| First Author | Craig VJ | Year | 2013 |
| Journal | J Immunol | Volume | 190 |
| Issue | 8 | Pages | 4283-96 |
| PubMed ID | 23487425 | Mgi Jnum | J:195119 |
| Mgi Id | MGI:5476557 | Doi | 10.4049/jimmunol.1201043 |
| Citation | Craig VJ, et al. (2013) Profibrotic Activities for Matrix Metalloproteinase-8 during Bleomycin-Mediated Lung Injury. J Immunol 190(8):4283-96 |
| abstractText | 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-beta, IL-13, JE, and IFN-gamma), Mmp-8(-/-) mice have higher lung levels of IFN-gamma-inducible protein-10 (IP-10) and MIP-1alpha. Genetically deleting either Ip-10 or Mip-1alpha 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-1alpha. These data indicate therapeutic strategies to reduce lung levels of MMP-8 may limit fibroproliferative responses to injury in the human lung. |
