Anti-inflammatory response is associated with mortality and severity of infection in sepsis

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 288; no. 4; pp. L633 - L640
• Main Authors: Ashare, Alix, Powers, Linda S, Butler, Noah S, Doerschug, Kevin C, Monick, Martha M, Hunninghake, Gary W
• Format: Journal Article
• Language: English
• Published: United States 01.04.2005
• Subjects: Animals; Cecum - pathology; Enzyme-Linked Immunosorbent Assay; Female; Interleukin 1 Receptor Antagonist Protein; Interleukin-1 - genetics; Interleukin-1 - metabolism; Ligation; Liver - metabolism; Mice; Mice, Inbred C57BL; Punctures; Receptors, Tumor Necrosis Factor, Type I - genetics; Receptors, Tumor Necrosis Factor, Type I - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Bacterial - genetics; RNA, Bacterial - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Sepsis - immunology; Sepsis - microbiology; Sepsis - mortality; Sialoglycoproteins - genetics; Sialoglycoproteins - metabolism; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00231.2004

1 Division of Pulmonary, Critical Care, and Occupational Medicine, Department of Internal Medicine, University of Iowa College of Medicine; and 2 Veterans Administration Medical Center, Iowa City, Iowa Submitted 22 June 2004 ; accepted in final form 30 November 2004 Using a murine model of sepsis, we found that the balance of tissue pro- to anti-inflammatory cytokines directly correlated with severity of infection and mortality. Sepsis was induced in C57BL/6 mice by cecal ligation and puncture (CLP). Liver tissue was analyzed for levels of IL-1 , IL-1 receptor antagonist (IL-1ra), tumor necrosis factor (TNF)- , and soluble TNF receptor 1 by ELISA. Bacterial DNA was measured using quantitative real-time PCR. After CLP, early predominance of proinflammatory cytokines (6 h) transitioned to anti-inflammatory predominance at 24 h. The elevated anti-inflammatory cytokines were mirrored by increased tissue bacterial levels. The degree of anti-inflammatory response compared with proinflammatory response correlated with the bacterial concentration. To modulate the timing of the anti-inflammatory response, mice were treated with IL-1ra before CLP. This resulted in decreased proinflammatory cytokines, earlier bacterial load, and increased mortality. These studies show that the initial tissue proinflammatory response to sepsis is followed by an anti-inflammatory response. The anti-inflammatory phase is associated with increased bacterial load and mortality. These data suggest that it is the timing and magnitude of the anti-inflammatory response that predicts severity of infection in a murine model of sepsis. bacterial load; anti-inflammation Address for reprint requests and other correspondence: A. Ashare, Div. of Pulmonary, Critical Care, and Occupational Medicine, Univ. of Iowa College of Medicine, 200 Hawkins Dr., C-33 GH, Iowa City, IA 52242 (E-mail address: alix-ashare{at}uiowa.edu