Ca2+ homeostasis and structural and functional remodelling of airway smooth muscle in asthma

Abstract

Asthma is characterised by airway hyper-responsiveness and remodelling, and there is mounting evidence that alterations in the phenotype of airway smooth muscle (ASM) play a central role in these processes. Although the concept that dysregulation of ASM Ca 2+ homeostasis may underlie at least part of these alterations has been around for many years, it is only relatively recently that the availability of ASM biopsies from subjects with mild and moderate asthma has allowed it to be properly investigated. In this article, critical components of the pathobiology of asthmatic ASM, including contractile function, proliferation, cell migration and secretion of proinflammatory cytokines and chemokines, are reviewed and related to associated changes in ASM Ca 2+ homeostasis. Based on this evidence, it is proposed that a unifying mechanism for the abnormal asthmatic phenotype is dysregulation of Ca 2+ homeostasis caused at least in part by a downregulation in expression and function of sarcoendoplasmic Ca 2+ ATPases (SERCAs).Asthma is a chronic inflammatory disease which is characterised by widespread structural changes in the airways (airway remodelling), encompassing epithelial dysfunction, mucous gland hypertrophy, deposition of extracellular matrix (ECM) and changes in airway smooth muscle (ASM) phenotype. 1 ASM from patients with asthma exhibits enhanced contractile activity, 2e4 as well as enhanced proliferation, migration and secretion of proinflammatory cytokines.5e8 This article reviews critical components of asthmatic ASM pathobiology and suggests that a unifying mechanism for the abnormal asthmatic phenotype is dysregulation of Ca 2+ homeostasis caused at least in part by a downregulation in expression of sarcoendoplasmic Ca 2+ ATPases (SERCAs).

Epigenetic Alterations by DNA Methylation in House Dust Mite–Induced Airway Hyperresponsiveness

“…We hypothesized that dysregulation of ASM functions via epigenetic modifications of gene expression may contribute to AHR because of the ASM's proliferative, contractile, and secretory properties (25,26). As a test of concept, we used the ASM cells isolated from trachea of control animals and HDM-challenged mice, and tested for the methylation status and expression of six potential candidate genes.…”

“…The model we studied leads to AHR after an acute allergen sensitization and challenge, and we hypothesize that this occurs by activating a set of genes responsible for ASM contraction, proliferation, and remodeling. ASM is postulated to play an important role in asthma pathophysiology because of its proliferative and migration phenotypes, together with its contractile and secretory properties (25,26). Airway remodeling involves thickening of the airway wall and increase in ASM mass (27).…”

Dissociation of FK506-Binding Protein 12.6 kD from Ryanodine Receptor in Bronchial Smooth Muscle Cells in Airway Hyperresponsiveness in Asthma

“…Alterations in agonist-induced calcium responses in BSMCs contribute to a stronger contractile response of the airways, a characteristic feature of asthma. Elevation of [Ca 21 ] i can result from increased Ca 21 influx from the extracellular fluid and Ca 21 release from the sarcoplasmic reticulum (SR) (11). In smooth muscle cells, excitation-contraction coupling involves depolarization of the plasma membrane to open voltage-gated calcium (Ca 21 ) channels.…”

“…Agonist-induced calcium release is largely from the SR (12,14). Ca 21 efflux from the SR is mediated by the SR-Ca 21 release channel, known as ryanodine receptor (RyR), and inositol 1,4,5-trisphosphate receptors (11 In the present study, we investigated the effects of IL-5, IL-13, and TNF-a on the calcium response of BSMCs to contractile agonists and on the interaction of FKBP12.6 with RyR2 in asthmatic AHR in vivo and in vitro. We found, for the first time, that chronic airway allergic inflammation causes dissociation of FKBP12.6 from RyR2 in BSMCs and enhances Ca 21 release response from the SR, leading to AHR in asthma.…”

Cissampelos sympodialis (Menispermaceae): A Novel Phytotherapic Weapon Against Allergic Diseases?

“…In vitro studies showed these drugs are responsible for increasing the levels of cAMP described as a regulatory second messenger of intracellular calcium-dependent mechanisms. Calcium is one of several molecules responsible for the smooth muscle contraction during acute phase of asthma crises (Mahn et al, 2010). Of note, side effects are observed in patients under 2-agonists therapy, mainly cardiac frequency increases in response to activation of cardiac 1-receptors.…”