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Theranostics 2020; 10(11):4749-4761. doi:10.7150/thno.43108 This issue Cite

Research Paper

A COX-2/sEH dual inhibitor PTUPB alleviates lipopolysaccharide-induced acute lung injury in mice by inhibiting NLRP3 inflammasome activation

Hui-Hui Yang^1*, Jia-Xi Duan^2,3,4*, Shao-Kun Liu^2,3,4, Jian-Bing Xiong¹, Xin-Xin Guan¹, Wen-Jing Zhong¹, Chen-Chen Sun¹, Chen-Yu Zhang¹, Xiao-Qin Luo¹, Yan-Feng Zhang¹, Ping Chen^2,3,4, Bruce D. Hammock⁵, Sung Hee Hwang⁵, Jian-Xin Jiang⁶, Yong Zhou^1✉, Cha-Xiang Guan^1✉

1. Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, China;
2. Department of Pulmonary and Critical Care Medicine, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China;
3. Research Unit of Respiratory Disease, Central South University, Changsha, Hunan 410011, China;
4. Hunan Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, Hunan 410011, China;
5. Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center, University of California, Davis, One Shields Avenue, Davis, CA 95616, USA;
6. State Key Laboratory of Trauma, Burns, and Combined Injury, Army Medical University, Chongqing, 400038, China.
*These authors contributed equally to this work

✉ Corresponding authors: Cha-Xiang Guan or Yong Zhou. Department of Physiology, Xiangya Medical School, Central South University, Changsha, Hunan 410078, China. Tel.: +86-731-82355051; Fax: +86-731-82355056; E-mail: guanchaxiangedu.cn or zhouyong421edu.cn More

Abstract

Rationale: Dysregulation of arachidonic acid (ARA) metabolism results in inflammation; however, its role in acute lung injury (ALI) remains elusive. In this study, we addressed the role of dysregulated ARA metabolism in cytochromes P450 (CYPs) /cyclooxygenase-2 (COX-2) pathways in the pathogenesis of lipopolysaccharide (LPS)-induced ALI in mice.

Methods: The metabolism of CYPs/COX-2-derived ARA in the lungs of LPS-induced ALI was investigated in C57BL/6 mice. The COX-2/sEH dual inhibitor PTUPB was used to establish the function of CYPs/COX-2 dysregulation in ALI. Primary murine macrophages were used to evaluate the underlying mechanism of PTUPB involved in the activation of NLRP3 inflammasome in vitro.

Results: Dysregulation of CYPs/COX-2 metabolism of ARA occurred in the lungs and in primary macrophages under the LPS challenge. Decrease mRNA expression of Cyp2j9, Cyp2j6, and Cyp2j5 was observed, which metabolize ARA into epoxyeicosatrienoic acids (EETs). The expressions of COX-2 and soluble epoxide hydrolase (sEH), on the other hand, was significantly upregulated. Pre-treatment with the dual COX-2 and sEH inhibitor, PTUPB, attenuated the pathological injury of lung tissues and reduced the infiltration of inflammatory cells. Furthermore, PTUPB decreased the pro-inflammatory factors, oxidative stress, and activation of NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome in LPS-induced ALI mice. PTUPB pre-treatment remarkably reduced the activation of macrophages and NLRP3 inflammasome in vitro. Significantly, both preventive and therapeutic treatment with PTUPB improved the survival rate of mice receiving a lethal dose of LPS.

Conclusion: The dysregulation of CYPs/COX-2 metabolized ARA contributes to the uncontrolled inflammatory response in ALI. The dual COX-2 and sEH inhibitor PTUPB exerts anti-inflammatory effects in treating ALI by inhibiting the NLRP3 inflammasome activation.

Keywords: acute lung injury, COX-2/sEH dual inhibitor, NLRP3 inflammasome, oxidative stress

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