Abstract
Airway smooth muscle (ASM) hyperplasia is a key feature of airway remodeling in development of lung diseases such as asthma. Anomalous proliferation of ASM cells directly contributes to ASM hyperplasia. However, the molecular mechanisms controlling ASM cell proliferation are not completely understood. Semaphorins are versatile regulators of various cellular processes including cell growth and proliferation. The role of semaphorins in ASM cell proliferation has remained to be addressed. Here, we report that semaphorin 3A (Sema3A) receptor, neuropilin 1 (Nrp1), is expressed on human ASM cells (HASMC) isolated from healthy and asthmatic donors and treatment of these cells with exogenous Sema3A inhibits growth factor-induced proliferation. Sema3A inhibitory effect on HASMC proliferation is associated with decreased tyrosine phosphorylation of PDGFR, downregulation of Rac1 activation, STAT3 and GSK-3β phosphorylation. Bronchial sections from severe asthmatics displayed immunoreactivity of Nrp1, suggestive of functional contribution of Sema3A-Nrp1 axis in airway remodeling. Together, our data suggest Sema3A-Nrp1 signaling as a novel regulatory pathway of ASM hyperplasia.
Highlights
Asthma is a chronic inflammation of conducting airways in association with airway hyperresponsiveness (AHR) and remodeling [1]
neuropilin 1 (Nrp1) is expressed by human ASM cells (HASMC) in healthy and asthmatic conditions
Nrp1 basal expression was detected by immunocytochemistry in HASMC cells from healthy donors (Figure 1D) or asthmatics
Summary
Asthma is a chronic inflammation of conducting airways in association with airway hyperresponsiveness (AHR) and remodeling [1]. Increased airway smooth muscle (ASM) mass is a hallmark of airway remodeling which causes airway narrowing in asthma and chronic obstructive pulmonary disease [2]. Proliferation of ASM cells induced by a wide spectrum of mitogens (e.g. growth factors, cytokines, inflammatory mediators and allergens) has been proposed as a primary mechanism underlying increase ASM mass [3]. Several signaling pathways could be activated in parallel or as a cascade upon stimulation of ASM cells with mitogens [4]. Previous studies have addressed that inhibition of these pathways using exogenous specific inhibitors or gene silencing strategies reduces mitogen-induced ASM cell proliferation and could be considered as novel treatment options to minimize ASM hyperplasia. Little is known about intrinsic mechanisms controlling these pathways which get dysregulated in ASM cells at pathological conditions
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