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Integrin ?7 expression is increased in asthmatic patients and its inhibition reduces Kras protein abundance in airway smooth muscle cells.

ABSTRACT: Airway smooth muscle (ASM) cells exhibit plastic phenotypic behavior marked by reversible modulation and maturation between contractile and proliferative phenotypic states. Integrins are a class of transmembrane proteins that have been implicated as novel therapeutic targets for asthma treatment. We previously showed that integrin ?7 is a novel marker of the contractile ASM phenotype suggesting that targeting this protein may offer new avenues to counter the increase in ASM cell mass that underlies airways hyperresponsiveness (AHR) in asthma. We now determine whether inhibition of integrin ?7 expression would revert ASM cells back to a proliferative phenotype to cause an increase in ASM cell mass. This would be detrimental to asthmatic patients who already exhibit increased ASM mass in their airways. Using immunohistochemical analysis of the Melbourne Epidemiological Study of Childhood Asthma (MESCA) cohort, we show for the first time that integrin ?7 expression in patients with severe asthma is increased, supporting a clinically relevant role for this protein in asthma pathophysiology. Moreover, inhibition of the laminin-integrin ?7 signaling axis results in a reduction in smooth muscle-alpha actin abundance and does not revert ASM cells back to a proliferative phenotype. We determined that integrin ?7-induced Kras isoform of p21 Ras acts as a point of convergence between contractile and proliferative ASM phenotypic states. Our study provides further support for targeting integrin ?7 for the development of novel anti-asthma therapies.

SUBMITTER: Teoh CM

PROVIDER: S-EPMC6616330 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Integrin α7 expression is increased in asthmatic patients and its inhibition reduces Kras protein abundance in airway smooth muscle cells.

Teoh Chun Ming CM Tan Sheryl S L SSL Langenbach Shenna Y SY Wong Amanda H AH Cheong Dorothy H J DHJ Tam John K C JKC New Chih Sheng CS Tran Thai T Tran Thai T

Scientific reports 20190709 1

Airway smooth muscle (ASM) cells exhibit plastic phenotypic behavior marked by reversible modulation and maturation between contractile and proliferative phenotypic states. Integrins are a class of transmembrane proteins that have been implicated as novel therapeutic targets for asthma treatment. We previously showed that integrin α7 is a novel marker of the contractile ASM phenotype suggesting that targeting this protein may offer new avenues to counter the increase in ASM cell mass that underl ...[more]

PMID: 31289310

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Project description:Background and objectiveAirway remodeling in asthma refers to numerous structural changes in the airway in asthmatic patients, with thickening of the airway smooth muscle layer as its core feature. However, the nature and sources of the abnormally increased airway smooth muscle cells (ASMCs) in airway remodeling remain unclear. ASMCs play a key role in the pathogenesis of fatal asthma; therefore, it is important to clarify the properties and sources of these ASMCs responsible for asthmatic airway remodeling, which may provide a new direction for the precise treatment for asthma.MethodsWe performed a narrative review of the literature on PubMed, Web of Science, and Google Scholar databases searching for the cellular sources of ASMCs in asthmatic airway remodeling and their clinical relevance.Key content and findingsIt has long been thought that ASMCs are the result of abnormal proliferation of the native ASMCs in asthma; however, increasing evidence suggests that increased "ASMCs" may be due to the differentiation/transdifferentiation of other cells including mesenchymal stem cells (MSCs), myofibroblasts (MYFs), pericytes, and epithelial-mesenchymal transition (EMT). Recently, several pharmacological and biological therapies aimed at "reducing asthmatic ASMCs" have been developed, among which gallopamil, JQ1 [an inhibitor of the bromodomain and extra-terminal domain (BET) protein family], and histone deacetylase (HDAC) inhibitors can alleviate asthma airway remodeling and hyperresponsiveness and improve asthma symptoms in both mouse models and preclinical experiments.ConclusionsAs one of the core features of asthma, ASMCs are an important effector of airway remodeling. It has become extremely important to develop therapies for the reduction and prevention of the "ASMCs" on the basis of the properties and sources of "ASMCs". Many studies have shown that epigenetic regulation is closely related to the abnormal increase of ASMCs in asthma, and interfering with epigenetic regulation factors can reduce the increased smooth muscle cells. Although the epigenetic regulation of asthma is still in its nascent stage, epigenetic therapy targeting "ASMCs" may become another new strategy for asthma prevention and treatment.

Dataset Information

Integrin ?7 expression is increased in asthmatic patients and its inhibition reduces Kras protein abundance in airway smooth muscle cells.

Publications

Integrin α7 expression is increased in asthmatic patients and its inhibition reduces Kras protein abundance in airway smooth muscle cells.

Similar Datasets

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