Recombinant human growth hormone improves the immune status of rats with septic encephalopathy: The role of VEGFR2 in the prevalence of endoplasmic reticulum stress repair module.

Autor: Zaky DA; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Aini street, Cairo, P.O. Box 11562, Egypt. Electronic address: doaa.zaky@pharma.cu.edu.eg., Eldehna WM; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, P.O. Box 33516, Egypt., El Kerdawy AM; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt., Abdallah DM; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Aini street, Cairo, P.O. Box 11562, Egypt., El Abhar HS; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Aini street, Cairo, P.O. Box 11562, Egypt; Department of Pharmacology & Toxicology, Faculty of Pharmacy, Future University in Egypt, Cairo, P.O. Box 11835, Egypt., Wadie W; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Aini street, Cairo, P.O. Box 11562, Egypt.
Jazyk: angličtina
Zdroj: International immunopharmacology [Int Immunopharmacol] 2021 Dec; Vol. 101 (Pt B), pp. 108370. Date of Electronic Publication: 2021 Nov 15.
DOI: 10.1016/j.intimp.2021.108370
Abstrakt: Septic encephalopathy results from the intense reaction of the immune system to infection. The role of growth hormone (GH) signaling in maintaining brain function is well established; however, the involvement of the vascular endothelial growth factor receptor-2 (VEGFR2) in the potential modulatory effect of GH on septic encephalopathy-associated endoplasmic reticulum stress (ERS) and blood-brain barrier (BBB) permeability is not well-understood. Therefore, after the induction of mid-grade sepsis by cecal ligation/perforation, rats were subcutaneously injected with recombinant human GH (rhGH)/somatropin alone or preceded by the VEGFR2 antagonist WAG-4S for 7 days. rhGH/somatropin reduced bodyweight loss and plasma endotoxin, maintained the hyperthermic state, and improved motor/memory functions. Additionally, rhGH/somatropin increased the junctional E-cadherin and β-catenin pool in the cerebral cortex to enhance the BBB competency, effects that were abolished by VEGFR2 blockade. Also, it activated cortical VEGFR2/mammalian target of the Rapamycin (mTOR) axis to mitigate ERS. The latter was reflected by the deactivation of the inositol-requiring enzyme-1α (IRE1α)/spliced X-box binding protein-1 (XBP1s) trajectory and the reduction in the protein levels of the death markers, C/EBP homologous protein (CHOP)/growth arrest and DNA damage-153 (GADD153), c-jun-N-terminal kinase (JNK), and caspase-3 with the simultaneous augmentation of expression of the unfolded protein response transducer proteinkinaseR-like ERkinase (PERK). Furthermore, rhGH/somatropin suppressed the phosphorylation of eukaryotic initiation factor-2α (eIF2α), upregulated the gene expression of activating transcription factor-4 (ATF4), GADD34, and glucose-regulated protein-78/binding immunoglobulin (GRP78/Bip). Moreover, it increased the glutathione level and reduced lipid peroxidation in the cerebral cortex. The VEGFR2 antagonist reversed the effect of rhGH/somatropin on PERK and IRE1α and boosted the apoptotic markers but neither affected p-eIF2α nor GADD34. Hence, we conclude that VEGFR2 activation by rhGH/somatropin plays a crucial role in assembling the BBB adherens junctions via its antioxidant capacity, ERS relief, and reducing endotoxemia in septic encephalopathy.
(Copyright © 2021 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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