Cassini-Vieira Puebla, Deconte Simone Ramos, Tomiosso Tatiana Carla, Campos Paula Peixoto, Montenegro Cyntia de Freitas, Selistre-de-Araújo Heloisa Sobreiro, Barcelos Lucíola Silva, Andrade Silvia Passos, Araújo Fernanda de Assis
Departamento de Ciências Fisiológicas - ARFIS, Universidade Federal de Uberlândia, Uberlândia, Minas Gerais, Brazil.
Instituto de Genética e Bioquímica - INGEB, Universidade Federal de Uberlândia, Uberlândia, Minas Gerais, Brazil.
Toxicon. 2014 Dec 15;92:81-9. doi: 10.1016/j.toxicon.2014.10.007. Epub 2014 Oct 15.
Integrins are involved in a number of physio-pathological processes including wound healing, chronic inflammation and neoplasias. Blocking its activity is potentially of therapeutic value in these conditions. We investigated whether DisBa-01, a recombinant His-tag RGD-disintegrin from Bothrops alternatus snake venom, could modulate key events (inflammatory cell recruitment/activation, neovascularization and extracellular matrix deposition) of the proliferative fibrovascular tissue induced by polyether polyurethane sponge implants in mice. The hemoglobin content (μg/mg wet tissue), blood flow measurements (laser Doppler perfusion imaging) and number of vessels in the implants, used as indices of vascularization, showed that the disintegrin dose-dependently reduced angiogenesis in the implants relative to the Saline-treated group. DisBa-01 inhibited neutrophil and macrophage content as determined by the myeloperoxidase (MPO) and N-acetyl-β-D-glucosaminidase (NAG) activities, respectively. Similarly, down regulation of the fibrogenic component studied (collagen deposition) was observed in DisBa-01-treated implants. VEGF, bFGF, TNF-α, CXCL1 and CCL2 levels were also decreased by the disintegrin. The inhibitory effect of this αvβ3-blocking disintegrin on the angiogenic, inflammatory, and fibrogenic components of the fibrovascular tissue induced by the synthetic matrix extends the range of DisBa-01 actions and may indicate its therapeutic potential in controlling angiogenesis in fibroproliferative diseases.
整合素参与了许多生理病理过程，包括伤口愈合、慢性炎症和肿瘤形成。在这些情况下阻断其活性可能具有治疗价值。我们研究了来自交替锯鳞蝰蛇毒的重组组氨酸标签RGD-去整合素DisBa-01是否能调节聚醚聚氨酯海绵植入小鼠后诱导的增殖性纤维血管组织的关键事件（炎症细胞募集/激活、新血管形成和细胞外基质沉积）。血红蛋白含量（μg/mg湿组织）、血流测量（激光多普勒灌注成像）和植入物中的血管数量用作血管化指标，结果显示，相对于生理盐水处理组，去整合素剂量依赖性地减少了植入物中的血管生成。分别通过髓过氧化物酶（MPO）和N-乙酰-β-D-氨基葡萄糖苷酶（NAG）活性测定，DisBa-01抑制了中性粒细胞和巨噬细胞含量。同样，在经DisBa-01处理的植入物中观察到所研究的纤维生成成分（胶原蛋白沉积）的下调。去整合素还降低了VEGF、bFGF、TNF-α、CXCL1和CCL2的水平。这种αvβ3阻断去整合素对合成基质诱导的纤维血管组织的血管生成、炎症和纤维生成成分的抑制作用扩展了DisBa-01的作用范围，并可能表明其在控制纤维增生性疾病中的血管生成方面的治疗潜力。
