Cigarette smoke and lipopolysaccharide induce a proliferative airway smooth muscle phenotype

Tonio Pera,Herman Meurs,Marco van der Toorn,Reinoud Gosens,Johan Zaagsma,Riham Sami,Andries H Lesterhuis

doi:10.1186/1465-9921-11-48

Abstract

BackgroundA major feature of chronic obstructive pulmonary disease (COPD) is airway remodelling, which includes an increased airway smooth muscle (ASM) mass. The mechanisms underlying ASM remodelling in COPD are currently unknown. We hypothesized that cigarette smoke (CS) and/or lipopolysaccharide (LPS), a major constituent of CS, organic dust and gram-negative bacteria, that may be involved in recurrent airway infections and exacerbations in COPD patients, would induce phenotype changes of ASM.MethodsTo this aim, using cultured bovine tracheal smooth muscle (BTSM) cells and tissue, we investigated the direct effects of CS extract (CSE) and LPS on ASM proliferation and contractility.ResultsBoth CSE and LPS induced a profound and concentration-dependent increase in DNA synthesis in BTSM cells. CSE and LPS also induced a significant increase in BTSM cell number, which was associated with increased cyclin D1 expression and dependent on activation of ERK 1/2 and p38 MAP kinase. Consistent with a shift to a more proliferative phenotype, prolonged treatment of BTSM strips with CSE or LPS significantly decreased maximal methacholine- and KCl-induced contraction.ConclusionsDirect exposure of ASM to CSE or LPS causes the induction of a proliferative, hypocontractile ASM phenotype, which may be involved in airway remodelling in COPD.

Highlights

A major feature of chronic obstructive pulmonary disease (COPD) is airway remodelling, which includes an increased airway smooth muscle (ASM) mass
We present evidence that both CS extract (CSE) and LPS induce a proliferative, hypocontractile phenotype of ASM independent of inflammation, which could be important in the development and progression of ASM growth in COPD
In this study, we demonstrated for the first time that CSE and LPS induce a profound and concentration-dependent increase in DNA synthesis and cell number of cultured ASM cells

Summary

Introduction

A major feature of chronic obstructive pulmonary disease (COPD) is airway remodelling, which includes an increased airway smooth muscle (ASM) mass. The mechanisms involved in the development and progression of small airway remodelling in COPD are largely unknown, chronic inflammation of the airways is presumably of major importance. This is indicated by persistent infiltration of inflammatory cells, including macrophages, neutrophils and T- and B-lymphocytes, in the airway wall, which is correlated with the severity of airflow obstruction [3,5]

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