Hydrogen alleviated organ injury and dysfunction in sepsis: The role of cross-talk between autophagy and endoplasmic reticulum stress: Experimental research

• Published in: International immunopharmacology Vol. 78; p. 106049
• Main Authors: Chen, Hong-guang, Han, Huan-zhi, Li, Yuan, Yu, Yong-hao, Xie, Ke-liang
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2020; Elsevier BV
• Subjects: Alveoli; Autophagy; Bronchus; Butyric acid; CCAAT/enhancer-binding protein; Cecum; Crosstalk; Cytokines; Deactivation; Endoplasmic reticulum; Endoplasmic reticulum stress; Enzyme-linked immunosorbent assay; Experimental research; High mobility group proteins; Homology; Hydrogen; Inactivation; Initiation factor eIF-2α; Injuries; Inositol; Interleukin 6; Kidneys; Kinases; Liver; Liver diseases; Lungs; Microtubule-associated protein 1; NF-κB protein; Parkin protein; Peroxidase; Phagocytosis; Proteins; PTEN protein; PTEN-induced putative kinase; Rapamycin; Sepsis; Stress; Transmission electron microscopy; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Sepsis; Hydrogen; Autophagy; Endoplasmic reticulum stress
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2019.106049

•Sepsis induced ERS and TM and 4-PBA increased and reduced ERS activity, respectively;•ERS up-regulation impaired autophagy activity, autophagy attenuated ERS activity;•The absence of ERS attenuated the tissue injury and dysfunction of vital organ;•Hydrogen attenuated ERS and augmented the autophagy activity in septic mice;•Hydrogen provided the protection of septic mice via autophagy and ERS cross-talk. Sepsis is defined as a life-threatening organ dysfunction that is caused by a dysregulated host response to infection. Although much progress has been made in understanding the pathophysiology of sepsis, further discussion and study of the detailed therapeutic mechanisms are needed. Autophagy and endoplasmic reticulum stress are two pathways of the complicated regulatory network of sepsis. Herein, we focus on the cellular mechanism in which autophagy and endoplasmic reticulum stress participate in hydrogen (H2)-protected sepsis-induced organ injury. Male C57BL/6 mice were randomly divided into the following groups: control group, cecal ligation puncture (CLP) group, CLP + tunicamycin(TM) group, CLP + 4-phenyl butyric acid (4-PBA) group, CLP + rapamycin (Rap) group, CLP + 3-methyladenine (3-MA) group, CLP + H2 group, CLP + H2 + 3-MA group, and CLP + H2 + TM group. After the experiment was completed, autophagosome was detected by transmission electron microscopy; protein PKR-like ER kinase (PERK), p-PERK, Eukaryotic translation initiation factor-2α (eIF2α), p-eIF2α, inositol-requiring enzyme1α(IRE1α), C/EBP homologous protein(CHOP), activating transcription factor(ATF), XBP-1, microtubule-associated protein 1 light(LC3), Beclin1, PTEN-induced putative kinase 1(PINK1), Parkin, and p65 subunit of Nuclear factor kappa B(NF-κb) were measured by Western blot; myeloperoxidase(MPO) activity in lung, bronchoalveolar lavage(BAL) total protein, lung wet-to-dry(W/D) ratio, serum biochemical indicators, 7-day survival rate, and pathological injury scores of lung, liver, and kidney were tested; and cytokines tumor necrosis factor-α(TNF-α), Interleukin(IL)-1β, and IL-6 and high mobility group box protein (HMGB)1 were detected by enzyme-linked immunosorbent assay(ELISA). We demonstrated that sepsis induced endoplasmic reticulum stress. Moreover, it was found that an increase in endoplasmic reticulum impaired autophagy activity in sepsis, and the absence of endoplasmic reticulum stress attenuated tissue histological injury and dysfunction of lung, liver, and kidney in septic mice. Intriguingly, hydrogen alleviated the endoplasmic reticulum stress via the autophagy pathway and also mitigated inflammation and organ injury. Hydrogen provided protection from organ injury induced by sepsis via autophagy activation and endoplasmic reticulum stress pathway inactivation.