Sterile kidney tissue injury induces neutrophil swarming in lung alveolar capillaries.
Sterile kidney tissue injury induces neutrophil swarming in lung alveolar capillaries.
复制标题
无菌性肾组织损伤会导致肺泡毛细血管中的中性粒细胞聚集。
DOI：
10.1101/2024.02.27.582396
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Herrlich,Andreas
中科院分区：
文献类型：
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作者：
Komaru,Yohei;Ning,Liang;Lama,Carine;Suresh,Anusha;Kefaloyianni,Eirini;Miller,MarkJ;Herrlich,Andreas
无菌性急性肾损伤 (AKI) 在临床上很常见，通常与低氧血症相关，而低氧血症不会通过透析得到改善，目前人们对此的了解还不完全。 AKI 在小鼠和人类中通过中性粒细胞募集诱发远程肺部炎症，但哪些细胞信号引起中性粒细胞炎症以及它如何导致低氧血症尚不清楚。在这里，我们报道，AKI 诱导肺泡毛细血管内中性粒细胞快速滞留，而没有任何明显的外渗到组织或肺泡中，在没有任何明显的肺间质或肺泡水肿的情况下，通过减少肺毛细血管血流量而导致低氧血症。与直接缺血性肺损伤相比，远程肺部炎症期间肺中性粒细胞的募集不需要来自血管内非经典单核细胞或组织驻留肺泡巨噬细胞的提示。相反，肺中性粒细胞滞留取决于激活的血管内经典单核细胞释放的中性粒细胞趋化剂CXCL2。对直接和远程肺部炎症的比较单细胞RNA测序分析表明，肺泡巨噬细胞高度激活，并且仅在直接肺部炎症中产生中性粒细胞趋化剂CXCL2。在 AKI 诱导的远端肺部炎症期间，通过气管内给予 CXCL2 在肺泡中建立 CXCL2 梯度，使中性粒细胞能够外渗。因此，我们发现了直接肺部炎症与远程肺部炎症中肺中性粒细胞募集的重要差异，并确定了肺毛细血管中性粒细胞滞留，其通过导致通气-灌注不匹配作为 AKI 引起的低氧血症的新驱动因素对氧合产生负面影响。
Sterile acute kidney injury (AKI) is common in the clinic and frequently associated with hypoxemia that does not improve with dialysis and remains incompletely understood. AKI induces remote lung inflammation with neutrophil recruitment in mice and humans, but which cellular cues establish neutrophilic inflammation and how it contributes to hypoxemia is not known. Here we report that AKI induces rapid intravascular neutrophil retention in lung alveolar capillaries without any significant extravasation into tissue or alveoli, causing hypoxemia by reducing lung capillary blood flow in the absence of any significant lung interstitial or alveolar edema. In contrast to direct ischemic lung injury, lung neutrophil recruitment during remote lung inflammation did not require cues from intravascular non-classical monocytes or tissue-resident alveolar macrophages. Instead, lung neutrophil retention depended on neutrophil chemoattractant CXCL2 released by activated intravascular classical monocytes. Comparative single-cell RNA-sequencing analysis of direct and remote lung inflammation revealed that alveolar macrophages are highly activated and produce the neutrophil chemoattractant CXCL2 only in direct lung inflammation. Establishing a CXCL2 gradient into the alveolus by intratracheal administration of CXCL2 during AKI-induced remote lung inflammation enabled neutrophils to extravasate. We thus discovered important differences in lung neutrophil recruitment in direct versus remote lung inflammation and identified lung capillary neutrophil retention that negatively affects oxygenation by causing a ventilation-perfusion mismatch as a novel driver of AKI-induced hypoxemia.