Protective Role of Matrix Metalloproteinase-9 in Ozone-Induced Airway Inflammation

Abstract

BackgroundExposure to ozone causes airway inflammation, hyperreactivity, lung hyper-permeability, and epithelial cell injury. An early inflammatory response induced by inhaled O3 is characterized primarily by release of inflammatory mediators such as cytokines, chemokines, and airway neutrophil accumulation. Matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of oxidative lung disorders including acute lung injury, asthma, and chronic obstructive pulmonary disease.ObjectiveWe hypothesized that MMPs have an important role in the pathogenesis of O3-induced airway inflammation.MethodsWe compared the lung injury responses in either Mmp7- (Mmp7−/−) or Mmp9-deficient (Mmp9−/−) mice and their wild-type controls (Mmp7+/+, Mmp9+/+) after exposure to 0.3 ppm O3 or filtered air.ResultsRelative to air-exposed controls, MMP-9 activity in bronchoalveolar lavage fluid (BALF) was significantly increased by O3 exposure in Mmp9+/+ mice. O3-induced increases in the concentration of total protein (a marker of lung permeability) and the numbers of neutrophils and epithelial cells in BALF were significantly greater in Mmp9−/− mice compared with Mmp9+/+ mice. Keratinocyte-derived chemokine (KC) and macrophage inflammatory protein (MIP)-2 levels in BALF were also significantly higher in Mmp9−/− mice than in Mmp9+/+ mice after O3 exposure, although no differences in mRNA expression for these chemokines were found between genotypes. Mean BALF protein concentration and numbers of inflammatory cells were not significantly different between Mmp7+/+ and Mmp7−/− mice after O3 exposure.ConclusionsResults demonstrated a protective role of MMP-9 but not of MMP-7, in O3-induced lung neutrophilic inflammation and hyperpermeability. The mechanism through which Mmp9 limits O3-induced airway injury is not known but may be via posttranscriptional effects on proinflammatory CXC chemokines including KC and MIP-2.

Constitutive expression of MMP9 in intestinal epithelium worsens murine acute colitis and is associated with increased levels of proinflammatory cytokine Kc

“…Beklen et al (7) showed that there was an upregulation of both MMP9 and IL-8 in periodontitis. Many studies related with airway epithelium have shown a direct link between the IL-8 secretion and MMP9 expression (15,31,55). Yoon et al (55) have shown that MMP9 protects from ozone induced airway injury may be via posttranscriptional effects on IL-8.…”

A therapeutic role for matrix metalloproteinase inhibitors in lung diseases?

“…BAL from MMP9-deficient mice exposed to ozone had increased protein content and greater numbers of neutrophils and epithelial cells compared to wild-type mice; this finding points to a protective role of MMP9 in ozone-induced inflammation [35]. This protective effect was not observed in MMP7-deficient mice [35]. It is important to note that, although often neglected by the authors, none of the presented MMP9 inhibition strategies was specific for MMP9 ( fig.…”

“…Inhibition of MMP9 activity with doxycycline reduced pancreatitis-associated lung injury and diminished expression of MMP9 in pulmonary tissue [69]. BAL from MMP9-deficient mice exposed to ozone had increased protein content and greater numbers of neutrophils and epithelial cells compared to wild-type mice; this finding points to a protective role of MMP9 in ozone-induced inflammation [35]. This protective effect was not observed in MMP7-deficient mice [35].…”

A rapid assessment of the impact of hazard reduction burning around Sydney, May 2016

“…Since 2005, there have been a number of key experimental animal studies carried out in mice that demonstrated acute inflammation and airway injury following acute (Damera et al, 2010) or sub-chronic exposure (Inoue et al, 2008;Yoon, Cho & Kleeberger, 2007) to environmentally pertinent ozone concentrations in the range 100-300 ppb. Additional subchronic and chronic ozone exposure studies (500 ppb) in rhesus monkeys have demonstrated structural changes in the distal and proximal airways (Fanucchi et al, 2006;Carey et al, 2011) and allergy-like patterns of response (increased globlet cells and eosinophils) to allergen and ozone co-challenges (Kajekar et al, 2007;Miller et al, 2009;van Winkle et al, 2010;Plopper et al, 2007).…”