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Endothelial mitochondria determine rapid barrier failure in chemical lung injury
Rebecca F. Hough, … , Shonit Das, Jahar Bhattacharya
Rebecca F. Hough, … , Shonit Das, Jahar Bhattacharya
Published February 7, 2019
Citation Information: JCI Insight. 2019;4(3):e124329. https://doi.org/10.1172/jci.insight.124329.
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Research Article Pulmonology Vascular biology

Endothelial mitochondria determine rapid barrier failure in chemical lung injury

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Abstract

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.

Authors

Rebecca F. Hough, Mohammad N. Islam, Galina A. Gusarova, Guangchun Jin, Shonit Das, Jahar Bhattacharya

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Figure 4

Alveolar HCl–induced activation of the calcineurin-cofilin-actin pathway in the endothelium.

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Alveolar HCl–induced activation of the calcineurin-cofilin-actin pathway...
(A) Confocal image shows endothelial fluorescence of cofilin-GFP. n = 5. Scale bar: 20 μm. (B) Bars are counts of edematous alveoli (>50% FITC-D70 filling) following alveolar HCl after indicated pretreatments. inCFLN, inactive cofilin; TAC, tacrolimus (60 μM, 30 minutes). *P < 0.05 versus HCl alone (dashed line). (C) Images show endothelial F-actin distribution before and after alveolar HCl injection. Lung capillaries were microinfused with 4% paraformaldehyde and 0.2% Triton X-100 (20 minutes), then with rhodamine phalloidin (1 U/ml, 5 minutes). Scale bar: 20 μm. (D) Bars quantify F-actin responses in terms of rhodamine phalloidin fluorescence normalized to nuclear fluorescence of Hoechst 33342 (not shown). *P < 0.05 versus baseline. Data are shown as mean ± SEM for the number of injections indicated by dots. n, number of lungs. One-way ANOVA with post hoc Bonferroni’s correction was used to determine statistical differences between groups.

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