RATIONALE Aberrant lung remodeling in idiopathic pulmonary fibrosis (IPF) is characterized by elevated MMP9 expression but the precise role of this matrix metalloproteinase in this disease has yet to be… Click to show full abstract
RATIONALE Aberrant lung remodeling in idiopathic pulmonary fibrosis (IPF) is characterized by elevated MMP9 expression but the precise role of this matrix metalloproteinase in this disease has yet to be fully elucidated. METHODS Quantitative genomic, proteomic, and functional analyses both in vitro and in vivo were used to determine MMP9 expression in IPF cells and the effects of MMP9 inhibition on profibrotic mechanisms. RESULTS In the present study, we demonstrate that MMP9 expression was increased in airway basal-like cells (ABC-like) from IPF lungs compared with ABC cells from normal lungs. Inhibition of MMP9 activity with an anti-MMP9 antibody, andecaliximab blocked TGF-β1-induced Smad2 phosphorylation. However, in a subset of IPF patients, TGF-β1 activation in their ABC-like cells was unaffected or enhanced by MMP9 blockade (i.e. Non-Responders). Further analysis of Non-Responder ABC-like cells treated with andecaliximab revealed an association with the expression of type 1 IFN expression, and the addition of IFNα to these cells modulated both MMP9 expression and TGF-β1 activation. Finally, inhibition of MMP9 ameliorated pulmonary fibrosis induced by Responder lung cells, but not a Non-Responder in a humanized immunodeficient mouse model of IPF. CONCLUSION Together, these data demonstrate that MMP9 regulates the activation of ABC-like cells in IPF and targeting this MMP might be beneficial to a subset of IPF patients who show sufficient expression of type 1 IFNs.
               
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