in Asthma

RATIONALE Airway smooth muscle (SM) of patients with asthma exhibits a greater velocity of shortening (Vmax) than that of normal subjects, and this is thought to contribute to airway hyperresponsiveness. A greater Vmax can result from increased myosin activation. This has been reported in sensitized human airway SM and in models of asthma. A faster Vmax can also result from the expression of specific contractile proteins that promote faster cross-bridge cycling. This possibility has never been addressed in asthma. OBJECTIVES We tested the hypothesis that the expression of genes coding for SM contractile proteins is altered in asthmatic airways and contributes to their increased Vmax. METHODS We quantified the expression of several genes that code for SM contractile proteins in mild allergic asthmatic and control human airway endobronchial biopsies. The function of these contractile proteins was tested using the in vitro motility assay. MEASUREMENTS AND MAIN RESULTS We observed an increased expression of the fast myosin heavy chain isoform, transgelin, and myosin light chain kinase in patients with asthma. Immunohistochemistry demonstrated the expression of these genes at the protein level. To address the functional significance of this overexpression, we purified tracheal myosin from the hyperresponsive Fisher rats, which also overexpress the fast myosin heavy chain isoform as compared with the normoresponsive Lewis rats, and found a faster rate of actin filament propulsion. Conversely, transgelin did not alter the rate of actin filament propulsion. CONCLUSIONS Selective overexpression of airway smooth muscle genes in asthmatic airways leads to increased Vmax, thus contributing to the airway hyperresponsiveness observed in asthma.

IL-9 in allergic inflammation.

Th2 type cytokines such as interleukin (IL)-4, IL-5, IL-9, and IL-13 are important mediators in allergic inflammation. The present review will focus on the role of IL-9 in allergic inflammation. The structure and genomic architecture of IL-9 and its receptor, the source of IL-9 and its regulation as well as its effects on different cell types will be reviewed. Furthermore, the specific role of IL-9 in allergic diseases and the potential therapeutic approach of blocking IL-9 will be discussed.

Influence of smoking on airway inflammation and remodelling in asthma

Background Although exposure to tobacco smoke has been associated with increased morbidity and mortality, cigarette smoking is still common in the asthmatic population. Induced sputum neutrophilia has been observed in asthmatic smokers, but the effects of regular smoking on their bronchial mucosa morphology remain to be defined. This study documents the inflammatory and remodelling features in bronchial biopsies of smoking compared with non‐smoking asthmatics.

Tools used to measure airway remodelling in research

Airway remodelling refers to changes in the airway structure and includes subepithelial fibrosis, increased smooth muscle mass, submucosal gland enlargement, neovascularisation and epithelial alterations. Remodelling is observed in response to chronic injury and is seen not only in asthma but in all airway diseases. Remodelling is associated with more severe airflow obstruction and airway hyperresponsiveness in asthma; however, the clinical significance of this is still a matter of debate. Research should be pursued to better understand the accurate implication of airway remodelling in disease and its therapeutic modulation. To allow research in this field, accurate and standardised methods should be utilised to measure airway alterations in disease and following therapy. The standard detection of structural alterations is through direct analyses of airway tissues obtained during a post mortem, surgically or by flexible bronchoscopy. To avoid invasive techniques, other tools have been developed to indirectly measure remodelling, including induced sputum, bronchoalveolar lavage fluid, blood and urine analyses, physiological and radiological assessments, as well as in vitro techniques. Although of great interest, the exact significance of airway remodelling measurements gained through such indirect techniques is uncertain and further research is needed. Despite their invasive nature, direct methods should be favoured to adequately measure airway remodelling in disease and its modulation by therapy.

Regulation of procollagen I (α1) by interleukin-4 in human bronchial fibroblasts: a possible role in airway remodelling in asthma

Background In bronchial mucosa, T cells are in close association with fibroblasts. This cell contact raises the possibility of cross‐talk between the two cell types through cytokines, such as interleukin‐4 (IL‐4).

