Laboratory of Immunobiology, Rega Institute for Medical Research, Catholic University of Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium.
Am J Respir Crit Care Med. 2010 May 1;181(9):957-68. doi: 10.1164/rccm.200905-0786OC. Epub 2010 Jan 21.
Malaria infection is often complicated by malaria-associated acute respiratory distress syndrome (MA-ARDS), characterized by pulmonary edema and hemorrhages. No efficient treatments are available for MA-ARDS and its pathogenesis remains poorly understood.
Development of a new animal model for MA-ARDS to explore the pathogenesis and possible treatments.
C57BL/6 mice were infected with Plasmodium berghei NK65, and the development of MA-ARDS was evaluated by the analysis of lung weight, histopathology, and bronchoalveolar lavages. Cytokine and chemokine expression in the lungs was analyzed by reverse transcription-polymerase chain reaction, and the accumulation of leukocyte subclasses was determined by flow cytometric analysis.
In this model, the pulmonary expression of several cytokines and chemokines was increased to a higher level than in mice infected with Plasmodium chabaudi AS, which does not cause MA-ARDS. By depletion experiments, CD8(+) T lymphocytes were shown to be pathogenic. High doses of dexamethasone blocked MA-ARDS, even when administered after appearance of the complication, and reduced pulmonary leukocyte accumulation and the expression of a monocyte/macrophage-attracting chemokine.
We developed a novel model of MA-ARDS with many similarities to human MA-ARDS and without cerebral complications. This contrasts with the more classical model with P. berghei ANKA, characterized by fulminant cerebral malaria. Hence, infection with P. berghei NK65 generates a broader time window to study the pathogenesis and to evaluate candidate treatments. The finding that high doses of dexamethasone cured MA-ARDS suggests that it might be more effective against MA-ARDS than it was in the clinical trials for cerebral malaria.
疟疾感染常伴有疟疾相关的急性呼吸窘迫综合征（MA-ARDS），其特征为肺水肿和出血。目前尚无有效的治疗方法，其发病机制也知之甚少。
建立一个新的 MA-ARDS 动物模型，以探讨其发病机制和可能的治疗方法。
用 Plasmodium berghei NK65 感染 C57BL/6 小鼠，通过肺重分析、组织病理学和支气管肺泡灌洗来评估 MA-ARDS 的发生。用反转录聚合酶链反应分析肺组织中细胞因子和趋化因子的表达，并用流式细胞术分析白细胞亚群的积聚。
在该模型中，几种细胞因子和趋化因子在肺部的表达水平高于不引起 MA-ARDS 的 Plasmodium chabaudi AS 感染的小鼠。通过耗竭实验，发现 CD8(+) T 淋巴细胞是致病的。大剂量地塞米松可阻断 MA-ARDS 的发生，即使在并发症出现后给予治疗也有效，且可减少肺部白细胞的积聚和单核细胞/巨噬细胞趋化因子的表达。
我们建立了一个新的 MA-ARDS 模型，与人类 MA-ARDS 有许多相似之处，且没有脑部并发症。这与更经典的用 P. berghei ANKA 感染建立的模型形成对比，后者的特点是暴发性脑型疟疾。因此，用 P. berghei NK65 感染可以产生更宽的时间窗口来研究发病机制和评估候选治疗方法。大剂量地塞米松治疗 MA-ARDS 有效的发现提示其可能比临床试验中的脑型疟疾更有效。
