Hypoxia combined with Escherichia coli produces irreversible gut mucosal injury characterized by increased intestinal cytokine production and DNA degradation

The objective of the present study was to determine whether hypoxia/reoxyge nation in the absence or presence of intestinal bacteria would affect the i ntegrity of the gut mucosal epithelium (as evidenced by histologic changes) and increase the local production of cytokines (interleukin 6 [IL-6] and t umor necrosis factor [TNF]). Rat ileal mucosal membranes were harvested and their electrophysiologic properties and barrier function were measured ex vivo in the Ussing chamber system. Membranes were exposed to normoxia, norm oxia + Escherichia coli, hypoxia for 40 min followed by normoxia, or hypoxi a for 40 min + E. coli followed by normoxia for 3 h. IL-6 and TNF levels we re measured using cytokine-dependent cellular assays. Morphological changes and the degree of DNA fragmentation were used as quantitative markers of g ut mucosal injury. Mucosal integrity was maintained in the normoxia group. The addition of bacteria increased the IL-6 response and reduced mucosal in tegrity. During the hypoxic period, a transient decline in resistance (R) o ccurred and cytokine production was reduced. In the hypoxic ileal membranes not exposed to E. coli, reoxygenation reversed the change in R and increas ed IL-6 production. The combination of hypoxia/reoxygenation plus E coli ba cterial challenge resulted in the greatest extent of gut mucosal injury and increase in TNF production. The results of this study support the hypothes is that the combination of increased intestinal bacterial levels superimpos ed on an ischemia/reperfusion injury increases the magnitude of gut mucosal injury and the production and subsequent release of proinflammatory cytoki nes.