Induction of Early Inflammatory Gene Expression in a Murine Model of Nonresuscitated, Fixed-Volume Hemorrhage

Abstract

The etiology of many end-organ problems associated with hemorrhage has been attributed to the inflammatory response to hemorrhage. In a murine model of nonresuscitated, fixed-volume hemorrhage, we sought to elucidate the role that hemorrhagic insult alone plays in the generation of the early inflammatory cascade. Differences could be appreciated as early as 1 h post-hemorrhage, with consistent differences detected by 3 h in all of the major cytokine genes studied. Significant upregulation of IL-1beta , IL-6, TNF-alpha, and IL-10 mRNA expression was observed in both the liver and lung samples of mice subjected to fixed-volume hemorrhage when compared with sham-hemorrhaged mice. The cyclooxygenase-2 (COX-2) and inducible nitric oxide synthetase (iNOS) genes also were upregulated in the livers and lungs of hemorrhaged mice. Finally, expression of the genes that encode the Toll-like receptors (TLR)-2 and -4 was increased by hemorrhage. Taken collectively, these data demonstrate that the initial inflammatory cascade associated with hemorrhage occurs within hours after the initial hemorrhagic event, and can be associated with significant modulation of expression of key pro- and anti-inflammatory cytokine, enzyme, and TLR genes, suggesting that these may be possible new therapeutic targets.

Injury Primes the Innate Immune System for Enhanced Toll-Like Receptor Reactivity

“…This upregulated LPS response has been described in most animal models of injury including lung injury, hemorrhagic shock, late sepsis, burn injury, and traumatic injury (57)(58)(59)(60)(61)(62)(63)(64). Moreover, similar findings have been described in injured patients (13,65).…”

Complement Component C5a Mediates Hemorrhage-Induced Intestinal Damage

“…Mice undergoing hemorrhage were subjected to retro-orbital removal of 25% of the calculated blood volume (approximately 0.5 ml) over a 90 sec period (25,26). Volume of blood to be removed was based on weight and ranged from 400 ul to 600 ul; (body weight in grams x 0.02 (27)). The determined blood volume was measured in water and marked on both the collection tubes and the capillary tubing used for retro-orbital punctures.…”

Comparison of longitudinal leukocyte gene expression after burn injury or trauma-hemorrhage in mice

“…This assumption has been supported by investigations of inflammatory and counter inflammatory reactions commonly seen early after traumatic, thermal, or major surgical procedure (2,17,21,23,27,30,32). However, surgeons and critical care specialists have also recognized that patients who have suffered major burns often have a clinical course quite different from that of patients who have sustained significant traumatic injury (12,29,30,33).…”