Malaria-associated acute respiratory distress syndrome (MA-ARDS) and acute lung injury (ALI) are complications that cause lung damage and often leads to death. The MA-ARDS/ALI is associated with a Type 1 inflammatory response mediated by T lymphocytes and IFN-γ. Here, we used the Plasmodium berghei NK65 (PbN)-induced MA-ALI/ARDS model that resembles human disease and confirmed that lung CD4⁺ and CD8⁺ T cells predominantly expressed Tbet and IFN-γ. Surprisingly, we found that development of MA-ALI/ARDS was dependent on functional CCR4, known to mediate the recruitment of Th2 lymphocytes and regulatory T cells. However, in this Type 1 inflammation-ARDS model, CCR4 was not involved in the recruitment of T lymphocytes, but was required for the emergence of TNF-α/iNOS producing dendritic cells (Tip-DCs) in the lungs. In contrast, recruitment of Tip-DCs and development of MA-ALI/ARDS were not altered in CCR2^-/- mice. Importantly, we showed that NOS2^-/- mice are resistant to PbN-induced lung damage, indicating that reactive nitrogen species produced by Tip-DCs play an essential role in inducing MA-ARDS/ALI. Lastly, our experiments suggest that production of IFN-γ primarily by CD8⁺ T cells is required for inducing Tip-DCs differentiation in the lungs and the development of MA-ALI/ARDS model.

中文翻译：

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在急性呼吸窘迫综合征 (ARDS) 的疟疾模型中，产生致病性 TNF/iNOS 的树突状细胞 (Tip-DC) 的出现依赖于 CCR4。

疟疾相关的急性呼吸窘迫综合征 (MA-ARDS) 和急性肺损伤 (ALI) 是导致肺损伤并常导致死亡的并发症。MA-ARDS/ALI 与 T 淋巴细胞和 IFN-γ 介导的 1 型炎症反应有关。在这里，我们使用了类似于人类疾病的伯氏疟原虫 NK65 (PbN) 诱导的 MA-ALI/ARDS 模型，并证实了肺 CD4 ⁺和 CD8 ⁺T 细胞主要表达 Tbet 和 IFN-γ。令人惊讶的是，我们发现 MA-ALI/ARDS 的发展依赖于功能性 CCR4，已知其可介导 Th2 淋巴细胞和调节性 T 细胞的募集。然而，在这种 1 型炎症-ARDS 模型中，CCR4 不参与 T 淋巴细胞的募集，而是肺中产生 TNF-α/iNOS 的树突状细胞 (Tip-DC) 的出现所必需的。相反，Tip-DC 的募集和 MA-ALI/ARDS 的发展在 CCR2 ^{-/ -}小鼠中没有改变。重要的是，我们表明 NOS2 ^{-/ -}小鼠对 PbN 诱导的肺损伤具有抵抗力，表明 Tip-DC 产生的活性氮物质在诱导 MA-ARDS/ALI 中起着重要作用。最后，我们的实验表明，诱导肺部 Tip-DC 分化和 MA-ALI/ARDS 模型的发展需要主要由 CD8 ^{+ T 细胞产生 IFN-γ。}