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 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 underlies airways hyperresponsiveness (AHR) in asthma. We now determine whether inhibition of integrin α7 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 α7 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 α7 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 α7-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 α7 for the development of novel anti-asthma therapies.
Highlights
Airway wall remodeling (AWR), a key feature of chronic asthma involves airway smooth muscle (ASM) hypertrophy and hyperplasia and increased deposition of extracellular matrix (ECM) proteins in the airway
We first determined whether the expression of integrin α7β1 in Airway smooth muscle (ASM) was clinically relevant by scoring the immunohistochemical staining of integrin α7 in human bronchial biopsies from patients with varying asthma severity (Fig. 1)
Histological sections of biopsy samples were taken from an existing collection of biopsy samples that were originally used in a cohort study called MESCA (Melbourne Epidemiological Study of Childhood Asthma)[8,9,10]
Summary
Airway wall remodeling (AWR), a key feature of chronic asthma involves airway smooth muscle (ASM) hypertrophy and hyperplasia and increased deposition of extracellular matrix (ECM) proteins in the airway. The contractile phenotype is characterized by low proliferative rate and an increase in the expression of cytoskeletal proteins as well as proteins that are involved in the regulation of ASM contraction signaling, such as smooth muscle (sm)-MHC, sm-α-actin, SM22, desmin and calponin[2,3]. Www.nature.com/scientificreports on ASM survival are induced exclusively by laminin-211 and involve signaling pathways that concomitantly regulate ASM cell survival and ASM cell maturation[6]. This suggests that targeting the laminin-211-integrin α7β1 signaling axis may reduce the mass of contractile ASM phenotype cells which is in line with recent studies by others in support of integrins as therapeutic targets in AHR7. In our current study, we determined whether inhibition of integrin α7β1 expression has an impact on ASM phenotype plasticity by inducing contractile ASM phenotype cells back to a proliferative phenotype and the underlying signaling mechanisms involved in this process
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