Oral administration of GW788388, an inhibitor of transforming growth factor beta signaling, prevents heart fibrosis in Chagas disease.
Oral administration of GW788388, an inhibitor of transforming growth factor beta signaling, prevents heart fibrosis in Chagas disease.
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DOI：
10.1371/journal.pntd.0001696
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发表时间：
2012
影响因子：
3.8
通讯作者：
Waghabi MC
中科院分区：
文献类型：
--
作者：
de Oliveira FL;Araújo-Jorge TC;de Souza EM;de Oliveira GM;Degrave WM;Feige JJ;Bailly S;Waghabi MC
由克氏锥虫(T.ruzi)感染引起的恰加斯病是影响心血管系统的死亡和发病的主要原因，而现有的治疗方法在很大程度上是不够的。转化生长因子β(转化生长因子β)参与了毛滴虫侵袭和宿主组织纤维化的几个调节步骤。GW788388是一种新的可口服的转化生长因子βI型和II型受体激酶抑制剂。在目前的工作中，我们在体内研究了它在实验性恰加斯病急性期的作用。用104只克氏毛滴虫(Y株)的锥虫感染雄性瑞士小鼠，并对其进行临床评价。我们发现，感染后3天给药一次(Dpi)可显著降低寄生虫血症，提高存活率，改善心电传导，恢复缝隙连接蛋白43的表达。我们可以进一步证明，这种化合物可以抑制I型胶原和纤维连接蛋白的表达来评估心肌纤维化的发展。有趣的是，我们进一步证明，在急性期末期(20dpi)给予GW788388仍然显著提高了存活率并减少了心肌纤维化(通过Masson的三色染色和I型胶原表达来评估)，在寄生虫生长不再是这一事件的中心的阶段。这项工作证实，抑制转化生长因子？信号通路可以被认为是治疗Chagas病急性期和慢性期症状性心肌病的一种潜在的替代策略。心脏损伤和功能障碍是慢性恰加斯病患者的显著特征，这种疾病是由原虫寄生虫克氏锥虫(T.ruzi)感染引起的，在南美洲和中美洲影响着1000-1200万人。我们的研究小组此前曾报道，转化生长因子β(转化生长因子β)与克氏毛滴虫侵袭和生长的几个调节方面以及宿主组织纤维化有关。在目前的工作中，我们评估了在实验性恰加斯病急性期给予一种转化生长因子？信号的口服抑制剂(GW788388)的治疗作用。GW788388治疗显著降低死亡率和寄生虫血症。心电图显示GW788388治疗能有效保护心脏传导系统，保护缝隙连接斑块分布，避免心肌纤维化的发展。在临床前的小鼠模型中，抑制体内的转化生长因子B信号似乎可以有效地减少弓形虫的感染，并防止心脏损伤。这表明这类分子可能代表了一种新的治疗急慢性恰加斯病的工具，值得进一步的临床前探索。应进一步评估在小鼠模型慢性感染期间应用转化生长因子抑制药，并应设想未来的临床试验。
Chagas disease induced by Trypanosoma cruzi (T. cruzi) infection is a major cause of mortality and morbidity affecting the cardiovascular system for which presently available therapies are largely inadequate. Transforming Growth Factor beta (TGFß) has been involved in several regulatory steps of T. cruzi invasion and in host tissue fibrosis. GW788388 is a new TGFß type I and type II receptor kinase inhibitor that can be orally administered. In the present work, we studied its effects in vivo during the acute phase of experimental Chagas disease. Male Swiss mice were infected intraperitoneally with 104 trypomastigotes of T. cruzi (Y strain) and evaluated clinically. We found that this compound given once 3 days post infection (dpi) significantly decreased parasitemia, increased survival, improved cardiac electrical conduction as measured by PR interval in electrocardiography, and restored connexin43 expression. We could further show that cardiac fibrosis development, evaluated by collagen type I and fibronectin expression, could be inhibited by this compound. Interestingly, we further demonstrated that administration of GW788388 at the end of the acute phase (20 dpi) still significantly increased survival and decreased cardiac fibrosis (evaluated by Masson's trichrome staining and collagen type I expression), in a stage when parasite growth is no more central to this event. This work confirms that inhibition of TGFß signaling pathway can be considered as a potential alternative strategy for the treatment of the symptomatic cardiomyopathy found in the acute and chronic phases of Chagas disease. Cardiac damage and dysfunction are prominent features in patients with chronic Chagas disease, which is caused by infection with the protozoan parasite Trypanosoma cruzi (T. cruzi) and affects 10–12 million individuals in South and Central America. Our group previously reported that transforming growth factor beta (TGFß) is implicated in several regulatory aspects of T. cruzi invasion and growth and in host tissue fibrosis. In the present work, we evaluated the therapeutic action of an oral inhibitor of TGFß signaling (GW788388) administered during the acute phase of experimental Chagas disease. GW788388 treatment significantly reduced mortality and decreased parasitemia. Electrocardiography showed that GW788388 treatment was effective in protecting the cardiac conduction system, preserving gap junction plaque distribution and avoiding the development of cardiac fibrosis. Inhibition of TGFß signaling in vivo appears to potently decrease T. cruzi infection and to prevent heart damage in a preclinical mouse model. This suggests that this class of molecules may represent a new therapeutic tool for acute and chronic Chagas disease that warrants further pre-clinical exploration. Administration of TGFß inhibitors during chronic infection in mouse models should be further evaluated, and future clinical trials should be envisaged.
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DOI：
10.1590/s0074-02762009000900042
发表时间：
2009-07-01
期刊：
Memórias do Instituto Oswaldo Cruz
影响因子：
--
作者：
Marin-Neto, J Antonio;Rassi Jr, Anis;Rassi, Anis
通讯作者：
Rassi, Anis
影响因子：
19.6
作者：
Petersen, M.;Thorikay, M.;Laping, N. J.
通讯作者：
Laping, N. J.
DOI：
10.1645/ge-2396.1
发表时间：
2010-08
期刊：
The Journal of parasitology
影响因子：
--
作者：
Eickhoff CS;Lawrence CT;Sagartz JE;Bryant LA;Labovitz AJ;Gala SS;Hoft DF
通讯作者：
Hoft DF
影响因子：
2.9
作者：
Peng, SB;Yan, L;Yingling, JM
通讯作者：
Yingling, JM
DOI：
10.1590/s0074-02762002000100001
发表时间：
2002-01-01
期刊：
Memórias do Instituto Oswaldo Cruz
影响因子：
--
作者：
Coura, José Rodrigues;Castro, Solange L de
通讯作者：
Castro, Solange L de