Laminin α4 contributes to airway remodeling and inflammation in asthma

Abstract

Airway inflammation and remodeling are characteristic features of asthma, with both contributing to airway hyperresponsiveness (AHR) and lung function limitation. Airway smooth muscle (ASM) accumulation and extracellular matrix deposition are characteristic features of airway remodeling, which may contribute to persistent AHR. Laminins containing the α2-chain contribute to characteristics of ASM remodeling in vitro and AHR in animal models of asthma. The role of other laminin chains, including the laminin α4 and α5 chains, which contribute to leukocyte migration in other diseases, is currently unknown. The aim of the current study was to investigate the role of these laminin chains in ASM function and in AHR, remodeling, and inflammation in asthma. Expression of both laminin α4 and α5 was observed in the human and mouse ASM bundle. In vitro, laminin α4 was found to promote a pro-proliferative, pro-contractile, and pro-fibrotic ASM cell phenotype. In line with this, treatment with laminin α4 and α5 function-blocking antibodies reduced allergen-induced increases in ASM mass in a mouse model of allergen-induced asthma. Moreover, eosinophilic inflammation was reduced by the laminin α4 function-blocking antibody as well. Using airway biopsies from healthy subjects and asthmatic patients, we found inverse correlations between ASM α4-chain expression and lung function and AHR, whereas eosinophil numbers correlated positively with expression of laminin α4 in the ASM bundle. This study, for the first time, indicates a prominent role for laminin α4 in ASM function and in inflammation, AHR, and remodeling in asthma, whereas the role of laminin α5 is more subtle.

Basement membranes in obstructive pulmonary diseases

“…In patients with asthma, increased expression of laminin in the ASM correlated with a reduced reversibility of airway obstruction in response to the β 2 -agonist salbutamol [45] . In line with these findings a higher expression of laminin α4 in the ASM of asthmatics was correlated with an reduced lung function and airway hyperresponsiveness [18] . Also in COPD, higher expression of laminin β2 in the ASM was associated with reduced lung function [41] .…”

“…In the BM of ASM cells of asthmatic patients there was decreased expression of laminin α4 and α5 compared to healthy subjects, whereas laminin α4 expression was increased in the endothelial BMs ( Fig. 1 ) [18] . Reduced expression of laminin α4 in the ASM BM appeared to be related to smoking and no reduction in laminin α4 expression in the ASM was observed between non-smoking asthmatics and control subjects.…”

“…In pulmonary endothelial BMs, laminins α4, α5, β1 and γ1 chains are expressed, whereas laminins α4, α5, β1-2 and γ1 expressed in ASM BMs ( Table 1 ) indicating that laminin α4β1γ1 and α5β1γ1 are assembled by both cell types. In addition, α4β2γ1 and α5β2γ1 appear to be assembled by the ASM cells [12] , [13] , [14] , [15] , [16] , [17] , [18] , [19] .…”

Serum laminin levels in eosinophilic and non-eosinophilic chronic obstructive pulmonary disease patients

“…Kranenburg et al [16] showed increased laminin beta2 expression in airway smooth muscle in patients with COPD which was inversely correlated with the FEV1 values. Prabhla et al [17] reported a prominent role for laminin in airway smooth muscle function and in inflammation, airway hyperresponsiveness, and remodeling in asthma. Reticular basement membrane thickening occurs both in asthma and COPD but ECM components such as collagen I and laminin were stained significantly stronger in asthma than in COPD [18].…”

Plasma Based Protein Signatures Associated with Small Cell Lung Cancer

“…Of the proteins with an OR ≥ 2, seven (C9, HCFC2, HYDIN, IGHM, LAMA4, RTKN and TRIM33) were also identified to be elevated (AUC ≥ 0.60) in case plasmas taken at the time of diagnosis or within 0-1 years of diagnosis (Table 4). These proteins are associated with inflammation as in the case of LAMA4 and TRIM33 [38,39].…”