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Research ArticleInflammation, Immunopharmacology, and Asthma

Resolvin Conjugates in Tissue Regeneration 1 Promote Alveolar Fluid Clearance by Activating Alveolar Epithelial Sodium Channels and Na, K-ATPase in Lipopolysaccharide-Induced Acute Lung Injury

Qian Yang, Hao-ran Xu, Shu-yang Xiang, Chen Zhang, Yang Ye, Chen-xi Shen, Hong-xia Mei, Pu-hong Zhang, Hong-yu Ma, Sheng-xing Zheng, Fang-gao Smith, Sheng-wei Jin and Qian Wang
Journal of Pharmacology and Experimental Therapeutics November 2021, 379 (2) 156-165; DOI: https://doi.org/10.1124/jpet.121.000712
Qian Yang
Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University (Q.Y., H.X., S.X., Y.Y., C.S., H.M., P.Z., H.Ma, S.Z. F.S., S.J., Q.W.), and Wenzhou Medical University (C.Z.), Zhejiang, China; and Institute of Inflammation and Aging, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom (F.S.)
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Hao-ran Xu
Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University (Q.Y., H.X., S.X., Y.Y., C.S., H.M., P.Z., H.Ma, S.Z. F.S., S.J., Q.W.), and Wenzhou Medical University (C.Z.), Zhejiang, China; and Institute of Inflammation and Aging, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom (F.S.)
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Shu-yang Xiang
Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University (Q.Y., H.X., S.X., Y.Y., C.S., H.M., P.Z., H.Ma, S.Z. F.S., S.J., Q.W.), and Wenzhou Medical University (C.Z.), Zhejiang, China; and Institute of Inflammation and Aging, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom (F.S.)
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Chen Zhang
Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University (Q.Y., H.X., S.X., Y.Y., C.S., H.M., P.Z., H.Ma, S.Z. F.S., S.J., Q.W.), and Wenzhou Medical University (C.Z.), Zhejiang, China; and Institute of Inflammation and Aging, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom (F.S.)
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Yang Ye
Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University (Q.Y., H.X., S.X., Y.Y., C.S., H.M., P.Z., H.Ma, S.Z. F.S., S.J., Q.W.), and Wenzhou Medical University (C.Z.), Zhejiang, China; and Institute of Inflammation and Aging, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom (F.S.)
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Chen-xi Shen
Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University (Q.Y., H.X., S.X., Y.Y., C.S., H.M., P.Z., H.Ma, S.Z. F.S., S.J., Q.W.), and Wenzhou Medical University (C.Z.), Zhejiang, China; and Institute of Inflammation and Aging, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom (F.S.)
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Hong-xia Mei
Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University (Q.Y., H.X., S.X., Y.Y., C.S., H.M., P.Z., H.Ma, S.Z. F.S., S.J., Q.W.), and Wenzhou Medical University (C.Z.), Zhejiang, China; and Institute of Inflammation and Aging, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom (F.S.)
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Pu-hong Zhang
Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University (Q.Y., H.X., S.X., Y.Y., C.S., H.M., P.Z., H.Ma, S.Z. F.S., S.J., Q.W.), and Wenzhou Medical University (C.Z.), Zhejiang, China; and Institute of Inflammation and Aging, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom (F.S.)
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Hong-yu Ma
Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University (Q.Y., H.X., S.X., Y.Y., C.S., H.M., P.Z., H.Ma, S.Z. F.S., S.J., Q.W.), and Wenzhou Medical University (C.Z.), Zhejiang, China; and Institute of Inflammation and Aging, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom (F.S.)
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Sheng-xing Zheng
Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University (Q.Y., H.X., S.X., Y.Y., C.S., H.M., P.Z., H.Ma, S.Z. F.S., S.J., Q.W.), and Wenzhou Medical University (C.Z.), Zhejiang, China; and Institute of Inflammation and Aging, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom (F.S.)
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Fang-gao Smith
Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University (Q.Y., H.X., S.X., Y.Y., C.S., H.M., P.Z., H.Ma, S.Z. F.S., S.J., Q.W.), and Wenzhou Medical University (C.Z.), Zhejiang, China; and Institute of Inflammation and Aging, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom (F.S.)
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Sheng-wei Jin
Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University (Q.Y., H.X., S.X., Y.Y., C.S., H.M., P.Z., H.Ma, S.Z. F.S., S.J., Q.W.), and Wenzhou Medical University (C.Z.), Zhejiang, China; and Institute of Inflammation and Aging, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom (F.S.)
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Qian Wang
Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University (Q.Y., H.X., S.X., Y.Y., C.S., H.M., P.Z., H.Ma, S.Z. F.S., S.J., Q.W.), and Wenzhou Medical University (C.Z.), Zhejiang, China; and Institute of Inflammation and Aging, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom (F.S.)
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Abstract

