Role of matrix metalloprotease-2 and MMP-9 in experimental lung fibrosis in mice
Tina Bormann1, Regina Maus1, Jennifer Stolper1
1Division of Experimental Pneumology, Hannover Medical School, Feodor-Lynen-Strasse 21, 30625, Hannover, Germany.
Background:
Idiopathic pulmonary fibrosis (IPF) is a diffuse parenchymal lung disease characterized by exuberant deposition of extracellular matrix (ECM) proteins in the lung interstitium, which contributes to substantial morbidity and mortality in IPF patients. Matrix metalloproteinases (MMPs) are a large family of zinc-dependent endopeptidases, many of which have been implicated in the regulation of ECM degradation in lung fibrosis. However, the roles of MMP-2 and -9 (also termed gelatinases A and B) have not yet been explored in lung fibrosis in detail.
Methods:
AdTGF-β1 was applied via orotracheal routes to the lungs of WT, MMP-2 KO, MMP-9 KO and MMP-2/-9 dKO mice on day 0 to induce lung fibrosis. Using hydroxyproline assay, FlexiVent based lung function measurement, histopathology, western blot and ELISA techniques, we analyzed MMP-2 and MMP-9 levels in BAL fluid and lung, collagen contents in lung and lung function in mice on day 14 and 21 post-treatment.
Result:
IPF lung homogenates exhibited significantly increased levels of MMP-2 and MMP-9, relative to disease controls. Enzymatically active MMP-2 and MMP-9 was increased in lungs of mice exposed to adenoviral TGF-β1, suggesting a role for these metalloproteinases in lung fibrogenesis. However, we found that neither MMP-2 or MMP-9 nor combined MMP-2/-9 deletion had any effect on experimental lung fibrosis in mice.
Conclusion:
Together, our data strongly suggest that both gelatinases MMP-2 and MMP-9 play only a subordinate role in experimental lung fibrosis in mice.
Insights
Matrix metalloproteinases (MMPs), specifically MMP-2 and MMP-9, are elevated in idiopathic pulmonary fibrosis (IPF). However, deleting these gelatinases did not impact experimental lung fibrosis in mice, suggesting a minor role.
Area of Science:
- Pulmonary Medicine
- Molecular Biology
- Biochemistry
Background:
- Idiopathic pulmonary fibrosis (IPF) is a severe lung disease marked by excessive extracellular matrix (ECM) deposition.
- Matrix metalloproteinases (MMPs) regulate ECM, but the roles of MMP-2 and MMP-9 in lung fibrosis are unclear.
Purpose of the Study:
- To investigate the role of MMP-2 and MMP-9 in the development of experimental lung fibrosis.
- To determine if MMP-2 and MMP-9 contribute to collagen deposition and lung function changes in fibrosis.
Main Methods:
- Induced lung fibrosis in wild-type, MMP-2 knockout, MMP-9 knockout, and double knockout mice using adenoviral TGF-β1.
- Assessed lung fibrosis via hydroxyproline assay, lung function tests (FlexiVent), histopathology, Western blot, and ELISA for MMP levels and collagen content.
Main Results:
- MMP-2 and MMP-9 levels were elevated in IPF lung homogenates and in mice treated with adenoviral TGF-β1.
- Deletion of MMP-2, MMP-9, or both did not alter the severity of experimental lung fibrosis or lung function.
Conclusions:
- Gelatinases MMP-2 and MMP-9 appear to play a subordinate role in experimental lung fibrosis.
- Targeting MMP-2 and MMP-9 may not be an effective strategy for treating lung fibrosis.
