Integrin αDβ2 (CD11d/CD18) mediates experimental malaria-associated acute respiratory distress syndrome (MA-ARDS).
Integrin αDβ2 (CD11d/CD18) mediates experimental malaria-associated acute respiratory distress syndrome (MA-ARDS).
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DOI：
10.1186/s12936-016-1447-7
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发表时间：
2016-07-30
期刊：
影响因子：
3
通讯作者：
Castro-Faria-Neto HC
中科院分区：
文献类型：
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作者：
de Azevedo-Quintanilha IG;Vieira-de-Abreu A;Ferreira AC;Nascimento DO;Siqueira AM;Campbell RA;Teixeira Ferreira TP;Gutierrez TM;Ribeiro GM;E Silva PM;Carvalho AR;Bozza PT;Zimmerman GA;Castro-Faria-Neto HC
疟疾相关急性呼吸窘迫综合征(MA-ARDS)是临床疟疾的一种潜在致命性并发症。MA-ARDS的急性肺损伤与其他原因引发的ARDS相似，包括肺泡炎和肺泡毛细血管通透性增加，导致富含蛋白质的肺水肿液泄漏。MA-ARDS的机制和生理变化可以在这种综合征的小鼠模型中进行研究。整合素αDβ2是整合素亚家族中白细胞的一员，新的研究表明它在白细胞的黏附、聚集和信号转导中具有重要的活性。目的是对野生型C57BL/6(ad+/+)和剔除C57BL/6(ad−/−)小鼠的肺进行分析，以更好地确定这两种小鼠模型的相关性，并探讨其发病机制。用105只伯氏疟原虫ANKA感染C57BL/6野生型(ad+/+)和CD11d亚单位缺失(ad−/−)小鼠。实时定量聚合酶链式反应检测CD11d亚单位表达RNA，伊文思蓝拒染法检测血管屏障完整性，ELISA法检测细胞因子。测定支气管肺泡灌洗液(BALF)中的蛋白质和白细胞。点计数法检测组织细胞密度，免疫组织化学方法检测F4/80和VCAM-1的表达。采用无创BUXCO呼吸机和机械通气机进行呼吸功能分析。感染伯氏疟原虫的野生型小鼠肺泡炎症、单核细胞和巨噬细胞的血管和间质聚集，肺泡-毛细血管屏障功能紊乱，并伴有富含蛋白的肺水肿液的渗出，在αDβ2基因缺陷的小鼠中得到改善。αD−/−小鼠的肺组织中关键的促炎细胞因子也减少了，这为减少肺泡毛细血管炎症和渗漏提供了机制解释。结果表明，αDβ2是伯氏疟原虫致急性呼吸窘迫综合征的重要炎症效应分子，白细胞整合素在复杂疟疾模型中调节关键的炎症和病理生理事件。小鼠整合素亚单位αD基因缺失，导致整合素αDβ2缺失，可改变伯氏假单胞菌致急性呼吸窘迫综合征小鼠的肺部炎症和急性肺损伤。
Malaria-associated acute respiratory distress syndrome (MA-ARDS) is a potentially lethal complication of clinical malaria. Acute lung injury in MA-ARDS shares features with ARDS triggered by other causes, including alveolar inflammation and increased alveolar-capillary permeability, leading to leak of protein-rich pulmonary oedema fluid. Mechanisms and physiologic alterations in MA-ARDS can be examined in murine models of this syndrome. Integrin αDβ2 is a member of the leukocyte, or β2 (CD18), sub-family of integrins, and emerging observations indicate that it has important activities in leukocyte adhesion, accumulation and signalling. The goal was to perform analysis of the lungs of mice wild type C57Bl/6 (aD+/+) and Knockout C57Bl/6 (aD−/−) with malaria-associated acute lung injury to better determine the relevancy of the murine models and investigate the mechanism of disease. C57BL/6 wild type (aD+/+) and deficient for CD11d sub-unit (aD−/−) mice were monitored after infection with 105Plasmodium berghei ANKA. CD11d subunit expression RNA was measured by real-time polymerase chain reaction, vascular barrier integrity by Evans blue dye (EBD) exclusion and cytokines by ELISA. Protein and leukocytes were measured in bronchoalveolar lavage fluid (BALF) samples. Tissue cellularity was measured by the point-counting technique, F4/80 and VCAM-1 expression by immunohistochemistry. Respiratory function was analysed by non-invasive BUXCO and mechanical ventilation. Alveolar inflammation, vascular and interstitial accumulation of monocytes and macrophages, and disrupted alveolar-capillary barrier function with exudation of protein-rich pulmonary oedema fluid were present in P. berghei-infected wild type mice and were improved in αDβ2-deficient animals. Key pro-inflammatory cytokines were also decreased in lung tissue from αD−/− mice, providing a mechanistic explanation for reduced alveolar-capillary inflammation and leak. The results indicate that αDβ2 is an important inflammatory effector molecule in P. berghei-induced MA-ARDS, and that leukocyte integrins regulate critical inflammatory and pathophysiologic events in this model of complicated malaria. Genetic deletion of integrin subunit αD in mice, leading to deficiency of integrin αDβ2, alters lung inflammation and acute lung injury in a mouse model of MA-ARDS caused by P. berghei.