Acute respiratory distress syndrome (ARDS), a common and fatal clinical condition, is characterized by the destruction of epithelium and augmented permeability of the alveolar-capillary barrier. Resolvin conjugates in tissue regeneration 1 (RCTR1) is an endogenous lipid mediator derived from docosahexaenoic acid , exerting proresolution effects in the process of inflammation. In our research, we evaluated the role of RCTR1 in alveolar fluid clearance (AFC) in lipopolysaccharide-induced ARDS/acute lung injury (ALI) rat model. Rats were injected with RCTR1 (5 μg/kg) via caudal veins 8 hours after lipopolysaccharide (LPS) (14 mg/kg) treatment, and then AFC was estimated after 1 hour of ventilation. Primary type II alveolar epithelial cells were incubated with LPS (1 ug/ml) with or without RCTR1 (10 nM) for 8 hours. Our results showed that RCTR1 significantly enhanced the survival rate, promoted the AFC, and alleviated LPS-induced ARDS/ALI in vivo. Furthermore, RCTR1 remarkably elevated the protein expression of sodium channels and Na, K-ATPase and the activity of Na, K-ATPase in vivo and in vitro. Additionally, RCTR1 also decreased neural precursor cell expressed developmentally downregulated 4-2 (Nedd4-2) level via upregulating Ser473-phosphorylated-Akt expression. Besides this, inhibitors of receptor for lipoxin A4 (ALX), cAMP, and phosphatidylinositol 3-kinase (PI3K) (BOC‐2, KH-7, and LY294002) notably inhibited the effects of RCTR1 on AFC. In summary, RCTR1 enhances the protein levels of sodium channels and Na, K-ATPase and the Na, K-ATPase activity to improve AFC in ALI through ALX/cAMP/PI3K/Nedd4-2 pathway, suggesting that RCTR1 may become a therapeutic drug for ARDS/ALI.

SIGNIFICANCE STATEMENT RCTR1, an endogenous lipid mediator, enhanced the rate of AFC to accelerate the resolution of inflammation in the LPS-induced murine lung injury model. RCTR1 upregulates the expression of epithelial sodium channels (ENaCs) and Na, K-ATPase in vivo and in vitro to accelerate the AFC. The efficacy of RCTR1 on the ENaC and Na, K-ATPase level was in an ALX/cAMP/PI3K/Nedd4-2-dependent manner.

Footnotes

    • Received April 29, 2021.
    • Accepted August 18, 2021.
  • This work was sponsored by the National Natural Science Foundation of China [Grant 81570076], the Natural Science Foundation of Zhejiang Province [Grant LY18H010005], Provincial Medical and health science and technology project [Grant 2021455293], and Research Fund for Lin He’s Academician Workstation of New Medicine and Clinical Translation [Grant 19331102].

  • The authors confirm that there are no conflicts of interest.

  • https://dx.doi.org/10.1124/jpet.121.000712.

  • Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 379 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 379, Issue 2
1 Nov 2021
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Research ArticleInflammation, Immunopharmacology, and Asthma

RCTR1 Promotes Alveolar Fluid Clearance

Qian Yang, Hao-ran Xu, Shu-yang Xiang, Chen Zhang, Yang Ye, Chen-xi Shen, Hong-xia Mei, Pu-hong Zhang, Hong-yu Ma, Sheng-xing Zheng, Fang-gao Smith, Sheng-wei Jin and Qian Wang
Journal of Pharmacology and Experimental Therapeutics November 1, 2021, 379 (2) 156-165; DOI: https://doi.org/10.1124/jpet.121.000712

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Research ArticleInflammation, Immunopharmacology, and Asthma

RCTR1 Promotes Alveolar Fluid Clearance

Qian Yang, Hao-ran Xu, Shu-yang Xiang, Chen Zhang, Yang Ye, Chen-xi Shen, Hong-xia Mei, Pu-hong Zhang, Hong-yu Ma, Sheng-xing Zheng, Fang-gao Smith, Sheng-wei Jin and Qian Wang
Journal of Pharmacology and Experimental Therapeutics November 1, 2021, 379 (2) 156-165; DOI: https://doi.org/10.1124/jpet.121.000712
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