Matrix metalloproteinases in cystic fibrosis: pathophysiologic and therapeutic perspectives

Abstract

Cystic fibrosis (CF) is the most common inherited disease in the Caucasian population. CF is caused by loss-of-function mutations in the CFTR gene leading to an altered electrolyte and water movement into the airway surface liquid, dehydration of the mucus layer, defective mucociliary clearance, and increased susceptibility to airway bacterial infections. CF is characterized by airway neutrophilic inflammation and activation of airway epithelial cells leading to increased airway levels of various matrix metalloproteinases (MMPs). Herein, we review MMP structure, regulation, and activity, along with the literature on MMPs expression in CF and the contributions of MMPs to CF pathogenesis. Numerous studies report elevated levels of MMPs (especially MMP-8, MMP-7, and MMP-9) in blood and/or lung samples from CF patients and have correlated MMP levels with measures of lung inflammation and injury and/or clinical parameters. No study has yet investigated the contributions of MMPs to the pathogenesis of CF using MMP gene-targeted murine of CF. Based upon the known activities of MMPs in animal models of other lung diseases, we hypothesize that some MMPs (such as MMP-8 and MMP-9) may amplify airway inflammation, and promote airway injury and airway-remodeling processes, or inhibit chloride epithelial transport by inhibiting activation of the CFTR (MMP-2). Other MMPs (such as MMP-7 and MMP-12) may limit the severity of CF by activating host defense proteins to enhance pathogen clearance from the airways, directly killing pathogens that colonize the airways of CF patients and/or promoting epithelial repair. We discuss potential approaches to selectively target MMPs to develop novel therapies that limit the high morbidity and mortality associated with CF.

Genetic Variants in Matrix Metalloproteinases MMP3 (rs3025058) and MMP9 (rs3918242) Associated with Colonic Diverticulosis

“…MMP3, a stromelysin produced by fibroblasts and myofibroblasts, is proficient at breaking down basal lamina proteins, proteoglycans, E-cadherin, plasminogen, interleukin (IL)-1β, and chemokine 7 [28]. The MMP3 rs3025058 is an upstream transcript variant that introduces an insertion (6A)/deletion (5A) variability at position −1612 within the promoter region.…”

“…MMP9, known as neutrophil gelatinase, is produced by epithelium, fibroblasts, and leukocytes, and is capable of degrading elastin, type IV collagen, other basal lamina proteins, gelatins, tumor growth factor (TGF)-β, IL-8, and α1-antitrypsin [28]. The MMP9 rs3918242 polymorphism represents a single nucleotide variation (SNV) resulting in a C to T substitution at position −1561 in the promoter region.…”

Antibody response against Pseudomonas aeruginosa and its relationship with immune mediators in the upper and lower airways of cystic fibrosis patients

“…MMP‐9 is a protease produced mostly by PMNs and acts in many ways, especially by degrading components of the extracellular matrix. Its role in the CF lung disease is well described and it has a dramatic increase during episodes of pulmonary exacerbations 31–34 . The knowledge about the role of MMP‐9 in UAW disorders is recent.…”

“…Its role in the CF lung disease is well described and it has a dramatic increase during episodes of pulmonary exacerbations. [31][32][33][34] The knowledge about the role of MMP-9 in UAW disorders is recent. A study showed increased MMP-9 expression in the bone and in the mucosa of patients with CRS and osteitis, despite intranasal and postoperative use of steroids, suggesting a role of MMP-9 in the pathogenesis of osteitis.…”