Tissue inhibitor of metalloproteinase-1 deficiency amplifies acute lung injury in bleomycin-exposed mice.
Bleomycin-induced lung injury triggers a profound and durable increase in tissue inhibitor of metalloproteinase (TIMP)-1 expression, suggesting a potential role for this antiproteinase in the regulation of lung inflammation and fibrosis. TIMP-1 protein induction is spatially restricted to areas of lung injury as determined by immunohistochemistry. Using TIMP-1 null mutation mice, we demonstrate that TIMP-1 deficiency amplifies acute lung injury as determined by exaggerated pulmonary neutrophilia, hemorrhage, and vascular permeability compared with wild-type littermates after bleomycin exposure. The augmented pulmonary neutrophilia observed in TIMP-1-deficient animals was not found in similarly treated TIMP-2-deficient mice. Using TIMP-1 bone marrow (BM) chimeric mice, we observed that the TIMP-1-deficient phenotype was abolished in wild-type recipients of TIMP-1-deficient BM but not in TIMP-1-deficient recipients of wild-type BM. Acute lung injury in TIMP-1-deficient mice was accompanied by exaggerated gelatinase-B activity in the alveolar compartment. TIMP-1 deficiency did not alter neutrophil chemotactic factor accumulation in the injured lung nor neutrophil migration in response to chemotactic stimuli in vivo or in vitro. Moreover, TIMP-1 deficiency did not modify collagen accumulation after bleomycin injury. Our results provide direct evidence that TIMP-1 contributes significantly to the regulation of acute lung injury, functioning to limit inflammation and lung permeability.
Kim
Kyoung-Hee
KH
Section of Pulmonary and Critical Care Medicine, Fred Hutchinson Cancer Research Center, University of Washington School of Medicine, 1100 Fairview Avenue N, Seattle, WA 98109-1024, USA.
Burkhart
Kristin
K
Chen
Peter
P
Frevert
Charles W
CW
Randolph-Habecker
Julie
J
Hackman
Robert C
RC
Soloway
Paul D
PD
Madtes
David K
DK
D000818:Animals; D000903:Antibiotics, Antineoplastic; D001761:Bleomycin; D002199:Capillary Permeability / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D015870:Gene Expression / Q000276:immunology; D006470:Hemorrhage / Q000276:immunology / Q000401:mortality / Q000503:physiopathology; D008070:Lipopolysaccharides; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009504:Neutrophils / Q000166:cytology / Q000276:immunology; D011650:Pulmonary Alveoli / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000276:immunology / Q000401:mortality / Q000503:physiopathology; D012128:Respiratory Distress Syndrome / Q000276:immunology* / Q000401:mortality / Q000503:physiopathology*; D013047:Specific Pathogen-Free Organisms; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics* / Q000276:immunology*; D015431:Weight Loss
D000903:Antibiotics, Antineoplastic; D008070:Lipopolysaccharides; D019715:Tissue Inhibitor of Metalloproteinase-1; D001761:Bleomycin; D020780:Matrix Metalloproteinase 9