Hemodynamics, metabolic and cytoprotective effects of anti-TNF-alpha antibody for intestinal ischemia/reperfusion injury

• Grant number: 06/02555-6
• Support Opportunities: Regular Research Grants
• Duration: November 01, 2007 - October 31, 2009
• Field of knowledge: Health Sciences - Medicine - Surgery
• Principal Investigator: Ruy Jorge Cruz Junior
• Grantee: Ruy Jorge Cruz Junior
• Host Institution: Instituto do Coração Professor Euryclides de Jesus Zerbini (INCOR). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

Intestinal transplantation has become the end-point treatment for patients who undergo intestinal failure and do not stand for long-lasting parenteral nutrition. The use of a third drug associated to Tacrolimus and steroids aims to reduce the toxicity of tacrolimus by reducing its dose. Some advantages have been shown on the association of monoclonal antibodies. Isquemia and reperfusion cause endothelial damage and activates the inflammatory cascade. The most expressive inflammatory mediators on intestinal transplantation are Tumoral necrosis factor-alpha, Interferon-gamma, 1-beta, 2 and 6 IL. TNF-alpha blockers may induce an expressive improvement on imune-mediated deseases. We intend to evaluate the hemodynamics, metabolic and cytoprotective effects of anti-TNF-alpha antibody for intestinal ischemia/reperfusion injury Material and method: 20 pigs (Minipig Br1) will be randomly assigned to two groups: GI (control) e GII (Infliximab). Anesthesia and surgical preparation will follow an established protocol. Justa after venous access, Group I will recieve 250ml of saline and Group II will recieve Infliximab (5mg/kg)diluted in 250ml of saline. 60 minutes of isquemia will be followed by a 240 min period of reperfusion. Cardiac frequency, mean arterial blood pressure, mean pulmonary blood pressure, blood flow at hepatic artery, porta and superior mesenteric veins will be observed continuously. Cardiac output, the mucosal carbon dioxide partial and central venous pressure will be measured at intervals. Systemic, lung and regional vascular resistance pressure will be calculated in specific formula the gradient established between mucosal and respiratory PCO2 will be set as PCO2-gap. Mucosal pH will be calculated from PrCO2, HCO3- and plasma solubility of CO2 (0,031) in a specific formula. Arterial, venous, portal and mesenteric blood samples will be analyzed for blood gas, hemoglobin, hematocrit, lactate, glucose, sodium and calcium by a Stat-Profile Ultra-C analyzer (Nova Biomedical, Walthan, MA, EUA). TNF-alpha, IL-1-beta, Il-2, IL-6 e INF-gamma will be measured at the reperfusion period. Tissue specimens will be formalin-fixed for HE and imunohistoquemistry. (Caspase 3 and MPO) for cellular apoptosis. At the end of the experiment, the animals will be euthanized with bolus injection of pentobarbital followed by 40 ml of KCl 19,1%. Statistics: Variance analysis of the median results among the different experimental moments. A p<0,05 will be considered. (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)

CRUZ, JR., RUY J.; GARRIDO, ALEJANDRA G.; CALY, DECIO DE NATALE; ROCHA-E-SILVA, MAURICIO. Hepatosplanchnic Vasoregulation and Oxygen Consumption During Selective Aortic Blood Flow Reduction and Reperfusion. JOURNAL OF SURGICAL RESEARCH, v. 171, n. 2, p. 532-539, DEC 2011. (06/02555-6)

CRUZ, JR., RUY J.; GARRIDO, ALEJANDRA G.; RIBEIRO, CRISTIANE M. F.; HARADA, TOMOYUKI; ROCHA-E-SILVA, MAURICIO. Regional Blood Flow Distribution and Oxygen Metabolism During Mesenteric Ischemia and Congestion. JOURNAL OF SURGICAL RESEARCH, v. 161, n. 1, p. 54-61, JUN 1 2010. (06/02555-6)

CRUZ JUNIOR, RUY J.; GARRIDO, ALEJANDRA G.; E SILVA, MAURICIO ROCHA. Early hemodynamics and metabolic changes after total abdominal evisceration for experimental multivisceral transplantation. Acta Cirurgica Brasileira, v. 24, n. 2, p. 156-161, MAR-APR 2009. (06/02555-6)