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Abstract: SA-PO181

AKI-Activated CCR2+ Classical Monocytes Drive Remote Lung Neutrophilic Capillaritis with Hypoxemia due to Ventilation-Perfusion Deficits and Endothelial Leakage

Session Information

  • AKI: Mechanisms - III
    November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Komaru, Yohei, Washington University in St Louis, St Louis, Missouri, United States
  • Ning, Liang, Washington University in St Louis, St Louis, Missouri, United States
  • Suresh, Anusha, Washington University in St Louis, St Louis, Missouri, United States
  • Lama, Carine, Washington University in St Louis, St Louis, Missouri, United States
  • Kefalogianni, Eirini, Washington University in St Louis, St Louis, Missouri, United States
  • Herrlich, Andreas, Washington University in St Louis, St Louis, Missouri, United States
Background

Acute respiratory distress syndrome and acute kidney injury frequently occur together in multiorgan failure patients and portend high mortality due to a lack of mechanistic understanding and therapeutic options. Pre-clinical animal models of this clinical kidney-lung interaction reveal that AKI induces remote lung inflammation with accumulation of neutrophils and interstitial macrophages in the lung, interstitial edema, and hypoxemia. How this remote lung inflammation is established and causes hypoxemia lacks understanding.

Methods

Flow-cytometry was used to determine the amount of classical/non-classical monocytes and of lung intravascular, marginated or extravasated neutrophils in the lung 24 hours after bilateral renal ischemia-reperfusion injury (IRI). Single-cell RNA sequencing (scRNAseq) analysis was used to study the remotely injured lung after AKI. In-vivo two-photon imaging was used to image lung neutrophils and monocytes after AKI. In vitro, permeability assays using primary lung endothelial cell monolayers were employed.

Results

After AKI, classical monocytes and neutrophils increased in the lung. Lung neutrophils accumulated in lung capillaries, impeded blood flow, and did not extravasate, unlike in LPS-induced direct lung injury, suggesting ventilation-perfusion deficits as important cause of the observed hypoxemia. scRNAseq analysis revealed that monocytes enter the lung and transition into interstitial macrophages. Depletion of CCR2+ classical monocytes, but not of non-classical monocytes, blocked lung interstitial macrophage and neutrophil accumulation after AKI. In vitro, primary lung endothelial cell permeability in the presence of AKI serum was strongly enhanced when neutrophils from AKI mice, but not sham mice, were added.

Conclusion

CCR2+ classical monocytes are required for neutrophil recruitment in remote lung inflammation after AKI and give rise to lung interstitial macrophages. In contrast to direct lung injury, AKI-induced remote lung inflammation after AKI shows massive neutrophilic capillaritis with neutrophil plugging of vessels that impedes capillary perfusion and thus oxygen uptake. This oxygenation deficit is further negatively affected by increased endothelial permeability.

Funding

  • NIDDK Support