Differential Effects of Brain Death on Rat Microcirculation and Intestinal Inflammation: Female Versus Male

Abstract

Brain death (BD) affects organs by multiple mechanisms related to hemodynamic effects, hormonal changes, and the systemic inflammatory response, which reduce organ function and viability. BD reduces microcirculatory perfusion in rat mesentery; this disturbance is also observed in the pancreas and lungs. Sex hormones can affect microcirculatory function, altering tissue perfusion and influencing the inflammatory process. Here, we present differences between sexes in the microcirculatory alterations generated by BD and in inflammatory infiltrate. Male, female, and ovariectomized-female Wistar rats were submitted to BD by intracranial balloon catheter sudden inflation. BD was confirmed by maximally dilated and fixed pupils, apnea, absence of reflexes, and a drop in mean arterial pressure. Perfusion and flow of the mesenteric microcirculation were analyzed. Intestinal myeloperoxidase activity and leukocyte infiltration were quantified. ELISA quantified serum estradiol, corticosterone, and inflammatory mediators, whereas expression of eNOS, endothelin, and endothelial adhesion molecule was measured by immunohistochemistry. Male rats presented lower percentages of mesenteric perfused microvessels and reduced blood flow compared to females. The female group presented higher eNOS and endothelin expression. Leukocyte infiltration into intestinal walls was higher in females in comparison to that in males. Moreover, the female group showed higher mesenteric vessel ICAM-1 expression than males, whereas serum TNF-α, IL-1β, and IL-10 levels did not differ between sexes. The high estradiol concentration before BD and high eNOS expression apparently favored the maintenance of microvascular perfusion/flow; however, BD caused an acute reduction of female sex hormone concentration and higher ICAM-1 level; thus, the proinflammatory organ status after BD is favored.

FGF15 improves outcomes after brain dead donor liver transplantation with steatotic and non-steatotic grafts in rats

“…34 To the best of our knowledge, only 1 study evaluates the impact of sex on BD-induced intestinal inflammation. 35 It indicates that intestinal inflammation induced by BD is more common in females, but without correlation between inflammatory cytokines and neutrophil infiltration. The effects on liver grafts were not elucidated in that study; but it should be noted that female sex hormones (mainly estradiol) play an important role in regulating inflammation and in the functionality of various organs.…”

Sex differences in the coagulation process and microvascular perfusion induced by brain death in rats

“…It is important to consider that platelet activity may be negatively modulated by substances such as NO which is released by several cells [29]. As mentioned earlier, female rats present a higher inflammatory response after BD and higher iNOS and eNOS expression than male rats [12,13]. Srihirun et al [30] showed that there is an inverse correlation between nitrite levels in the blood and ADP-induced platelet aggregation.…”

“…Along with hypoperfusion, BD leads to the activation of the inflammatory pathways and reduction in hormone synthesis and release [9,13]. BD‐generated inflammatory response is higher in female animals, occurring in parallel with the acute reduction in female sex hormone concentration [12,13]. Here, in order to investigate the sex‐influenced differences in the coagulation process after BD, thromboelastometry analysis was conducted and the different pathways involved in the coagulation cascade were evaluated.…”

“…Previous studies have pointed to microcirculatory changes in male rats subjected to BD, suggesting that hypoperfusion could reduce the viability of various organs [5–11]. In female rats, the initially high estradiol concentration before BD and elevated expression of eNOS seemed to favour the maintenance of microvascular perfusion/flow [12]. In this context, despite better perfusion, female rats present higher inflammatory infiltrates in the organs and higher concentrations of inflammatory markers associated with female sex hormone reduction [13].…”

Metformin Preconditioning and Postconditioning to Reduce Ischemia Reperfusion Injury in an Isolated Ex Vivo Rat and Porcine Kidney Normothermic Machine Perfusion Model

“…Therefore, potential gender effects could have arisen, as previous studies showed differences in effects of brain death on IRI and microcirculation between sexes. 23,24 Moreover, even sex-dependent differences in the anticancer effects of metformin have been reported. 25 Whether this is also the case with metformin used in transplantation settings is worth elucidating.…”