You are here
Tissue inhibitor of metalloproteinase-1 deficiency amplifies acute lung injury in bleomycin-exposed mice.
Title | Tissue inhibitor of metalloproteinase-1 deficiency amplifies acute lung injury in bleomycin-exposed mice. |
Publication Type | Journal Article |
Year of Publication | 2005 |
Authors | Kim, K-H, Burkhart, K, Chen, P, Frevert, CW, Randolph-Habecker, J, Hackman, RC, Soloway, PD, Madtes, DK |
Journal | Am J Respir Cell Mol Biol |
Volume | 33 |
Issue | 3 |
Pagination | 271-9 |
Date Published | 2005 Sep |
ISSN | 1044-1549 |
Keywords | Animals, Antibiotics, Antineoplastic, Bleomycin, Capillary Permeability, Chemotaxis, Leukocyte, Gene Expression, Hemorrhage, Lipopolysaccharides, Male, Matrix Metalloproteinase 9, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Neutrophils, Pulmonary Alveoli, Pulmonary Fibrosis, Respiratory Distress Syndrome, Adult, Specific Pathogen-Free Organisms, Tissue Inhibitor of Metalloproteinase-1, Weight Loss |
Abstract | 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. |
DOI | 10.1165/rcmb.2005-0111OC |
Alternate Journal | Am. J. Respir. Cell Mol. Biol. |
PubMed ID | 15947421 |
PubMed Central ID | PMC2715316 |
Grant List | HL 63994 / HL / NHLBI NIH HHS / United States |