Laminin α4 contributes to airway remodeling and inflammation in asthma

被引:17
|
作者
Prabhala, Pavan [1 ,2 ,3 ]
Wright, David B. [1 ,2 ,3 ]
Robbe, Patricia [1 ,2 ,3 ]
Bitter, Catrin [1 ,2 ,3 ]
Pera, Tonio [4 ]
ten Hacken, Nick H. T. [2 ,5 ]
van den Berge, Maarten [2 ,5 ]
Timens, Wim [2 ,6 ]
Meurs, Herman [1 ,2 ,3 ]
Dekkers, Bart G. J. [1 ,2 ,3 ,7 ]
机构
[1] Univ Groningen, Dept Mol Pharmacol, Groningen, Netherlands
[2] Univ Groningen, Univ Med Ctr Groningen, Groningen Res Inst Asthma & COPD, Groningen, Netherlands
[3] Univ Groningen, Groningen Res Inst Pharm, Groningen, Netherlands
[4] Thomas Jefferson Univ, Ctr Translat Med, Philadelphia, PA 19107 USA
[5] Univ Groningen, Univ Med Ctr Groningen, Dept Pulm Dis, Groningen, Netherlands
[6] Univ Groningen, Univ Med Ctr Groningen, Dept Pathol & Med Biol, Groningen, Netherlands
[7] Univ Groningen, Univ Med Ctr Groningen, Dept Clin Pharm & Pharmacol, Hanzepl 1, NL-9713 GZ Groningen, Netherlands
关键词
airway hyperresponsiveness; airway inflammation; airway smooth muscle remodeling; laminin alpha 4; laminin alpha 5; EXTRACELLULAR-MATRIX PROTEINS; SMOOTH-MUSCLE PHENOTYPE; MEDIATE ENHANCEMENT; INTEGRIN RECEPTORS; CELL RECRUITMENT; EXPRESSION; HYPERRESPONSIVENESS; PROLIFERATION; MODEL; ACTIVATION;
D O I
10.1152/ajplung.00222.2019
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
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 alpha 2-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 alpha 4 and alpha 5 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 alpha 4 and alpha 5 was observed in the human and mouse ASM bundle. In vitro, laminin alpha 4 was found to promote a pro-proliferative, pro-contractile, and profibrotic ASM cell phenotype. In line with this, treatment with laminin alpha 4 and alpha 5 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 alpha 4 function-blocking antibody as well. Using airway biopsies from healthy subjects and asthmatic patients, we found inverse correlations between ASM alpha 4-chain expression and lung function and AHR, whereas eosinophil numbers correlated positively with expression of laminin alpha 4 in the ASM bundle. This study, for the first time, indicates a prominent role for laminin alpha 4 in ASM function and in inflammation, AHR, and remodeling in asthma, whereas the role of laminin alpha 5 is more subtle.
引用
收藏
页码:L768 / L777
页数:10
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