Absence or inhibition of matrix metalloproteinase-8 decreases ventilator-induced lung injury.
Mechanical ventilation is a life-saving therapy that can also damage the lungs. Ventilator-induced lung injury (VILI) promotes inflammation and up-regulates matrix metalloproteinases (MMPs). Among these enzymes, MMP-8 is involved in the onset of inflammation by processing different immune mediators. To clarify the role of MMP-8 in a model of VILI and their relevance as a therapeutic target, we ventilated wild-type and MMP-8-deficient mice with low or high pressures for 2 hours. There were no significant differences after low-pressure ventilation between wild-type and knockout animals. However, lack of MMP-8 results in better gas exchange, decreased lung edema and permeability, and diminished histological injury after high-pressure ventilation. Mmp8(-/-) mice had a different immune response to injurious ventilation, with decreased neutrophilic infiltration, lower levels of IFN-γ and chemokines (LPS-induced CXC chemokine, macrophage inflammatory protein-2), and significant increases in anti-inflammatory cytokines (IL-4, IL-10) in lung tissue and bronchoalveolar lavage fluid. There were no differences in MMP-2, MMP-9, or tissue inhibitor of metalloproteinase-1 between wild-type and knockout mice. These results were confirmed by showing a similar protective effect in wild-type mice treated with a selective MMP-8 inhibitor. We conclude that MMP-8 promotes acute inflammation after ventilation with high pressures, and its short-term inhibition could be a therapeutic goal to limit VILI.
Albaiceta
Guillermo M
GM
Department of Biología Funcional, Universidad de Oviedo, Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain. guillermo.muniz@sespa.princast.es
Gutierrez-Fernández
Ana
A
García-Prieto
Emilio
E
Puente
Xose S
XS
Parra
Diego
D
Astudillo
Aurora
A
Campestre
Cristina
C
Cabrera
Sandra
S
Gonzalez-Lopez
Adrian
A
Fueyo
Antonio
A
Taboada
Francisco
F
López-Otin
Carlos
C
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D008168:Lung / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020784:Matrix Metalloproteinase 8 / Q000172:deficiency* / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D018345:Mice, Knockout; D011659:Pulmonary Gas Exchange / Q000187:drug effects; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D055397:Ventilator-Induced Lung Injury / Q000201:enzymology* / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*
D015415:Biomarkers; D016207:Cytokines; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1; D020778:Matrix Metalloproteinase 2; D020784:Matrix Metalloproteinase 8; D020780:Matrix Metalloproteinase 9