Effects of hydrofluoroalkane and dry powder- formulated corticosteroids on sputum inflammatory markers in asthmatic patients

BACKGROUND Inhaled corticosteroids are powerful drugs that can suppress airway inflammation in asthmatic patients. Deposition of most of the inhaled corticosteroid occurs mainly in the central airways. However, a new hydrofluoroalkane formulation of beclomethasone dipropionate (HFA-BDP) is preferentially deposited in the distal airways. Inflammatory characteristics of induced sputum have been shown to differ in samples collected early after sputum induction compared with later. OBJECTIVE To compare the effects of HFA-BDP and budesonide in a dry powder inhaler (DPI-BUD) on inflammatory cells and inflammatory cytokine expression in early and late induced sputa compared with placebo. METHODS Seventeen patients with mild, intermittent bronchial asthma were randomly assigned to two treatment groups: eight patients received HFA-BDP and nine patients received DPI-BUD. Each patient was treated with one of the active treatments and placebo (for four weeks), with a two-week washout interval in between. Inflammatory cells and expression of interleukin (IL)-4 and IL-5 were measured in early and late induced sputa before and after active treatment, as well as before and after placebo treatment using immunocytochemistry and in situ hybridization. RESULTS Compared with placebo, eosinophils were significantly reduced in both early and late induced sputa after HFA-BDP treatment (P<0.05), whereas DPI-BUD had a significant effect only on early induced sputum. Both HFA-BDP and DPI-BUD decreased IL-4 expression in early and late induced sputa, but the effect was more prominent with HFA-BDP. IL-5 expression was reduced in both early and late induced sputa after HFA-BDP treatment. DPI-BUD significantly decreased IL-5 expression in early but not in late induced sputum. The number of lymphocytes was not altered by either treatment. CONCLUSIONS HFA-BDP reduced eosinophilic inflammation and T helper 2-type cytokine expression in both early and late induced sputa, whereas the effect of DPI-BUD on inflammation was predominantly demonstrated in early induced sputum.

Do We Know the Minimal Clinically Important Difference (MCID) for COPD Exacerbations

Abstract Frequent exacerbations of COPD are associated with accelerated loss of lung function, declining health status, increased mortality, and increased health care costs. Thus, a key objective in the management of COPD is preventing exacerbations or at least reducing their number and severity. When new interventions are examined, their value is sometimes assessed in reference to the minimal clinically important difference (MCID), a theoretical construct that may be defined and estimated numerically in several different ways. There have been limited attempts to calculate the MCID for COPD exacerbations but a figure of 20% reduction in exacerbation frequency is occasionally cited as the “established” MCID from a single manuscript reviewing six clinical trials. Our review suggests that defining and calculating the MCID for COPD exacerbations is problematic, not only because the methodology around developing endpoints for MCIDs is inconsistent, but because the impact of exacerbation reduction is likely to be influenced dramatically by the definitions of exacerbation severity used and the populations baseline status. Reference to current literature shows that at least one other estimate for exacerbation MCID as low as 4%. MCID is sometimes estimated by expert consensus; a review of articles used to shape COPD guidelines shows frequent reference to articles in which interventions yielded exacerbation differences as low as 11%. We find no evidence of an established MCID but suggest that interventions reducing exacerbations by as little as 11% appear to be regarded widely as clinically important.

Increased expression of the calcium-activated chloride channel hCLCA1 in airways of patients with obstructive chronic bronchitis.

BACKGROUND Interleukin (IL)-9 and its effect on enhancing the human calcium-activated chloride channel 1 (hCLCA1) expression have been shown to induce mucin production. Increased expression of hCLCA1 may, in turn, contribute to mucus overproduction in chronic obstructive pulmonary disease (COPD) with a chronic bronchitis (CB) phenotype. OBJECTIVE To determine the expression of IL-9, IL-9 receptor (IL-9R), hCLCA1 and mucoglycoconjugates in COPD. METHODS Bronchial biopsies were obtained from six patients with obstructive CB and six healthy control subjects. IL-9, IL-9R and hCLCA1 expression were detected using immunohistochemistry. Additionally, in situ hybridization was performed to determine the expression of hCLCA1 messenger RNA. Mucin production was assessed using periodic acid-Schiff staining. RESULTS There was a significantly higher number of IL-9 immunoreactive cells in the submucosa of patients with COPD than that of healthy control subjects (P<0.05). Also, a significant increase in the expression of IL-9R, hCLCA1 (protein and messenger RNA) and mucin (periodic acid-Schiff-positive cells) was noted in the bronchial epithelium of patients with COPD compared the control subjects (P<0.05). CONCLUSION Increased expression of IL-9, IL-9R and hCLCA1 in the bronchial mucosa of patients with obstructive CB suggests that mucus overproduction in this disease may be, at least in part, due to hCLCA1.