期刊
JOURNAL OF LEUKOCYTE BIOLOGY
卷 77, 期 1, 页码 16-23出版社
WILEY
DOI: 10.1189/jlb.0704382
关键词
macrophages; inflammation; endotoxic shock; lipopolysaccharide
资金
- NIGMS NIH HHS [GM57664, GM35633] Funding Source: Medline
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM035633, R01GM057664, R55GM057664] Funding Source: NIH RePORTER
Severe injury can initiate an exaggerated systemic inflammatory response and multiple organ failure (MOF) if a subsequent immune stimulus, second hit, occurs. Using a mouse thermal injury model, we tested whether changes in innate immune cell reactivity following injury can contribute to the development of heightened inflammation and MOF. Using high-purity Escherichia coli lipopolysaccharide (LPS) to selectively stimulate Toll-like receptor 4 (TLR4), we demonstrate augmented interleukin (IL)-1beta, tumor necrosis factor alpha (TNF-alpha), and IL-6 production by 1 day but particularly, at 7 days after injury. The in vivo significance of enhanced TLR4 responsiveness was explored by challenging sham or burn mice with LPS at I or 7 days after injury and determining mortality along with in vivo cytokine and chemokine levels. Mortality was high (75%) in LPS-challenged burn but not sham mice at 7 days, although not at I day, after injury. Death was associated with leukocyte sequestration in the lungs and livers along with increased proinflammatory cytokine and chemokine levels in these organs. Blocking TNF-alpha activity prevented this mortality, suggesting that excessive TNF-alpha production contributes to this lethal response. These findings demonstrate the potential lethality of excessive TLR4 reactivity after injury and provide an explanation for the exaggerated inflammatory response to a second hit, which can occur following severe injury.
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