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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 1

Fluorescence responses to intra-alveolar HCl injection in the alveolar epithelium and endothelium.

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Fluorescence responses to intra-alveolar HCl injection in the alveolar e...
Epithelial and endothelial cytosols were loaded with calcein green (CG, 10 μM) and calcein red (CR, 2.5 μM), respectively. (A) High-power confocal image shows separation of the alveolar epithelium from the juxtaposed capillary endothelium. Cap, capillary lumen; alv, alveolus. n = 5 lungs. Scale bar: 20 μm. (B) Fluorescence of CG, CR, and tetramethylrhodamine ethyl ester (TMRE, intravascularly, 2 μM) at indicated time points before (baseline) and after alveolar HCl injection. Images at 30 minutes were obtained after repeat injections of CG and TMRE. Scale bars: 20 μm. (C) Bars are quantifications in cytosol (calcein) and mitochondria (TMRE) for the indicated cell types following alveolar injections of PBS or HCl. White, PBS; orange, 10 minutes after HCl; blue, 30 minutes after HCl. *P < 0.05 versus PBS. (D) Effects of indicated treatments on endothelial TMRE following alveolar HCl or microvascular H2O2 injection. EV, intranasal empty vector; CAT, alveolar catalase transfection; NAC, intravascular N-acetyl cysteine. *P < 0.05 versus EV. 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 test was used to determine statistical differences between groups.

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