Organ-specific cytokine gene expression in sepsis - An experimental study in a two-hit septic model

Background: Intestinal ischemia and the subsequent cytokine response are believed to play a pivotal role in the pathogenesis of multiple organ failure after trauma, shock, and sepsis. However, the relative importance of the intestinal inflammatory response in comparison with other organs has not been investigated. Material and Methods: Rats were subjected to 45 min of superior mesenteric artery occlusion (first hit) and intraperitoneal endotoxin (15 mg/kg body weight)/sodium chloride challenge 6 h later (second hit). Plasma tumor necrosis factor-alpha (TNF-α), interleukin-(IL-)6 and IL-10 levels were measured by enzyme-linked immunosorbent assay (ELISA). The mRNA expression of TNF-α, IL-1β, IL-6 and IL-10 in lung, liver, mesenteric lymph node and ileum were determined by competitive reverse transcriptase polymerase chain reaction (RT-PCR). Results: Superior mesenteric artery occlusion and endotoxin challenge led to an early increase of plasma TNF-α and IL-10 levels, while the plasma IL-6 response peaked 3 h after intraperitoneal injection of endotoxin. The mRNA expression of all cytokines was significantly increased in the two-hit compared to the one-hit group. Although cytokine mRNA was expressed in the ileum, all cytokines showed significantly higher mRNA levels in the lungs compared to the other organs in the two-hit group. Even in the one-hit group, the TNF-α mRNA expression in the lung was significantly higher compared to the liver. Conclusions: The lung was the primary source of pro- and anti-inflammatory cytokines compared to all other organs in this two-hit sepsis model. However, the gut could be identified as a site of cytokine gene expression. These results further confirm the concept, that intestinal mediators reach the systemic circulation via the intestinal lymphatic duct and not the portal vein and therefore lead to an inflammatory response of the lung rather than the liver.