Critical Care: Mechanisms of Lung Injury |

Protective Effects and Mechanisms of Suppressing STAT3 Pathway on LPS-Induced Acute Lung Injury FREE TO VIEW

Liang Dong
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Qilu Hospital of Shandong University, Jinan, China

Copyright 2016, American College of Chest Physicians. All Rights Reserved.

Chest. 2016;149(4_S):A183. doi:10.1016/j.chest.2016.02.189
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SESSION TITLE: Mechanisms of Lung Injury

SESSION TYPE: Original Investigation Slide

PRESENTED ON: Saturday, April 16, 2016 at 04:00 PM - 05:00 PM

PURPOSE: Acute lung injury (ALI), the basis of acute respiratory distress syndrome (ARDS) is a critically clinic syndrome with high morbidity and mortality in intensive care units (ICU). Currently, there is no effective pharmacological treatment for acute lung injury. STAT3 signaling pathway plays a crucial role in the inflammation process of acute lung injury (ALI). This study aimed to investigate the protective effect of LLL12, an inhibitor of STAT3, and SOCS3, a negative regulator of STAT3, on LPS-induced ALI.

METHODS: The protein content of pro-inflammatory cytokines and chemokines in bronchoalveolar lavage fluid, the histopathologic of the lung, the innate immunity cells in lung tissue in vivo, as well as the protein expressions of STAT3, STAT1, ERK1/2, and NF-κB in cultured macrophages in vitro were detected.

RESULTS: The C57BL/6,SOCS3fl/fl and LysMCre-SOCS3fl/fl mice were randomly divided into 3 groups: control, LPS and LLL12 + LPS groups. The mice were sacrificed using arotic phlebotomy at 24, 48, 72 and 96 h after LPS deposition and injured lung specimens were harvested. LPS induces STAT3 activation and gene expression in cells isolated from the BALF in vivo. LLL12 pretreatment significantly ameliorated lung inflammatory responses in LPS-induced ALI. In addition, LLL12 suppresses STAT3 activation and pro-inflammatory cytokines expression in macrophages from SOCS3fl/fl and LysMCre-SOCS3fl/fl mice. SOCS3 negatively regulates LPS-induced STAT3 activation and production of inflammatory mediators in BAL fluids. However, the enhanced lung inflammation in LPS-induced lung injury in mice with myeloid deletion of SOCS3 could be inhibited by LLL12.

CONCLUSIONS: Our experimental findings indicated that the specific inhibitor of STAT3, LLL12, can protect mice against LPS-induced ALI and that its underlying mechanism may be related to the inhibition of STAT3 signaling pathway activation.

CLINICAL IMPLICATIONS: The identification of STAT3-regulated downstream mediators (including cytokines/chemokines) will lead to a better understanding how STAT3 regulates acute lung inflammatory responses. Elucidating the function of STAT3 may help identify new prospective targets for therapeutic intervention in lung diseases.

DISCLOSURE: The following authors have nothing to disclose: Liang Dong

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