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
Yohei Komaru, Liang Ning, Carine Lama, Anusha Suresh, Eirini Kefaloyianni, Mark J. Miller, Shinichi Kawana, Hailey M. Shepherd, Wenjun Li, Daniel Kreisel, Andreas Herrlich
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Research Article Inflammation Nephrology Pulmonology

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

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 induced 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 nonclassical monocytes or tissue-resident alveolar macrophages. Instead, lung neutrophil retention depended on the neutrophil chemoattractant CXCL2 released by activated classical monocytes. Comparative single-cell RNA-Seq analysis of direct and remote lung inflammation revealed that alveolar macrophages were highly activated and produced 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 affected oxygenation by causing a ventilation-perfusion mismatch as a driver of AKI-induced hypoxemia.

Authors

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

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Figure 6

CCR2+ classical monocytes and CXCL2/CXCR2 signaling drive lung capillary neutrophil retention after AKI.

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CCR2+ classical monocytes and CXCL2/CXCR2 signaling drive lung capillary...
(A) Schematic of classical monocyte depletion using anti-CCR2 Ab in vivo. (B) Lung monocytes after pretreatment with anti-CCR2 Ab or control IgG. n = 6 per group. (C) Serum BUN indicating kidney injury level on day 1 after AKI. n = 6 per group. (D) Lung immunofluorescence staining after AKI in control versus anti-CCR2 Ab–treated animals. Shown are alveolar and interstitial macrophages (CD68+, red) and neutrophils (Ly6G+, green). Hoechst 33342 dye (blue) was used to visualize nuclei. Scale bar: 100 μm. n = 6 per group. (E) Total number of cell-cell communications inferred by CellChat based on the scRNA-Seq analysis for sham-operated versus AKI mice (also see Supplemental Figure 2). (F) Cell-cell communications from monocytes or macrophages to neutrophils were predicted at single ligand-receptor resolution (unbiased); the neutrophil chemoattractant CXCL2 in monocytes and macrophages and their receptor CXCR2 in neutrophils was predicted to be significantly increased in AKI versus sham groups and are underlined. (G) Lung immunofluorescence staining for Ly6G+ neutrophils (green) from WT C57BL/6 mice injected with anti-CXCL2 or control Ab and subjected to AKI. Scale bar: 100 μm. n = 4–5 per group. The graph shows a quantification of lung neutrophils detected by immunofluorescence. Data represent the mean ± SD. *P < 0.05 and **P < 0.01, by unpaired, 2-tailed Student’s t test.