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Am J Pathol ; 160(5): 1755-65, 2002 May.
Article in English | MEDLINE | ID: mdl-12000727

ABSTRACT

TSG-14/PTX3 is a gene inducible by tumor necrosis factor (TNF)-alpha, interleukin-1 beta, and lipopolysaccharide in fibroblasts, macrophages, and endothelial cells. It encodes a 42-kd secreted glycoprotein that belongs to the pentraxin family of acute-phase proteins. Recently, we demonstrated that TSG-14 transgenic mice (TSG-14tg) overexpressing the murine TSG-14 gene under control of its own promoter are more resistant to lipopolysaccharide-induced shock and to polymicrobial sepsis caused by cecal ligation and puncture. Here we show that after ischemia and reperfusion (I/R) injury, TSG-14tg mice have an impaired survival rate, which appeared secondary to a markedly increased inflammatory response, as assessed by the local (duodenum and ileum) and remote (lung) enhancement in vascular permeability, hemorrhage, and neutrophil accumulation. Moreover, tissue concentrations of TNF-alpha, interleukin-1 beta, KC, and MCP-1 were higher in TSG-14tg as compared to wild-type mice after I/R injury. Of note, elevated TNF-alpha concentrations in serum were only observed in TSG-14tg mice and blockage of TNF-alpha action prevented lethality of TSG-14tg mice. These results demonstrate that transgenic expression of TSG-14 induces an enhanced local and systemic injury and TNF-alpha-dependent lethality after I/R. Taken together, our data point to a critical role of TSG-14 in controlling acute inflammatory response in part via the modulation of TNF-alpha expression.


Subject(s)
C-Reactive Protein/physiology , Inflammation/pathology , Reperfusion Injury/physiopathology , Serum Amyloid P-Component/physiology , Animals , Antigens, CD/genetics , Antigens, CD/physiology , C-Reactive Protein/genetics , Capillary Permeability/physiology , Chemokines/metabolism , Cytokines/metabolism , Duodenum/blood supply , Duodenum/metabolism , Duodenum/pathology , Gene Expression Regulation , Genotype , Inflammation/etiology , Lung/blood supply , Lung/metabolism , Lung/pathology , Mice , Mice, Inbred C57BL , Mice, Inbred Strains , Mice, Transgenic , Receptors, Tumor Necrosis Factor/genetics , Receptors, Tumor Necrosis Factor/physiology , Receptors, Tumor Necrosis Factor, Type I , Reperfusion Injury/complications , Reperfusion Injury/mortality , Serum Amyloid P-Component/genetics , Survival Rate , Time Factors
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