Mitochondria of lung venular capillaries mediate lung-liver cross talk in pneumonia.

Failure of the lung's endothelial barrier underlies lung injury, which causes the high mortality acute respiratory distress syndrome (ARDS). Multiple organ failure predisposes to the mortality, but mechanisms are poorly understood. Here, we show that mitochondrial uncoupling protein 2 (UCP2), a component of the mitochondrial inner membrane, plays a role in the barrier failure. Subsequent lung-liver cross talk mediated by neutrophil activation causes liver congestion. We intranasally instilled lipopolysaccharide (LPS). Then, we viewed the lung endothelium by real-time confocal imaging of the isolated, blood-perfused mouse lung. LPS caused alveolar-capillary transfer of reactive oxygen species and mitochondrial depolarization in lung venular capillaries. The mitochondrial depolarization was inhibited by transfection of alveolar Catalase and vascular knockdown of UCP2. LPS instillation caused lung injury as indicated by increases in bronchoalveolar lavage (BAL) protein content and extravascular lung water. LPS or Pseudomonas aeruginosa instillation also caused liver congestion, quantified by liver hemoglobin and plasma aspartate aminotransferase (AST) increases. Genetic inhibition of vascular UCP2 prevented both lung injury and liver congestion. Antibody-mediated neutrophil depletion blocked the liver responses, but not lung injury. Knockdown of lung vascular UCP2 mitigated P. aeruginosa-induced mortality. Together, these data suggest a mechanism in which bacterial pneumonia induces oxidative signaling to lung venular capillaries, known sites of inflammatory signaling in the lung microvasculature, depolarizing venular mitochondria. Successive activation of neutrophils induces liver congestion. We conclude that oxidant-induced UCP2 expression in lung venular capillaries causes a mechanistic sequence leading to liver congestion and mortality. Lung vascular UCP2 may present a therapeutic target in ARDS.NEW & NOTEWORTHY We report that mitochondrial injury in lung venular capillaries underlies barrier failure in pneumonia, and venular capillary uncoupling protein 2 (UCP2) causes neutrophil-mediated liver congestion. Using in situ imaging, we found that epithelial-endothelial transfer of H2O2 activates UCP2, depolarizing mitochondria in venular capillaries. The conceptual advance from our findings is that mitochondrial depolarization in lung capillaries mediates liver cross talk through circulating neutrophils. Pharmacologic blockade of UCP2 could be a therapeutic strategy for lung injury.

The impact of a fellow-driven debriefing program after pediatric cardiac arrests.

BACKGROUND: In the United States, post-cardiac arrest debriefing has increased, but historically it has occurred rarely in our pediatric intensive care unit (PICU). A fellow-led debriefing tool was developed as a tool for fellow development, as well as to enhance communication amongst a multidisciplinary team. METHODS: A curriculum and debriefing tool for fellow facilitators was developed and introduced in a 41-bed cardiac and medical PICU. Pre- and post-intervention surveys were sent to multidisciplinary PICU providers to assess effectiveness of debriefings using newly-trained leaders, as well as changes in team communication. RESULTS: Debriefing occurred after 84% (63/75) of cardiac arrests post-intervention. Providers in various team roles participated in pre-intervention (129 respondents/236 invitations) and post-intervention (96 respondents /232 invitations) surveys. Providers reported that frequently occurring debriefings increased from 9 to 58%, pre- and post-intervention respectively (p < .0001). Providers reported frequent identification and discussion of learning points increased from 32% pre- to 63% post-intervention. In the 12 months post-intervention, 62% of providers agreed that the overall quality of communication during arrests had improved, and 61% would be more likely to request a debriefing after cardiac arrest. CONCLUSION: The introduction of a fellow-led debriefing tool resulted in regularly performed debriefings after arrests. Despite post-intervention debriefings being led by newly-trained facilitators, the majority of PICU staff expressed satisfaction with the quality of debriefing and improvement in communication during arrests, suggesting that fellow facilitators can be effective debrief leaders.

COVID-19 Inflammatory Syndrome With Clinical Features Resembling Kawasaki Disease.

We describe 2 patients with coronavirus disease who had multiple clinical features suggestive of Kawasaki disease (KD). Both patients presented with fever lasting >5 days and were found to have rash, conjunctival injection, and swollen lips. One patient also had extremity swelling, whereas the other developed desquamation of the fingers. In both cases, laboratory results were similar to those seen in KD. These patients had highly unusual but similar features, and both appeared to respond favorably to treatment. It remains unclear whether these patients had true KD or manifestations of coronavirus disease that resembled KD.

Endothelial mitochondria determine rapid barrier failure in chemical lung injury.

Acid aspiration, which can result from several etiologies, including postoperative complications, leads to direct contact of concentrated hydrochloric acid (HCl) with the alveolar epithelium. As a result, rapid endothelial activation induces alveolar inflammation, leading to life-threatening pulmonary edema. Because mechanisms underlying the rapid endothelial activation are not understood, here we determined responses in real time through optical imaging of alveoli of live mouse lungs. By alveolar micropuncture, we microinfused concentrated HCl in the alveolar lumen. As expected, acid contact with the epithelium caused rapid, but transient, apical injury. However, there was no concomitant membrane injury to the endothelium. Nevertheless, H2O2-mediated epithelial-endothelial paracrine signaling induced endothelial barrier failure, as detected by microvascular dextran leakage and lung water quantification. Remarkably, endothelial mitochondria regulated the barrier failure by activating uncoupling protein 2 (UCP2), thereby inducing transient mitochondrial depolarization that led to cofilin-induced actin depolymerization. Knockdown, or endothelium-targeted deletion of UCP2 expression, blocked these responses, including pulmonary edema. To our knowledge, these findings are the first to mechanistically implicate endothelial mitochondria in acid-induced barrier deterioration and pulmonary edema. We suggest endothelial UCP2 may be a therapeutic target for acid-induced acute lung injury.

Crosstalk signaling between alveoli and capillaries.

Crosstalk signaling between the closely juxtaposed epithelial and endothelial membranes of pulmonary alveoli establishes the lung's immune defense against inhaled and blood-borne pathogens. The crosstalk can occur in a forward direction, as from alveolus to capillary, or in a reverse direction, as from capillary to alveolus. The crosstalk direction likely depends on the site at which pathogens first initiate signaling. Thus, forward crosstalk may occur when inhaled pathogens encounter the alveolar epithelium, while reverse crosstalk may result from interactions of blood-borne pathogens with the endothelium. Here, we review the factors that regulate these two directions of signaling.