Detrimental role for matrix metalloprotease-1 in the pathogenesis of pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease, characterized by accumulation of extracellular matrix (ECM) proteins. Matrix metalloprotease 1 (MMP-1) is an endopeptidase capable of degrading ECM proteins like fibrillar collagens, although pleiotropic actions have been described. We investigated MMP-1 expression in a cohort of IPF patients and determined the effect of genetic ablation of MMP-1 in the development of lung fibrosis in mice. We confirmed that MMP-1 levels are significantly increased in IPF lungs as compared to control lungs at both the mRNA and protein level. Interestingly, MMP-1 protein levels negatively correlated with Forced Vital Capacity (Spearman r = -0.45, p = 0.009). Next, wildtype and MMP-1a null (MMP-1a-/-) mice were subjected to bleomycin-induced lung fibrosis. MMP-1a-/- mice were protected from bleomycin-induced lung fibrosis as assessed by lung hydroxyproline content at d14, compared to wildtype mice (196±16 μg vs 146±11 μg/lung). Inflammatory cell influx in the BALF was significantly lower in MMP-1a-/- mice at d14 compared to wildtype mice (1.18x10^6±2.7x10^5 vs 0.54x10^6±0.67x10^5 cells/mL), whereas there was no difference at d7. We conclude that MMP-1 plays a detrimental role in the pathogenesis of lung fibrosis in mice and human. These data support our efforts in targeting MMP-1 as a new option against lung fibrosis progression.