FK409 inhibits both local and remote organ damage after intestinal ischaemia

Abstract

In addition to localized tissue injury, intestinal ischaemia-reperfusion (I/R) leads to remote organ damage, in particular to the lungs. Given that nitric oxide (NO) can attenuate I/R-induced tissue injury in many situations, this study evaluated the effects of the NO donor, FK409, on leukocyte adhesion in the microcirculation of the intestinal villus and also assessed pulmonary tissue damage after intestinal I/R injury. PVG rats were subjected to 30 min intestinal ischaemia and a sub-group of animals received the NO donor FK409 (10 mg/kg; i.v.) both 30 min prior to ischaemia and 30 min post-reperfusion. The intestinal mucosal surface was visualized via an incision made in an exteriorized ileal segment and leukocyte adhesion in the villous microcirculation was determined by in vivo microscopy. Total and differential leukocyte counts from peripheral blood were evaluated. Lungs were removed at the end for histological assessment. Six out of ten untreated I/R animals failed to survive the 2 h reperfusion period, whereas all ten FK409-treated animals survived. I/R induced a significant increase in villous leukocyte adhesion of untreated I/R animals (p<0.001) and this was significantly decreased by FK409 treatment (p<0.001). The total leukocyte count was significantly decreased in untreated I/R animals (p<0.001) and this primarily resulted from a reduction in circulating neutrophil numbers. This effect was not observed in FK409-treated animals. Collapsed alveoli, thickened interstitial walls, and a dense neutrophilic infiltrate were apparent in the lungs of untreated I/R animals, whereas lung histology was normal in FK409-treated animals. In conclusion, FK409 prevented mortality, significantly reduced villous leukocyte adhesion, maintained circulating leukocyte numbers, and prevented pulmonary tissue injury following intestinal I/R. FK409 may therefore be of value in reducing both local and remote tissue damage and improving outcome in situations where intestinal I/R injury is obligatory, such as small bowel transplantation.

The Novel NF-κB Inhibitor, Dehydroxymethylepoxyquinomicin, Prevents Local and Remote Organ Injury Following Intestinal Ischemia/Reperfusion in Rats

“…It is well known that the serum levels of TNF-␣, IL-1, or IL-6 are elevated after intestinal reperfusion and that these pro-inflammatory cytokine levels reflect animal mortality [22][23][24][25]. The biological properties of TNF-␣ and IL-1 are very similar in that they are primarily released from macrophages during the early phase of an inflammatory response, and they stimulate endothelial cells and macrophages to release IL-6 and IL-8 [26,27].…”

Pyrrolidine dithiocarbamate protects the small bowel from warm ischaemia/reperfusion injury of the intestine: the role of haem oxygenase

“…Microscopically, the areas of necroses were associated with total stasis of blood flow. This patchy response is consistent with previous studies [1,17]. Because of this patchy response, the antimesenteric incision for the exposure of the mucosa was made in a relatively viable segment of the ileum which was associated with an area of reflow in order to study the effects of IR injury and PDTC.…”

Mannitol attenuates acute lung injury induced by infrarenal aortic occlusion-reperfusion in rats

“…Collectively, these observations give the appearance of a dense interstitium. 35 Some of these changes can be seen within minutes after reperfusion. Acute lung injury seen in our study is consistent with that described by others, with diffuse, patchy hemorrhage observed grossly, and interstitial and intra-alveolar edema, alveolar hemorrhage, and fi brin microthrombi seen on microscopic examination.…”