Influencing the macro- and microcirculatory complications of nonocclusive mesenteric ischemia by complement C5a inhibitor treatments

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Abstract in foreign language

Nonocclusive mesenteric ischemia (NOMI) can develop in the absence of apparent anatomical obstruction of the mesenteric circulation in a variety of low flow states. The pathophysiology of NOMI is unexplored, the early diagnosis is challenging and the available treatments are of questionable effectiveness. In this respect, new experimental models are sought to clarify the exact pathomechanisms and new, effective therapeutic ways are needed to reduce the increasingly high mortality. Our first aim was to develop clinically relevant in vivo models to investigate the macro- and microcirculatory effects of NOMI. Also, we hypothesized the role of complement activation in the acute and subacute consequences of NOMI and our objectives were to characterize the effects of the inhibition of complement protein known as C5a during this condition. Acetyl-peptide-A (AcPepA) is an antisense-homology box-derived peptide, which is capable to inhibit the C5a effects by binding directly to the anaphylatoxin. We hypothesized that the inhibition of C5a can decrease the intensity of inflammatory reactions and in parallel, to normalize the impaired mesenteric circulation. Acute experimental pericardial tamponade (PT) was established in anesthetized minipigs, while partial aorta occlusion (PAO) was induced in rats to investigate the circulatory and inflammatory changes of NOMI in clinically relevant time frames. After the relief of PT, elevated levels of oxidative stress markers and inflammatory mediators were detected in association with the signs of diminished splanchnic microcirculation. 24 hours after PAO the macrocirculatory parameters improved significantly, while the intramural microcirculation was significantly impaired and accompanied by increased leukocyte infiltration. The in vivo histology confirmed the structural and microvascular damage of the mucosa. In both animal models of NOMI, the administration of AcPepA moderated the hemodynamic changes, improved the intramural microcirculation, reduced the inflammatory activations and the histological signs of mucosal damage. In conclusion we can say that our newly developed animal models provide a cross section for events in the short and long time frames and proved to be suitable for the investigations of the pathophysiology of NOMI. The hemodynamic changes in the acute PT together with those observed after PAO suggest that complement activation plays central role in the early and late macro- and microcirculatory disturbances during NOMI. The results suggest that C5a inhibitor treatment influences favourably the hemodynamic effects and reduces the potentially harmful inflammatory activation after experimental NOMI as well.

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