Use of methotrexate associated with lipid nanoparticles in the treatment of acute rejection of transplanted heart in rabbits

Abstract

Heart transplantation is the treatment of choice for refractory heart failure, despite the great improvement in life expectancy with clinical treatment. The prevention of acute rejection still presents important challenges in diagnosis and therapy, with 20-40% of transplant patients having an episode of acute cellular rejection in the first year after transplantation. A cholesterol-rich (LDE) nanoparticle, with a lipid composition similar to natural LDL, is concentrated in inflammatory and proliferative tissues. In a graft vascular disease model, methotrexate (MTX) associated with LDE decreased coronary stenosis in graft vascular disease, macrophage infiltration and gene expression of inflammatory cytokines in the myocardium of the transplanted heart.OBJECTIVE: To evaluate the effect of LDE-MTX treatment on the acute rejection of the transplanted heart in a rabbit heterotopic heart transplant model.METHODS: Red New Zealand rabbits will be the donors and white New Zealand rabbits will be the recipients of heterotopic heart transplantation. The transplanted animals will be divided into 2 protocols. Protocol 1: the post-transplantation graft viability time will be evaluated, allocated into 3 groups: Group I: 10 animals will receive LDE without the drug; Group II: 10 animals will receive commercial MTX at a dose of 8 mg/kg of weight; Group III: 10 animals will receive LDE-MTX at a dose of 8 mg/kg. Protocol 2: the efficiency of treatments in acute cellular rejection will be evaluated, allocated into 3 groups: Group I: 10 animals will receive LDE without the drug; Group II: 10 animals will receive commercial MTX at a dose of 8 mg/kg of weight; Group III: 10 animals will receive LDE-MTX at a dose of 8 mg/kg. At the end of the protocol, echocardiography will be performed and the animals will be euthanized for studies of cell death, inflammatory process, metalloproteinases and fibrosis by morphological and molecular analyzes of transplanted and native hearts. (AU)