Cyclic mechanical strain‐induced proliferation and migration of human airway smooth muscle cells: role of EMMPRIN and MMPs

Abstract

Airway smooth muscle (ASM) proliferation and migration are major components of airway remodeling in asthma. Asthmatic airways are exposed to mechanical strain, which contributes to their remodeling. Matrix metalloproteinase (MMP) plays an important role in remodeling. In the present study, we examined if the mechanical strain of human ASM (HASM) cells contributes to their proliferation and migration and the role of MMPs in this process. HASM were exposed to mechanical strain using the FlexCell system. HASM cell proliferation, migration and MMP release, activation, and expression were assessed. Our results show that cyclic strain increased the proliferation and migration of HASM; cyclic strain increased release and activation of MMP-1, -2, and -3 and membrane type 1-MMP; MMP release was preceded by an increase in extracellular MMP inducer; Prinomastat [a MMP inhibitor (MMPI)] significantly decreased cyclic strain-induced proliferation and migration of HASM; and the strain-induced increase in the release of MMPs was accompanied by an increase in tenascin-C release. In conclusion, cyclic mechanical strain plays an important role in HASM cell proliferation and migration. This increase in proliferation and migration is through an increase in MMP release and activation. Pharmacological MMPIs should be considered in the pursuit of therapeutic options for airway remodeling in asthma.

Dual Modulation of Airway Smooth Muscle Contraction by Th2 Cytokines via Matrix Metalloproteinase-1 Production

“…However, so far, no studies have suggested MMP-1 as a cause of hyperresponsiveness. MMPs have been proposed as a potential cause of airway remodeling (43), but the present study has clearly demonstrated that MMP-1 production might also contribute to altered contractions induced by Th2 cytokines. Thus, although Ca 2ϩ mobilization and the phosphorylation state of MLC are the main determinants of the contractile state of SM cells (22,44), it is likely that the interaction between SM cells and the extracellular collagen network is another important regulatory factor of the contractile response especially in allergic situations.…”

Magnetic approaches to study collective three-dimensional cell mechanics in long-term cultures (invited)

“…These stresses are modulated both by the contractile forces generated by cells and by the stiffness of the ECM that opposes those forces. For example, it has been found that increases in cell contractility and ECM stiffness promote cell proliferation 1,2 and assembly of focal adhesions, 3,4 whereas reduction in cell contractility and ECM stiffness induces cytoskeleton depolymerization 3 and apoptosis. 5,6 Several technical developments have enabled these recent insights into the role of mechanics in biology.…”

Pathophysiology of bronchial smooth muscle remodelling in asthma

“…Indeed, in canine BSM cells subjected to a stretch-relaxation regimen, proliferation in a MMP-dependent manner [113]. Mechanical stress was accompanied by an increased expression and activation of several MMPs including MMP-1, MMP-2, MMP-3 and MT1-MMP, suggesting that such a proliferation of human BSM cells requires the release and activation of MMPs [113]. Indeed, mechanical stress is influenced by the abundance of ECM.…”

“…Myofibroblasts could, therefore, be viewed as precursors of BSM cells or the result of a dedifferentiation process of the BSM cells. Furthermore, it may be suggested that BSM cells degrade surrounding ECM and migrate from their original bundles towards the epithelium to eventually form new bundles [113].…”