Matrix Metalloproteinase-9 and Airway Remodeling in Asthma

Abstract

Airway remodeling is a major change responsible for irreversible asthmatic airflow restriction. The Th-2 cytokines-dominant eosinophilic inflammatory mechanism cannot fully explain the progressive subepithelial fibrosis and structural changes in the extracellular matrix (ECM). Matrix metalloproteinases (MMPs) are the key enzymes responsible for ECM degradation. MMPs are normally produced and secreted under the tight regulation of, at least, 3 different levels: the gene transcriptional level, the activation of the latent form of enzyme, and the inactivation by specific endogenous inhibitors. In asthmatic condition, as shown by the large amount of accumulated evidence in this review, MMP-9 is the most relevant among the 23 kinds of human MMPs at present detected. Although the mechanism is still under investigation and not accurately known, the imbalance between MMP-9 and tissue inhibitor of metalloproteinase-1 is considered a major theory to explain the progression of asthmatic airway remodeling. Various inflammatory cytokines including TGF beta and growth factors play a pivotal role in MMP-9 production and secretion. This review mainly focuses upon the pivotal role of MMP-9 in airway remodeling, and also upon major cellular source of MMP-9 in asthma such as eosinophils, neutrophils, epithelial cells and alveolar macrophages. This review also refers to the partial contribution of nitric oxide to MMP-9 in asthma.

Inhibition of airway epithelial-to-mesenchymal transition and fibrosis by kaempferol in endotoxin-induced epithelial cells and ovalbumin-sensitized mice

“…34,35 MMP can be produced during EMT process by triggering signaling cascades in epithelial cells by TGF-b and other factors. 8,26 Kaempferol attenuated MT1-MMP expression with concurrent TIMP-2 induction in TGF-binduced epithelial cells.…”

Airway Inflammation after Bronchial Thermoplasty for Severe Asthma

“…One of these, TGF-b, has a complex role in the pathogenesis of severe asthma (35). It is produced by several cell types, including epithelial cells, eosinophils, macrophages, fibroblasts, and helper T cells (36,37), and is involved in epithelial transformation, subepithelial fibrosis, airway smooth muscle remodeling, microvascular changes, mucus production, and both suppressing and activating inflammatory cytokines (38)(39)(40)(41). TGF-b 1 is a major regulator as well as effector in the immune response.…”

HMGB1 contributes to allergen-induced airway remodeling in a murine model of chronic asthma by modulating airway inflammation and activating lung fibroblasts

“…The primary cellular sources of MMP-9 in airway remodeling are eosinophils, epithelial cells, alveolar macrophages and neutrophils. 17 Thus, we evaluated the MMP-9 expression and activity in human peripheral blood eosinophils, neutrophils, alveolar macrophages, U937 cells, THP-1 monocytes, human primary bronchial epithelial cells and two epithelial cell lines (A549 and 16-HBE). Treatment with HMGB1 alone or the HMGB1/IL-1b complex did not result in increased MMP-9 secretion or expression by eosinophils, alveolar macrophages, U937 cells or THP-1 monocytes compared with the untreated control cells.…”