Abstract: SA-PO077
AKI Induces Neutrophil Swarms in Lung Alveolar Capillaries That Cause Perfusion Deficits and Hypoxemia
Session Information
- AKI: Inflammation and Cell Cycle
October 26, 2024 | Location: Exhibit Hall, 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 School of Medicine, St Louis, Missouri, United States
- Ojha, Rupal, Washington University in St Louis School of Medicine, St Louis, Missouri, United States
- Ning, Liang, Washington University in St Louis School of Medicine, St Louis, Missouri, United States
- Suresh, Anusha, Washington University in St Louis School of Medicine, St Louis, Missouri, United States
- Lama, Carine, Washington University in St Louis School of Medicine, St Louis, Missouri, United States
- Kefalogianni, Eirini, Washington University in St Louis School of Medicine, St Louis, Missouri, United States
- Miller, Mark J., Washington University in St Louis School of Medicine, St Louis, Missouri, United States
- Herrlich, Andreas, Washington University in St Louis School of Medicine, St Louis, Missouri, United States
Background
Acute kidney injury (AKI) complicated by respiratory failure is common among critically ill patients and associated with high mortality. We recently showed that circulating osteopontin released from the injured kidney causes remote lung inflammation with hypoxemia (Sci Adv 2022). However, mechanisms that rapidly establish remote lung inflammation after AKI and the underlying cause of hypoxemia remain incompletely understood.
Methods
Single-cell RNA-seq analysis with cell-cell communication analysis was employed to investigate remote lung inflammation 24 hours after bilateral renal ischemia-reperfusion injury (IRI). Intravital imaging of the lung conducted by two-photon microscopy, was performed 1.5-2 hours after IRI, with capillary flow assessment by iv injection of 1-μm beads. Intracellular F-actin in circulating neutrophils was visualized using phalloidin staining. Fibrinogen and CD41 were used as markers for thrombosis in immunofluorescent staining.
Results
AKI induces rapid intravascular “neutrophil train” formation in lung capillaries, a novel form of neutrophil swarming. Neutrophils are rapidly captured in lung capillaries due to AKI-induced actin cytoskeleton rearrangement leading to reduced deformability that impedes neutrophil lung capillary passage. Unlike in direct lung injury where neutrophils extravasate driven by the concerted action of non-classical monocytes and alveolar macrophages, in remote lung inflammation after AKI neutrophils do not extravasate and are retained and assembled into lung capillary neutrophil trains by CXCL2 released by lung classical monocytes; this occurs independent of non-classical monocytes or alveolar macrophages. Lung capillary neutrophil trains significantly impede perfusion and cause thrombosis in a significant part of the lung capillary network.
Conclusion
We thus discovered a novel feature of kidney-lung crosstalk after AKI, capillary perfusion deficits that lead to reduced oxygenation despite proper alveolar function and ventilation, unlike in infectious inflammatory lung processes, such as bacterial pneumonia, where alveolar ventilation is typically compromised by inflammatory exudates. Our findings highlight potential therapeutic targets in post-AKI remote organ inflammation, which cannot be addressed by existing therapies including dialysis.
Funding
- NIDDK Support