Immunopathology and Dexamethasone Therapy in a New Model for Malaria-associated Acute Respiratory Distress Syndrome
Immunopathology and Dexamethasone Therapy in a New Model for Malaria-associated Acute Respiratory Distress Syndrome
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DOI：
10.1164/rccm.200905-0786oc
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发表时间：
2010-05-01
影响因子：
24.7
通讯作者：
Opdenakker, Ghislain
中科院分区：
文献类型：
--
作者：
Van den Steen, Philippe E.;Geurts, Nathalie;Opdenakker, Ghislain
基本原理：疟疾感染常并发疟疾相关急性呼吸窘迫综合征（MA-ARDS），其特征为肺水肿和肺水肿。方法：用伯氏疟原虫（PlasmodiumbergheiNK 65）感染C57 BL/6小鼠，通过肺重量、组织病理学和支气管肺泡灌洗等方法观察MA-ARDS的发生发展。细胞因子和趋化因子在肺中的表达进行了分析，通过逆转录-聚合酶链反应，和白细胞亚类的积累，通过流式细胞仪analysis.Measurements和主要结果：在这个模型中，几种细胞因子和趋化因子的肺表达增加到一个更高的水平比感染疟原虫chabaudi AS，这不会导致MA-ARDS的小鼠。通过耗竭实验，CD 8（+）T淋巴细胞显示出致病性。高剂量的地塞米松阻断MA-ARDS，即使当给药后出现的并发症，减少肺白细胞的积累和表达的单核细胞/巨噬细胞吸引chemokine.Conclusions：我们开发了一种新的模型MA-ARDS与许多相似之处，人类MA-ARDS，没有脑并发症。这与更经典的伯氏疟原虫ANKA模型形成对比，其特征在于暴发性脑型疟疾。因此，感染伯氏疟原虫NK 65产生了更宽的时间窗来研究发病机制和评价候选治疗。高剂量地塞米松治愈MA-ARDS的发现表明，它可能比在脑型疟疾的临床试验中对MA-ARDS更有效。
Rationale: 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.Objectives: Development of a new animal model for MA-ARDS to explore the pathogenesis and possible treatments.Methods: 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.Measurements and Main Results: 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.Conclusions: 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.