Soluble complement receptor type 1 ameliorates the local and remote organ injury after intestinal ischemia-reperfusion in the rat.

Abstract

We examined the role of C activation in ischemia reperfusion injury by inhibiting C activation in a rat model of mesenteric arterial occlusion. In anesthetized rats, 60 min of mesenteric arterial occlusion was followed by 3 h of reperfusion. PBS alone or containing soluble C receptor 1 (3 or 6 mg) was administered i.v. Controls underwent laparotomy without ischemia. Relative serum C activities were assessed by hemolytic assay, neutrophil (polymorphonuclear leukocyte) sequestration by tissue content of myeloperoxidase (MPO) activity, intestinal mucosal injury by histologic grading, lung vascular permeability by the ratio of bronchoalveolar lavage to blood concentration of radiolabeled BSA, and endothelial cell injury was quantified by measurement of plasma factor VIII-related Ag. After reperfusion, PBS-treated animals had increased intestinal MPO (0.048 +/- 0.007 U/g) compared to sham (0.022 +/- 0.005 U/g (p less than 0.05)) and intestinal mucosal injury score (2.490 +/- 0.221) compared to sham (0.331 +/- 0.045 (p less than 0.05)). Treatment with 6 mg soluble C receptor 1 15 min before reperfusion reduced intestinal MPO (0.017 +/- 0.003 U/g (p less than 0.05)) and mucosal injury (1.733 +/- 0.168 (p less than 0.05)) compared to PBS control. PBS-treated animals also demonstrated increased lung MPO (0.314 +/- 0.025 U/g vs 0.085 +/- 0.018 in sham (p less than 0.05)) and increased lung permeability (bronchoalveolar lavage/blood cpm 11.32 +/- 1.35 x 10(-3) vs sham 2.22 +/- 0.19 x 10(-3) (p less than 0.05)). Treatment with 6 mg soluble C receptor 1 15 min before reperfusion or at reperfusion reduced the lung permeability (bronchoalveolar lavage/blood cpm 3.90 +/- 0.79 x 10(-3) and 5.08 +/- 0.75, respectively (both p less than 0.05)) compared to PBS control, but did not reduce lung MPO (0.342 +/- 0.031 U/g and 0.246 +/- 0.025), respectively. Treatment with sCR1 also reduced the release of factor VIII-related Ag, 5-day mortality, and C hemolytic activity. In this model, C is a major mediator of intestinal injury and extraintestinal injury.

Pyrrolidine Dithiocarbamate Reduces Lung Injury Caused by Mesenteric Ischemia/Reperfusion in a Rat Model

“…The reperfusion‐induced pulmonary microvascular injury in the intestinal ischemia appears to be due largely to neutrophil‐mediated injury [5, 40], and the systemic activation of neutrophils following reperfusion appears to be secondary to mediators such as cytokines and reactive oxygen species [41]. Activated neutrophils increase the degree of injury by further promoting oxidative injury and inflammation.…”

Pyrrolidine Dithiocarbamate Prevents Deleterious Effects of Remote Ischemia/Reperfusion Injury on Healing of Colonic Anastomoses in Rats

“…Further clinical studies are needed to clarify whether PDTC may be a useful therapeutic agent for increasing the safety of the anastomosis during particular operations where remote organ I/R injury occurs.Mesenteric ischemia/reperfusion (I/R) injury is an important clinical problem associated with high morbidity and mortality. It is well documented that reperfusion damage may be more harmful to the tissues than the preceding ischemia, depending on the duration [1,2]. A wide range of cellular events, including production of reactive oxygen species (ROS), complement components, coagulation factors, and proinflammatory and vasoactive mediators such as eicosanoids, nitric oxide, and cytokines from resident and inflammatory cells cause the systemic effects of mesenteric I/R [1,[3][4][5].…”

“…It is well documented that reperfusion damage may be more harmful to the tissues than the preceding ischemia, depending on the duration [1,2]. A wide range of cellular events, including production of reactive oxygen species (ROS), complement components, coagulation factors, and proinflammatory and vasoactive mediators such as eicosanoids, nitric oxide, and cytokines from resident and inflammatory cells cause the systemic effects of mesenteric I/R [1,[3][4][5].…”