title: Profibrotic activities for matrix metalloproteinase-8 during bleomycin-mediated lung injury.
abstract: Matrix metalloproteinase-8 (MMP-8) is a potent interstitial collagenase thought to be expressed mainly by polymorphonuclear neutrophils. To determine whether MMP-8 regulates lung inflammatory or fibrotic responses to bleomycin, we delivered bleomycin by the intratracheal route to wild-type (WT) versus Mmp-8(-/-) mice and quantified MMP-8 expression, and inflammation and fibrosis in the lung samples. Mmp-8 steady state mRNA and protein levels increase in whole lung and bronchoalveolar lavage samples when WT mice are treated with bleomycin. Activated murine lung fibroblasts express Mmp-8 in vitro. MMP-8 expression is increased in leukocytes in the lungs of patients with idiopathic pulmonary fibrosis compared with control lung samples. Compared with bleomycin-treated WT mice, bleomycin-treated Mmp-8(-/-) mice have greater lung inflammation, but reduced lung fibrosis. Whereas bleomycin-treated Mmp-8(-/-) and WT mice have similar lung levels of several pro- and antifibrotic mediators (TGF-β, IL-13, JE, and IFN-γ), Mmp-8(-/-) mice have higher lung levels of IFN-γ-inducible protein-10 (IP-10) and MIP-1α. Genetically deleting either Ip-10 or Mip-1α in Mmp-8(-/-) mice abrogates their lung inflammatory response to bleomycin, but reconstitutes their lung fibrotic response to bleomycin. Studies of bleomycin-treated Mmp-8 bone marrow chimeric mice show that both leukocytes and lung parenchymal cells are sources of profibrotic MMP-8 during bleomycin-mediated lung fibrosis. Thus, during bleomycin-mediated lung injury, MMP-8 dampens the lung acute inflammatory response, but promotes lung fibrosis by reducing lung levels of IP-10 and MIP-1α. These data indicate therapeutic strategies to reduce lung levels of MMP-8 may limit fibroproliferative responses to injury in the human lung.
authors.affiliation: Pulmonary Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Vanessa J
authors.initials: VJ
authors.lastname: Craig
authors.forename: Pablo A
authors.initials: PA
authors.lastname: Quintero
authors.forename: Susanne E
authors.initials: SE
authors.lastname: Fyfe
authors.forename: Avignat S
authors.initials: AS
authors.lastname: Patel
authors.forename: Martin D
authors.initials: MD
authors.lastname: Knolle
authors.forename: Lester
authors.initials: L
authors.lastname: Kobzik
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Owen
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D000818:Animals; D001761:Bleomycin / Q000008:administration & dosage*; D004195:Disease Models, Animal; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology*; D020784:Matrix Metalloproteinase 8 / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D061965:Matrix Metalloproteinase Inhibitors / Q000008:administration & dosage; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D061251:Primary Cell Culture
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D001761:Bleomycin; C576328:MMP8 protein, mouse; D020784:Matrix Metalloproteinase 8