Abstract
ObjectivesMatrix metalloproteinase-8 (MMP-8) promotes lung fibrotic responses to bleomycin in mice. Although prior studies reported that MMP-8 levels are increased in plasma and bronchoalveolar lavage fluid (BALF) samples from IPF patients, neither the bioactive forms nor the cellular sources of MMP-8 in idiopathic pulmonary fibrosis (IPF) patients have been identified. It is not known whether MMP-8 expression is dys-regulated in IPF leukocytes or whether MMP-8 plasma levels correlate with IPF outcomes. Our goal was to address these knowledge gaps.MethodsWe measured MMP-8 levels and forms in blood and lung samples from IPF patients versus controls using ELISAs, western blotting, and qPCR, and assessed whether MMP-8 plasma levels in 73 IPF patients correlate with rate of lung function decline and mortality. We used immunostaining to localize MMP-8 expression in IPF lungs. We quantified MMP-8 levels and forms in blood leukocytes from IPF patients versus controls.ResultsIPF patients have increased BALF, whole lung, and plasma levels of soluble MMP-8 protein. Active MMP-8 is the main form elevated in IPF lungs. MMP-8 mRNA levels are increased in monocytes from IPF patients, but IPF patients and controls have similar levels of MMP-8 in PMNs. Surprisingly, macrophages and airway epithelial cells are the main cells expressing MMP-8 in IPF lungs. Plasma and BALF MMP-8 levels do not correlate with decline in lung function and/or mortality in IPF patients.ConclusionBlood and lung MMP-8 levels are increased in IPF patients. Active MMP-8 is the main form elevated in IPF lungs. Surprisingly, blood monocytes, lung macrophages, and airway epithelial cells are the main cells in which MMP-8 is upregulated in IPF patients. Plasma and BALF MMP-8 levels are unlikely to serve as a prognostic biomarker for IPF patients. These results provide new information about the expression patterns of MMP-8 in IPF patients.
Highlights
idiopathic pulmonary fibrosis (IPF) is associated with high morbidity and mortality [1] and its incidence is increasing [2,3]
Blood monocytes, lung macrophages, and airway epithelial cells are the main cells in which Matrix metalloproteinase-8 (MMP-8) is upregulated in IPF patients
Plasma and bronchoalveolar lavage fluid (BALF) MMP-8 levels are unlikely to serve as a prognostic biomarker for IPF patients
Summary
IPF is associated with high morbidity and mortality [1] and its incidence is increasing [2,3]. No therapies have been shown to reduce mortality in IPF patients [4,5,6]. One molecule that has recently been linked to fibrotic lung diseases is matrix metalloproteinase-8 (MMP-8 or neutrophil collagenase). MMP-8 degrades type I collagen (the major collagen deposited in IPF lungs) in vitro [9]. Recent studies have shown that MMP-8 promotes (rather than inhibits) lung fibrosis in bleomycin-treated mice, and this is linked to MMP-8’s activities in reducing lung levels of macrophage inflammatory protein 1a (MIP-1a) and interferon-inducible protein-10 (IP-10) which is an anti-fibrotic cytokine [10,11,12]
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