Tissue inhibitor of metalloproteinase-1 deficiency amplifies acute lung injury in bleomycin-exposed mice.

Publication Type:

Journal Article

Source:

American journal of respiratory cell and molecular biology, Volume 33, Issue 3, p.271-9 (2005)

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.