Department of Biochemistry and Immunology, Institute of Biological Science, Federal University of Minas Gerais, Belo Horizonte, Brazil.
Adv Parasitol. 2011;76:1-31. doi: 10.1016/B978-0-12-385895-5.00001-3.
Chagas disease is caused by Trypanosoma cruzi, a protozoan parasite. Chagas disease remains a serious health problem in large parts of Mexico and Central and South America, where it is a major cause of morbidity and mortality. This disease is being increasingly recognized in non-endemic regions due to immigration. Heart disease develops in 10-30% of infected individuals. It is increasingly clear that parasite- and host-derived bioactive lipids potently modulate disease progression. Many of the changes that occur during acute and chronic Chagas disease can be accounted for by the effects of arachidonic acid (AA)-derived lipids such as leukotrienes, lipoxins, H(P)ETEs, prostaglandins (PGs) and thromboxane. During the course of infection with T. cruzi, changes in circulating levels of AA metabolites are observed. Antagonism of PG synthesis with cyclooxygenase (COX) inhibitors has both beneficial and adverse effects. Treatment with COX inhibitors during acute infection may result in increased parasite load and mortality. However, treatment instituted during chronic infection may be beneficial with no increase in mortality and substantial improvement with cardiac function. Recently, T. cruzi infection of mice deficient in AA biosynthetic enzymes for various pathways has yielded more insightful data than pharmacological inhibition and has highlighted the potential deleterious effects of inhibitors due to "off-target" actions. Using COX-1 null mice, it was observed that parasite biosynthesis is dependent upon host metabolism, that the majority of TXA(2) liberated during T. cruzi infection is derived from the parasite and that this molecule may act as a quorum sensor to control parasite growth/differentiation. Thus, eicosanoids present during acute infection may act as immunomodulators aiding the transition to, and maintenance of, the chronic stage of the disease. It is also likely that the same mediators that initially function to ensure host survival may later contribute to cardiovascular damage. Collectively, the eicosanoids represent a new series of targets for therapy in Chagas disease with defined potential therapeutic windows in which to apply these agents for greatest effect. A deeper understanding of the mechanism of action of non-steroidal anti-inflammatory drugs may provide clues to the differences between host responses in acute and chronic T. cruzi infection.
恰加斯病是由克氏锥虫引起的原生动物寄生虫病。恰加斯病在墨西哥和中美洲及南美洲的大部分地区仍然是一个严重的健康问题，是发病率和死亡率的主要原因。由于移民，这种疾病在非流行地区的认识度越来越高。在感染的 10-30%的个体中会发展成心脏病。越来越明显的是，寄生虫和宿主来源的生物活性脂质可有效地调节疾病进展。急性和慢性恰加斯病期间发生的许多变化可以归因于花生四烯酸（AA）衍生脂质的作用，如白三烯、脂氧素、H（P）ETE、前列腺素（PG）和血栓素。在感染克氏锥虫的过程中，观察到循环 AA 代谢物水平的变化。环氧化酶（COX）抑制剂对 PG 合成的拮抗作用既有有益作用也有不利作用。在急性感染期间用 COX 抑制剂治疗可能导致寄生虫负荷增加和死亡率增加。然而，在慢性感染期间进行治疗可能是有益的，不会增加死亡率，并可显著改善心脏功能。最近，用各种途径缺乏 AA 生物合成酶的小鼠进行克氏锥虫感染的研究产生了比药理学抑制更有洞察力的数据，并强调了抑制剂由于“脱靶”作用而可能产生的有害影响。用 COX-1 缺失小鼠观察到寄生虫的生物合成依赖于宿主代谢，在克氏锥虫感染期间释放的大多数 TXA（2）来源于寄生虫，并且该分子可能作为群体感应分子来控制寄生虫的生长/分化。因此，急性感染期间存在的类二十烷酸可能作为免疫调节剂，有助于疾病的慢性阶段的过渡和维持。最初用于确保宿主存活的相同介质也可能后来导致心血管损伤。总的来说，类二十烷酸代表了恰加斯病治疗的一系列新靶点，在这些靶点中有明确的治疗窗口，可以应用这些药物以达到最大效果。对非甾体抗炎药作用机制的更深入了解可能为急性和慢性克氏锥虫感染中宿主反应的差异提供线索。
