title: OXYGEN MITIGATES THE INFLAMMATORY RESPONSE IN A MODEL OF HEMORRHAGE AND ZYMOSAN-INDUCED INFLAMMATION.
abstract: Sequential insults (hits) may change the inflammatory reaction that develops in response to separate single hits (e.g., injury, infection); however, their effects on the long-term clinical outcome are still only partially elucidated. Double-hit models are typically severe and fatal. We characterized in C57BL/6 mice a moderate double-hit model of hemorrhage (35%-40% of total blood volume) and resuscitation, followed by peritoneal injection of zymosan A that induced local and systemic inflammation with 58% mortality. This model allowed exploration of the inflammatory response over time in the surviving mice. We show that after 2 days, mice subjected to the double-hit model had elevated proinflammatory systemic and local peritoneal cytokine response (interleukin [IL]-1β, tumor necrosis factor-α, IL-6) and moderately elevated anti-inflammatory cytokines (IL-10, transforming growth factor-β), compared with the single-hit and sham mice. However, this dynamically changed, and by day 7, proinflammatory cytokines were reduced, and anti-inflammatory cytokines were markedly (P < 0.05) elevated in the double-hit group. Mice in the double-hit group that inhaled 100% oxygen intermittently for 6 h every day exhibited markedly reduced serum proinflammatory cytokines as early as day 2 (P < 0.05), inhibited macrophage infiltration into the peritoneum (by 13-fold; P < 0.05), and substantially increased survival rates of 85% (P = 0.00144). Oxygen mitigates the inflammatory response and exerts a beneficial effect on survival in a double-hit model of hemorrhage and zymosan-induced inflammation.
authors.affiliation: *Immunology Research Laboratory †Ischemia-shock Research Laboratory, Carmel Medical Center, The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Michal A
authors.initials: MA
authors.lastname: Rahat
authors.forename: Vera
authors.initials: V
authors.lastname: Brod
authors.forename: Bat-Chen
authors.initials: BC
authors.lastname: Amit-Cohen
authors.forename: Oryan
authors.initials: O
authors.lastname: Henig
authors.forename: Said
authors.initials: S
authors.lastname: Younis
authors.forename: Haim
authors.initials: H
authors.lastname: Bitterman
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D006470:Hemorrhage / Q000188:drug therapy* / Q000276:immunology; D007249:Inflammation / Q000139:chemically induced* / Q000188:drug therapy*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010100:Oxygen / Q000627:therapeutic use*; D015054:Zymosan / Q000633:toxicity*
chemical_list: D000893:Anti-Inflammatory Agents; D015054:Zymosan; D010100:Oxygen