Mechanisms of inflammation-mediated airway smooth muscle plasticity and airways remodeling in asthma

Abstract

Recent evidence points to progressive structural change in the airway wall, driven by chronic local inflammation, as a fundamental component for development of irreversible airway hyperresponsiveness. Acute and chronic inflammation is orchestrated by cytokines from recruited inflammatory cells, airway myofibroblasts and myocytes. Airway myocytes exhibit functional plasticity in their capacity for contraction, proliferation, and synthesis of matrix protein and cytokines. This confers a principal role in driving different components of the airway remodeling process, and mediating constrictor hyperresponsiveness. Functional plasticity of airway smooth muscle (ASM) is regulated by an array of environmental cues, including cytokines, which mediate their effects through receptors and a number of intracellular signaling pathways. Despite numerous studies of the cellular effects of cytokines on cultured airway myocytes, few have identified how intracellular signaling pathways modulate or induce these cellular responses. This review summarizes current understanding of these concepts and presents a model for the effects of inflammatory mediators on functional plasticity of ASM in asthma.

Introduction

Asthma is a chronic disease characterized by reversible airway obstruction, inflammation and structural changes in the bronchial walls that includes epithelial cell denudation, mucus gland hyperplasia, smooth muscle hypertrophy and hyperplasia, thickening of the lamina reticularis and accumulation of sub-epithelial extracellular matrix (ECM), increased numbers of sub-mucosal myofibroblasts, increased vascularization, and neurite outgrowth (Holgate et al., 2000, Jeffery, 2001). These structural changes, defined as airway remodeling, are likely initiated by noxious, infectious, and allergic insult leading to cellular damage and/or bronchial inflammation characterized by infiltration of the airway wall and lumen by a variety of activated cell types, including T lymphocytes and eosinophils (Azzawi et al., 1990). Importantly, although allergen exposure and development of T-helper-2 lymphocyte polarization is associated with asthma severity and airway hyperresponsiveness (Holt et al., 1999), only 50% of asthma cases are associated with atopy (Beasley et al., 2001), indicating that factors in addition to allergen exposure contribute to the asthma phenotype. Recent evidence points to progressive structural change in the airway wall, driven by chronic local inflammation, as a fundamental component for development of irreversible airway hyperresponsiveness and asthma (Holgate, 2002, Van Eerdewegh et al., 2002). Both acute and chronic inflammation is orchestrated, in part, by various T cell- and mast cell-derived cytokines, such as interleukin (IL)-1β, IL-5, IL-4, IL-9, IL-10, IL-13 and tumour necrosis factor-alpha (TNFα), and mediators, such as the cysteinyl leukotrienes and isoprostanes, that are increased in asthmatic airways (Antczak et al., 2002). In addition, there is now compelling evidence that resident myofibroblasts and airway myocytes may perpetuate local chronic airway wall inflammation and structural change (Ghaffar et al., 1999, Doucet et al., 2002).

Airway smooth muscle (ASM) cells are multifunctional, having the capacity for contraction, migration, proliferation, and synthesis of ECM, growth factors, cytokines, and chemokines (Halayko and Stephens, 1994, Halayko and Solway, 2001). Exogenous stimuli, such as contractile agonists, ECM, inflammation, and mitogens differentially effect myocyte responses in a phenotype-dependent manner (Halayko et al., 1999, Hirst et al., 2000b). Further, as a population, airway myocytes display marked phenotypic heterogeneity based on expression of genes encoding contractile proteins, ECM, receptors, and cytokines and appear to be comprised of divergent mesenchymal sublineages (Halayko et al., 1998, Halayko et al., 1999, Halayko and Solway, 2001). Contractile myocytes also possess intrinsic mechanical plasticity of contractile function in response to stretch and during contraction (Seow et al., 2000), and cytokines can modulate G-protein coupled receptor (GPCR)-mediated contraction and relaxation (Amrani and Panettieri, 2002), further extending the range of contractile function of smooth muscle in the airway wall. Collectively, this ability for functional plasticity uniquely equips bronchial myocytes to differentially regulate airway lumen diameter both transiently, via reversible contraction, and chronically, via structural remodeling due to fibrosis and muscle hypertrophy.

The aim of this review is to summarize current understanding of the plastic functional capacity of ASM cells, and mechanisms by which local inflammation may affect ASM cell phenotype and function, and contribute to progressive structural reorganization of the airway wall and hyperresponsiveness associated with asthma.