Published ahead of print on June 9, 2005, doi:10.1165/rcmb.2005-0111OC
Am. J. Respir. Cell Mol. Biol., Volume 33, Number 3, September 2005, 271-279
A more recent version of this article appeared on September 1, 2005
Submitted on March 21, 2005
Revised on June 9, 2005
Tissue Inhibitor of MP-1 Deficiency Amplifies Acute Lung Injury in Bleomycin Exposed Mice
Kyoung-Hee Kim1, Kristin Burkhart1, Peter Chen2, Charles W Frevert3, Julie Randolph-Habecker4, Robert C Hackman5, Paul D Soloway6, and David K Madtes2*
1 Department of Pulmonary Critical Care Medicine, Fred Hutchinson Cancer Research Center, Seattle, WA, USA,
2 Department of Pulmonary Critical Care Medicine, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA,
3 Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA,
4 Department of Pathology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA,
5 Department of Pathology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA,
6 Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA
* To whom correspondence should be addressed. E-mail: dmadtes{at}fhcrc.org.
Bleomycin-induced lung injury triggers a profound and durable increase in TIMP-1 expression suggesting a potential role for this anti-proteinase 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 to wild-type littermates following 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.
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