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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-?, IL-13, JE, and IFN-?), Mmp-8(-/-) mice have higher lung levels of IFN-?-inducible protein-10 (IP-10) and MIP-1?. Genetically deleting either Ip-10 or Mip-1? 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-1?. These data indicate therapeutic strategies to reduce lung levels of MMP-8 may limit fibroproliferative responses to injury in the human lung.

SUBMITTER: Craig VJ

PROVIDER: S-EPMC3639121 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Profibrotic activities for matrix metalloproteinase-8 during bleomycin-mediated lung injury.

Craig Vanessa J VJ Quintero Pablo A PA Fyfe Susanne E SE Patel Avignat S AS Knolle Martin D MD Kobzik Lester L Owen Caroline A CA

Journal of immunology (Baltimore, Md. : 1950) 20130313 8

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 samp ...[more]

PMID: 23487425

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Project description:Fatty acid nitroalkenes are reversibly-reactive electrophiles, endogenously detectable at nM concentrations, displaying anti-inflammatory actions. Nitroalkenes like 9- or 10-nitro-octadec-9-enoic acid (e.g. nitro-oleic acid, OA-NO2) pleiotropically suppress cardiovascular inflammatory responses, with pulmonary responses less well defined. C57BL/6 J male mice were intratracheally administered bleomycin (3 U/kg, ITB), to induce pulmonary inflammation and acute injury, or saline and were treated with 50 μL OA-NO2 (50 μg) or vehicle in the same instillation and 72 h post-exposure to assess anti-inflammatory properties. Bronchoalveolar lavage (BAL) and lung tissue were collected 7d later. ITB mice lost body weight, with OA-NO2 mitigating this loss (-2.3 ± 0.94 vs -0.4 ± 0.83 g). Histology revealed ITB induced cellular infiltration, proteinaceous debris deposition, and tissue injury, all significantly reduced by OA-NO2. Flow cytometry analysis of BAL demonstrated loss of Siglec F+/F4/80+/CD45+ alveolar macrophages with ITB (89 ± 3.5 vs 30 ± 3.7%). Analysis of CD11b/CD11c expressing cells showed ITB-induced non-resident macrophage infiltration (4 ± 2.3 vs 43 ± 2.4%) was decreased by OA-NO2 (24 ± 2.4%). Additionally, OA-NO2 attenuated increases in mature, activated interstitial macrophages (23 ± 4.8 vs. 43 ± 5.4%) in lung tissue digests. Flow analysis of CD31-/CD45-/Sca-1+ mesenchymal cells revealed ITB increased CD44+ populations (1 ± 0.4 vs 4 ± 0.4MFI), significantly reduced by OA-NO2 (3 ± 0.4MFI). Single cell analysis of mesenchymal cells by western blotting showed profibrotic ZEB1 protein expression induced by ITB. Lung digest CD45+ cells revealed ITB increased HMGB1+ cells, with OA-NO2 suppressing this response. Inhibition of HMGB1 expression correlated with increased basal phospholipid production and SP-B expression in the lung lining. These findings indicate OA-NO2 inhibits ITB-induced pro-inflammatory responses by modulating resident cell function.

Project description:This study aimed to determine whether a novel nutrient mixture (NM), composed of lysine, ascorbic acid, proline, green tea extracts and other micronutrients, attenuates impairments induced by spinal cord injury (SCI) and to investigate the related molecular mechanisms. A mouse model of SCI was established. Thirty-two mice were divided into four groups. The sham group received vehicle only. The SCI groups were treated orally with saline (saline group), a low dose (500 ?g 3 times/day) of NM (NM-LD group) or a high dose (2,000 ?g 3 times/day) of NM (NM-HD group). The levels of mouse hindlimb movement were determined every day in the first week post-surgery. The protein expression levels of matrix metalloproteinase (MMP)-2 and MMP-9 were determined by western blotting. Wild-type and mutant MMP-2- and MMP-9-directed luciferase constructs were generated and their luciferase activities were determined. NM significantly facilitated the recovery of hindlimb movement of the mice in comparison to that in the saline group. The expression levels of MMP-2 in the NM-LD and NM-HD groups were decreased by ~50% compared with the saline group as indicated by western blotting results. The expression levels of MMP-9 in the NM-LD and NM-HD groups were decreased to ~25 and ~10%, respectively. These results suggest that NM significantly inhibits the expression of MMP-2 and MMP-9 proteins. Reverse transcription quantitative polymerase chain reaction results indicated that NM reduced the levels of MMP-2 and MMP-9 mRNA. Furthermore, the luciferase results indicated that site-directed mutagenesis comprising a -1306 C to T (C/T) base change in the MMP-2 promoter and a -1562 C/T base change in the MMP-9 promoter abolished the inhibitory effects of NM on MMP-2 and MMP-9 promoters. These results suggest that NM attenuates SCI-induced impairments in mice movement by negatively affecting the promoter activity of MMP-2 and MMP-9 genes and thus decreasing the expression of MMP-2 and MMP-9 proteins.

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Profibrotic activities for matrix metalloproteinase-8 during bleomycin-mediated lung injury.

Publications

Profibrotic activities for matrix metalloproteinase-8 during bleomycin-mediated lung injury.

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