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Hypothermia Induces Anti-Inflammatory Cytokines and Inhibits Nitric Oxide and Myeloperoxidase-Mediated Damage in the Hearts of Endotoxemic Rats^*

^* From the Departments of Pediatrics (Mr. Scumpia and Mr. Sarcia) and Physiology and Functional Genomics (Ms. Kelly), University of Florida, Gainesville, FL; and Department of Child Health (Dr. Skimming and Dr. DeMarco), University of Missouri, Columbia, MO.

Correspondence to: Jeffrey W. Skimming, MD, Department of Child Health, One Hospital Dr, Columbia, MO 65211; e-mail: skimmingj{at}missouri.edu

Study objectives: The impairment of cardiac contractility during endotoxemia involves induction of nitric oxide formation through a cascade of events initiated by overexpression of proinflammatory cytokines. We previously showed that hypothermia attenuates endotoxin-induced overexpression of nitric oxide in rat lungs. In the present study, we tested the hypothesis that hypothermia protects against endotoxin-induced myocardial inflammation by changing the balance of pro- and anti-inflammatory cytokines, inhibiting myeloperoxidase, an indicator of neutrophil activity, and inhibiting nitric oxide-mediated protein damage.

Design: Rats were randomized to treatment with either hypothermia (n = 6; 18 to 24°C) or normothermia (n = 6; 36 to 38°C). Endotoxin (15 mg/kg) was administered intravascularly to anesthetized animals, and heart tissue was harvested 150 min later.

Measurements and results: Using enzyme-linked immunosorbent assays (ELISAs), we found that hypothermia induced myocardial expression of the anti-inflammatory cytokines interleukin (IL)-4 and IL-10, while decreasing concentrations of the pro-inflammatory cytokines IL-1ß and growth-related oncogene/cytokine-induced neutrophil chemoattractant (rat homolog of IL-8). Electromobility shift assay revealed that hypothermia inhibited the nuclear translocation of nuclear factor-B. Reverse transcriptase-polymerase chain reaction and Western blot assays revealed that hypothermia attenuated the endotoxin-induced overexpression of both inducible nitric oxide synthase (iNOS) messenger RNA and iNOS protein, respectively. Hypothermia also attenuated nitric oxide-mediated myocardial protein damage, as determined by a nitrotyrosine ELISA. Myocardial myeloperoxidase content, an indicator of neutrophil accumulation and oxidative activity, was also inhibited by hypothermia in endotoxemic rats.

Conclusion: These data demonstrate that hypothermia induces an anti-inflammatory cytokine profile, inhibits neutrophil aggregation, and inhibits the formation of nitric oxide during endotoxemia in the rat.

Key Words: growth-related oncogene/chemoattractant • inducible nitric oxide synthase • interleukin-4 • interleukin-10 • lipopolysaccharide • nitrotyrosine • nuclear factor-B

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