Effect of intestinal ischemia and reperfusion on intestinal contraction, generation of inflammatory mediators and mesenteric microcirculation. role of gender and lymphatic system

• Grant number: 13/15291-0
• Support Opportunities: Regular Research Grants
• Duration: October 01, 2013 - February 29, 2016
• Field of knowledge: Biological Sciences - Pharmacology - General Pharmacology
• Principal Investigator: Wothan Tavares de Lima
• Grantee: Wothan Tavares de Lima
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Ana Cristina Breithaupt Faloppa ; Bernardo Boris Jorge Vargaftig

Abstract

Intestinal Ischemia and reperfusion (intestinal I/R) can cause local lesions, bacterial translocation, systemic inflammation and multiple organ failure. Notably, intestinal I/R is clinically relevant by triggering acute lung inflammation, which in severe cases may evolve to acute respiratory distress syndrome (ARDS). The etiology of intestinal I/R includes arterial embolism, arterial thrombosis, splanchnic vasoconstriction or venous thrombosis. Other causes of intestinal I/R include surgical procedures for aorta aneurism repair, heart-lung bypass and small intestine transplantations.The metabolic and functional alterations that occur in the course of an intestinal I/R event stimulate an immune response, which in turn mediates the intestinal lesion. Regarding the origin of the systemic inflammation, the intestinal reperfusion contributes for its installation, since toxic products and inflammatory mediators generated during the period of ischemia are thereby systemically disseminated. It is noteworthy that some functional alterations of the mesenteric microcirculation that occur during the periods of hypoperfusion overcome the intestinal compensatory mechanisms which are called into play to maintain homeostasis. As a consequence, there is a rise in the volume and pressure of the interstitial fluid, a fact which may impair the physiology of lymph pumping.Studies from our laboratory demonstrated that the lymph from mesentery is rich in cytokines and eicosanoids. Thus, after an intestinal I/R, the intestine is maintained in a 'pro-reactive state' to generate inflammatory mediators which are transported by the lymph system and reach lung, thus contributing for the acute lung lesion. In this context, it is noteworthy that there are gender-related differences as far as the role of the lymphatic system is concerned. In fact, our preliminary data obtained in female rats subjected to obstruction of thoracic lymph flow revealed that such an obstruction exacerbates lung and intestinal inflammation after intestinal I/R. Interestingly, this event was not found in males. Overall, these data suggest that the response of small intestines to intestinal I/R may be modulated by female sex hormones and by the lymphatic system. There are remarkable evidences that men and women present different reactions to trauma, including intestinal injury. Clinical and experimental studies suggest that females are more tolerant to injury than males. However, available data show that women are more sensitive to the deleterious effects of sepsis, and that women present higher mortality rates. Being so, the role of sex hormones in those events is not totally identified. This study is based on the following facts: 1. estradiol can modulate the functional activity of organs and systems after an intestinal injury; 2. receptors for estradiol are present in immune cells; 3. the lymphatic system acts as a path to inflammatory mediators produced in the gut; 4. the quality of estradiol effects may be gender-dependent. Accordingly, the objectives of the present study are to investigate gender-related differences in the magnitude of intestinal repercussions (gut contractility, generation of inflammatory mediators, alterations of mesenteric microcirculation) and of lung inflammation triggered by an intestinal I/R, with emphasis on the role of estradiol. In parallel, studies regarding the importance gender-related differences of lymph drainage will be conducted. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

RICARDO-DA-SILVA, FERNANDA YAMAMOTO; FANTOZZI, EVELYN THAIS; RODRIGUES-GARBIN, SARA; OLIVEIRA-FILHO, RICARDO MARTINS; VARGAFTIG, BERNARDO BORIS; BREITHAUPT-FALOPPA, ANA CRISTINA; DE LIMA, WOTHAN TAVARES. ESTRADIOL MODULATES LOCAL GUT INJURY INDUCED BY INTESTINAL ISCHEMIA-REPERFUSION IN MALE RATS. Shock, v. 48, n. 4, p. 477-483, OCT 2017. (13/15291-0)

RICARDO-DA-SILVA, FERNANDA YAMAMOTO; FANTOZZI, EVELYN THAIS; RODRIGUES-GARBIN, SARA; DOMINGOS, HELORI VANNI; OLIVEIRA-FILHO, RICARDO MARTINS; VARGAFTIG, BERNARDO BORIS; RIFFO-VASQUEZ, YANIRA; BREITHAUPT-FALOPPA, ANA CRISTINA; TAVARES-DE-LIMA, WOTHAN. Estradiol prevented intestinal ischemia and reperfusion-induced changes in intestinal permeability and motility in male rats. Clinics, v. 76, 2021. (13/15291-0)