Related Experiment Video
Updated: May 13, 2026
Oropharyngeal Administration of Bleomycin in the Murine Model of Pulmonary Fibrosis
Published on: May 9, 2025
Profibrotic activities for matrix metalloproteinase-8 during bleomycin-mediated lung injury
Vanessa J Craig1, Pablo A Quintero, Susanne E Fyfe
1Pulmonary Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
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.
Insights
Matrix metalloproteinase-8 (MMP-8) dampens lung inflammation but promotes fibrosis after bleomycin injury. Reducing MMP-8 levels may limit human lung fibroproliferative responses to injury.
Area of Science:
- Pulmonary Medicine
- Immunology
- Biochemistry
Background:
- Matrix metalloproteinase-8 (MMP-8) is an interstitial collagenase primarily expressed by neutrophils.
- Its role in regulating lung inflammatory and fibrotic responses to injury is not fully understood.
Purpose of the Study:
- To investigate the role of MMP-8 in bleomycin-induced lung inflammation and fibrosis.
- To determine the cellular sources and regulatory mechanisms of MMP-8 in lung injury.
Main Methods:
- Intratracheal bleomycin administration to wild-type (WT) and Mmp-8(-/-) mice.
- Quantification of MMP-8 expression, inflammation, and fibrosis in lung tissues.
- Analysis of pro- and anti-fibrotic mediator levels (e.g., TGF-β, IL-13, IP-10, MIP-1α).
- Studies using Mmp-8 bone marrow chimeric mice.
Main Results:
- MMP-8 expression increased in WT mice following bleomycin treatment.
- Mmp-8(-/-) mice exhibited greater lung inflammation but reduced fibrosis compared to WT mice.
- MMP-8 deficiency led to increased levels of IP-10 and MIP-1α, which were found to regulate inflammation and fibrosis.
- Both leukocytes and lung parenchymal cells contribute to profibrotic MMP-8 production.
Conclusions:
- MMP-8 dampens acute lung inflammatory responses while promoting lung fibrosis.
- MMP-8 exerts its profibrotic effects by reducing IP-10 and MIP-1α levels.
- Targeting MMP-8 may offer a therapeutic strategy to mitigate fibroproliferative responses in the human lung.
