IL-1β suppression of VE-cadherin transcription underlies sepsis-induced inflammatory lung injury
Shiqin Xiong, Zhigang Hong, Long Shuang Huang, Yoshikazu Tsukasaki, Saroj Nepal, Anke Di, Ming Zhong, Wei Wu, Zhiming Ye, Xiaopei Gao, Gadiparthi N. Rao, Dolly Mehta, Jalees Rehman, Asrar B. Malik
Shiqin Xiong, Zhigang Hong, Long Shuang Huang, Yoshikazu Tsukasaki, Saroj Nepal, Anke Di, Ming Zhong, Wei Wu, Zhiming Ye, Xiaopei Gao, Gadiparthi N. Rao, Dolly Mehta, Jalees Rehman, Asrar B. Malik
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Research Article Inflammation Vascular biology

IL-1β suppression of VE-cadherin transcription underlies sepsis-induced inflammatory lung injury

Abstract

Unchecked inflammation is a hallmark of inflammatory tissue injury in diseases such as acute respiratory distress syndrome (ARDS). Yet the mechanisms of inflammatory lung injury remain largely unknown. Here we showed that bacterial endotoxin lipopolysaccharide (LPS) and cecal ligation and puncture–induced (CLP-induced) polymicrobial sepsis decreased the expression of transcription factor cAMP response element binding (CREB) in lung endothelial cells. We demonstrated that endothelial CREB was crucial for VE-cadherin transcription and the formation of the normal restrictive endothelial adherens junctions. The inflammatory cytokine IL-1β reduced cAMP generation and CREB-mediated transcription of VE-cadherin. Furthermore, endothelial cell–specific deletion of CREB induced lung vascular injury whereas ectopic expression of CREB in the endothelium prevented the injury. We also observed that rolipram, which inhibits type 4 cyclic nucleotide phosphodiesterase–mediated (PDE4-mediated) hydrolysis of cAMP, prevented endotoxemia-induced lung vascular injury since it preserved CREB-mediated VE-cadherin expression. These data demonstrate the fundamental role of the endothelial cAMP-CREB axis in promoting lung vascular integrity and suppressing inflammatory injury. Therefore, strategies aimed at enhancing endothelial CREB-mediated VE-cadherin transcription are potentially useful in preventing sepsis-induced lung vascular injury in ARDS.

Authors

Shiqin Xiong, Zhigang Hong, Long Shuang Huang, Yoshikazu Tsukasaki, Saroj Nepal, Anke Di, Ming Zhong, Wei Wu, Zhiming Ye, Xiaopei Gao, Gadiparthi N. Rao, Dolly Mehta, Jalees Rehman, Asrar B. Malik

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Figure 4

Augmentation of cAMP signaling by rolipram suppresses inflammatory lung injury.

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Augmentation of cAMP signaling by rolipram suppresses inflammatory lung ...
(A) C57BL/6J mice (n = 4) were administrated with rolipram (2, 5, and 10 mg/kg) for 1 hour, and injected intraperitoneally with LPS (12 mg/kg) for 1 day. Intracellular cAMP levels of the lung lysates were measured by ELISA. (B) Lung lysates were prepared for expression detection of IL-1β maturation, CREB, and VE-cadherin by Western blot. (C) Measurement of IL-1β levels in mouse serum, as determined by ELISA (n = 4). (D) H&E staining of the lung is shown (scale bar: 200 μm; n = 3). (E) Quantitative analysis for leukocyte infiltration in lungs (n = 6). (F) Quantitative analysis of neutrophil infiltration by measurement of lung tissue MPO activity (n = 4). (G) Lung vascular permeability is detected by EBD leakage in the lungs (n = 3–5). Extracted dye contents in the formamide extracts are quantified by measuring at 620 nm. (H) The ratios of the wet lung to dry lung weight were assessed (n = 3–5). Results are shown as mean ± SEM. ***P < 0.001. Statistics obtained from ANOVA.