Avaliação do efeito do inibidor da enzima xantina oxidase (alopurinol) no modelo murino de angiogênese inflamatória

Abstract

Xanthine oxidase inhibitors, key regulators of reactive oxygen species, have been used in the treatment of various ischemic conditions and vascular lesions, besides their classical use in hyperurecemia and gout. Here, we have evaluated the effects of allopurinol on inflammatory angiogenesis induced by subcutaneous implantation of polyether-polyurethane matrix in C57/BL6 mice. Groups of animals (n=8 - 15) that received oral administration of allopurinol (0.01, 0.1 or 1.0 mg/kg) were treated 24h after implantation, during the acute formation of the fibrovascular tissue. Another group of animals (n= 9) were treated with allopurinol (1.0 mg/kg) 8 days after implantation for 6 consecutive days (chronic phase). Angiogenesis, was determined by hemoglobin content, VEGF levels and number of vessels intraimplant, inflammation (myeloperoxidase –MPO, n-acetyl-β-D glucosaminidase –NAG, TNF-α and CCL2 levels) were reduced by allopurinol. Similarly, the treatment inhibited nitric oxide and H2O2 production. However, fibrogenesis determined by collagen deposition and levels of TGF-β1 increased in the implants after allopurinol treatment. In marked contrast with the effects of the treatment initiated on the acute phase of the process, allopurinol increased angiogenesis, inflammation, NO, and H2O2 production but reduced collagen and TGF-β1 levels intraimplant when the treatment was started during the chronic inflammatory process. The dual effects of allopurinol described here, extend its range of actions as a potential agent able to modulate the components of the fibrovascular tissue present in both physiological (healing processes) as well as in chronic fibroprolifertive diseases. This modulatory effects depends of thephase at which is treatment is initiated that in turn is dependent on the generation of ROS.