期刊
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
卷 33, 期 3, 页码 271-279出版社
AMER THORACIC SOC
DOI: 10.1165/rcmb.2005-0111OC
关键词
inflammation; vascular permeability; hemorrhage
资金
- NHLBI NIH HHS [HL 63994] Funding Source: Medline
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 TIM P-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 TIM P-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.
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