Acute kidney injury triggers hypoxemia by lung intravascular neutrophil retention that reduces capillary blood flow

Yohei Komaru; Liang Ning; Carine Lama; Anusha Suresh; Eirini Kefaloyianni; Mark J. Miller; Shinichi Kawana; Hailey M. Shepherd; Wenjun Li; Daniel Kreisel; Andreas Herrlich

doi:10.1172/JCI186705

Acute kidney injury triggers hypoxemia by lung intravascular neutrophil retention that reduces capillary blood flow

Yohei Komaru,¹ Liang Ning,¹ Carine Lama,¹ Anusha Suresh,¹ Eirini Kefaloyianni,² Mark J. Miller,³ Shinichi Kawana,⁴ Hailey M. Shepherd,⁴ Wenjun Li,⁴ Daniel Kreisel,⁴ and Andreas Herrlich⁵

Published March 6, 2025 - More info

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Abstract

Sterile acute kidney injury (AKI) is common in the clinic and frequently associated with unexplained hypoxemia that does not improve with dialysis. 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 extravasation into tissue or alveoli, causing hypoxemia by reducing lung capillary blood flow in the absence of substantial 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 classical monocytes. Comparative single-cell RNA-sequencing analysis of direct and remote lung inflammation revealed that alveolar macrophages are highly activated and produce CXCL2 only in direct lung inflammation. Establishing a CXCL2 gradient into the alveolus by intratracheal CXCL2 administration 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 driver of AKI-induced hypoxemia.

Acute kidney injury triggers hypoxemia by lung intravascular neutrophil retention that reduces capillary blood flow

Yohei Komaru,¹ Liang Ning,¹ Carine Lama,¹ Anusha Suresh,¹ Eirini Kefaloyianni,² Mark J. Miller,³ Shinichi Kawana,⁴ Hailey M. Shepherd,⁴ Wenjun Li,⁴ Daniel Kreisel,⁴ and Andreas Herrlich⁵

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Acute kidney injury triggers hypoxemia by lung intravascular neutrophil retention that reduces capillary blood flow

Yohei Komaru,1 Liang Ning,1 Carine Lama,1 Anusha Suresh,1 Eirini Kefaloyianni,2 Mark J. Miller,3 Shinichi Kawana,4 Hailey M. Shepherd,4 Wenjun Li,4 Daniel Kreisel,4 and Andreas Herrlich5

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Yohei Komaru,¹ Liang Ning,¹ Carine Lama,¹ Anusha Suresh,¹ Eirini Kefaloyianni,² Mark J. Miller,³ Shinichi Kawana,⁴ Hailey M. Shepherd,⁴ Wenjun Li,⁴ Daniel Kreisel,⁴ and Andreas Herrlich⁵