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CORM-2 inhibits TXNIP/NLRP3 inflammasome pathway in LPS-induced acute lung injury

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Abstract

Objective

Accumulated studies suggest that exogenously administered carbon monoxide is beneficial for the resolution of acute lung inflammation. The present study aimed to examine the effects and the underlying mechanisms of CORM-2 on thioredoxin-interacting protein (TXNIP)/NLRP3 inflammasome pathway in lipopolysaccharide (LPS)-induced acute lung injury (ALI).

Methods

ALI was intratracheally induced by LPS in C57BL6 mice. CORM-2 or iCORM-2 (30mg/kg i.p.) was administered immediately before LPS instillation. 6 h later, lung bronchoalveolar lavage (BAL) fluids were acquired for IL-18, IL-1β, and cell measurement, and lung issues were collected for histologic examination, wet/dry weight ratio, and determination of TXNIP/NLRP3 inflammasome expression, NLRP3 inflammasome and NF-ΚB activity, and reactive oxygen species (ROS) production.

Results

LPS triggered significant lung edema, lung injury, and leukocyte infiltration, and elevated the levels of IL-1β and IL-18 in lung BAL fluids. CORM-2 pretreatment resulted in a marked amelioration of lung injury and reduced IL-1β and IL-18 secretion in BAL fluids. In lung tissues; CORM-2 down-regulated mRNA and protein level of TXNIP, NLRP3, ASC, and caspase-1. Furthermore, CORM-2 reduced ROS production, inhibited NLRP3 inflammasome and NF-κB activity, and interaction of TXNIP-NLRP3. However, no significant differences were detected between the LPS and iCORM-2 (an inactive variant of CORM-2) group.

Conclusion

CORM-2 suppresses TXNIP/NLRP3 inflammasome pathway and protects against LPS-induced lung injury.

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Acknowledgments

This work was supported by the National Natural Scientific Foundation of China (Grant No. 81171785), the Natural Scientific Foundation of Heilongjiang Province (Grant No. ZJY0704-02) and the Graduate Innovative Research Program of Harbin Medical University (Grant No. YJSCX2015-21HYD). The authors sincerely thank Dr. Changming Xie, Dr. Jihua Han, Dr. You Zhou and Dr. Bowen Dong for their technical support in our experiments.

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Authors and Affiliations

  1. Department of ICU, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang province, China

    Lei Jiang, Dongsheng Fei, Rui Gong, Wei Yang, Wei Yu & Mingyan Zhao

  2. The Key Hepatosplenic Surgery Laboratory, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China

    Shangha Pan

  3. Department of Pediatrics, Children’s Hospital of Harbin City, Harbin, China

    Mingran Zhao

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  1. Lei Jiang
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  2. Dongsheng Fei
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Correspondence to Mingyan Zhao.

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Responsible Editor: Yoshiya Tanaka.

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Jiang, L., Fei, D., Gong, R. et al. CORM-2 inhibits TXNIP/NLRP3 inflammasome pathway in LPS-induced acute lung injury. Inflamm. Res. 65, 905–915 (2016). https://doi.org/10.1007/s00011-016-0973-7

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  • DOI: https://doi.org/10.1007/s00011-016-0973-7

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