The role of estradiol in the maintenance of brain-dead organ donors:from pathophysiology to treatment

Organ transplantation is considered the ideal treatment for some diseases, such as terminal heart failure. Clinical and experimental evidence emphasizes the impact of brain death (BD) on the viability of the organ to be transplanted and highlights the importance of the donor's status in the final results of the transplant. BD affects organ function through several mechanisms, including hemodynamic changes, hormonal changes, and systemic inflammation resulting from the activation of the immune system, characterized by increased release/synthesis of inflammatory mediators, expression of adhesion molecules, and by inflammatory cell infiltrate. Studies confirm the donor's sex as one of the factors that influence the success of organ transplantation and show a worse prognosis in heart transplantation with grafts from women. Female sex hormones participate in modulating the magnitude of the inflammatory response and acute reductions in the concentration of female sex hormones can cause changes in several systems, including the immune system. Importantly, estradiol protects the cardiovascular system against ischemic, inflammatory, and metabolic injuries. Preliminary data indicate an acute reduction in estrogen concentrations and exacerbation of the pulmonary inflammatory process in females after BD. In this context, this thesis aims to describe the effects of female sex hormone modulation on systemic inflammation and organ damage in brain-dead donors. Differences in microcirculatory changes caused by BD and inflammatory mediators between sexes were analyzed. Considering female sex hormones as immunomodulators and the association between severe organ inflammation in female animals after BD with acute estradiol reduction, we investigated the potential therapeutic effects of treatment with 17β-estradiol to mitigate the deleterious process in the heart, lung, and kidney of rats with BD

17β-Estradiol Treatment Protects Lungs Against Brain Death Effects in Female Rat Donor

Background: Brain death (BD) affects the viability of lungs for transplantation. A correlation exists between high lung inflammation after BD and the decrease in female sex hormones, especially estradiol. Therefore, we investigated the effects of 17β-estradiol (E2) treatment on the lungs of female brain dead rats. Methods: Female Wistar rats were divided into 4 groups: BD (submitted to BD for 6 h), sham (false-operated), E2-T0 (treated with E2 immediately after BD; 50 μg/ml, 2 ml/h), and E2-T3 (treated with E2 after 3 h of BD; 50 μg/ml, 2 ml/h). Lung edema, hemorrhage, and leukocyte infiltration were analyzed. Adhesion molecules were evaluated and analysis of NO synthase gene and protein expression was performed using RT-PCR and immunohistochemistry, respectively. Release of chemokines and matrix degradation in the lungs were analyzed. Results: BD increased leukocyte infiltration, as shown by intravital microscopy (P=0.017), bronchoalveolar lavage cell count (P=0.016), the release of inflammatory mediators (P=0.02), and expression of adhesion molecules. BD also increased microvascular permeability and the expression and activity of MMP-9 in the lungs. E2 treatment reduced leukocyte infiltration, especially in the E2-T3 group, release of inflammatory mediators, adhesion molecules, and MMP activity in the lungs. Conclusions: E2 treatment was successful in controlling the lung inflammatory response in females submitted to BD. Our results suggest that E2 directly decreases the release of chemokines, restraining cell traffic into the lungs. Thus, E2 has a therapeutic potential, and its role in improving donor lung quality should be explored further

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

Brain death (BD) leads to a systemic inflammation associated with the activation of coagulation, which could be related to decreased microcirculatory perfusion. Evidence shows that females exhibit higher platelet aggregability than males. Thus, we investigated sex differences in platelets, coagulation and microcirculatory compromise after BD. BD was induced in male and female (proestrus) Wistar rats. After 3 h, we evaluated: (i) intravital microscopy to evaluate mesenteric perfusion and leucocyte infiltration; (ii) platelet aggregation assay; (iii) rotational thromboelastometry; and (iv) SerumNOx-. Female rats maintained the mesenteric perfusion, whereas male reduced percentage of perfused vessels. Male BD presented higher platelet aggregation than the controls. In contrast, female BD had lower platelet aggregation than the control. Thromboelastometry indicated a reduction in clot firmness with increased clotting time in the female group compared with the male group. SerumNOx-level in female BD was higher than that in the male BD and female control. There is sex dimorphism in platelet function and clotting process, which are altered in different ways by BD. Thus, it is possible to connect the reduction in microcirculatory perfusion in males to intravascular microthrombi formation and the maintenance of perfusion in females to a higher inflammatory response and NO synthesis

Glutamine dipeptide supplementation improves clinical responses in patients with diabetic foot syndrome

ABSTRACT The effect of glutamine dipeptide (GDP) supplementation in patients with diabetic foot syndrome was evaluated. A total of 22 patients took part in the study. GDP was supplied in 10 g sachets, and was dissolved in water immediately before use, with ingestion once a day, after lunch or after dinner (20 g/day) over a period of 30 days. Quantification of foot insensitive areas, oxidative stress, blood cytokines, and biochemical, hematological and toxicological parameters was performed before and after GDP supplementation. We observed an increase in blood levels of interferon-&#945; (P=0.023), interferon-&#947; (P=0.038), interleukin-4 (P=0.003), interleukin-6 (P=0.0025), interleukin-7 (P=0.028), interleukin-12 p40 (P=0.017), interleukin-13 (P=0.001), leukocytes (P=0.037), eosinophils (P=0.049), and typical lymphocytes (P<0.001) due to GDP administration. In addition, we observed a reduced number (P=0.048) of insensitive areas on the foot, and reduction (P=0.047) of fasting hyperglycemia. Patients also showed increased blood high density lipoprotein (P<0.01) and protein thiol groups (P=0.004). These favorable results were associated with the absence of renal and hepatic toxicity. These results are of clinical relevance, since supplementation with GDP over 30 days improved clinical responses in patients with diabetic foot syndrome

Outcomes of elective liver surgery worldwide: a global, prospective, multicenter, cross-sectional study

Background: The outcomes of liver surgery worldwide remain unknown. The true population-based outcomes are likely different to those vastly reported that reflect the activity of highly specialized academic centers. The aim of this study was to measure the true worldwide practice of liver surgery and associated outcomes by recruiting from centers across the globe. The geographic distribution of liver surgery activity and complexity was also evaluated to further understand variations in outcomes. Methods: LiverGroup.org was an international, prospective, multicenter, cross-sectional study following the Global Surgery Collaborative Snapshot Research approach with a 3-month prospective, consecutive patient enrollment within January–December 2019. Each patient was followed up for 90 days postoperatively. All patients undergoing liver surgery at their respective centers were eligible for study inclusion. Basic demographics, patient and operation characteristics were collected. Morbidity was recorded according to the Clavien–Dindo Classification of Surgical Complications. Country-based and hospital-based data were collected, including the Human Development Index (HDI). (NCT03768141). Results: A total of 2159 patients were included from six continents. Surgery was performed for cancer in 1785 (83%) patients. Of all patients, 912 (42%) experienced a postoperative complication of any severity, while the major complication rate was 16% (341/2159). The overall 90-day mortality rate after liver surgery was 3.8% (82/2,159). The overall failure to rescue rate was 11% (82/ 722) ranging from 5 to 35% among the higher and lower HDI groups, respectively. Conclusions: This is the first to our knowledge global surgery study specifically designed and conducted for specialized liver surgery. The authors identified failure to rescue as a significant potentially modifiable factor for mortality after liver surgery, mostly related to lower Human Development Index countries. Members of the LiverGroup.org network could now work together to develop quality improvement collaboratives