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Tissue Inhibitor of Metalloproteinase-1 Deficiency Amplifies Acute Lung Injury in Bleomycin-Exposed Mice

Sections of Pulmonary and Critical Care Medicine and Pathology, Fred Hutchinson Cancer Research Center; Departments of Medicine and Pathology, University of Washington School of Medicine, Seattle, Washington; and Division of Nutritional Sciences, Cornell University, Ithaca, New York

Correspondence and requests for reprints should be addressed to David K. Madtes, M.D., Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, D3-190 P.O. Box 19024, Seattle, WA 98109-1024. E-mail: dmadtes{at}fhcrc.org

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.

Key Words: inflammation • vascular permeability • hemorrhage

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