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Cromoglycate, not ketotifen, ameliorated the injured effect of warm ischemia/reperfusion in rat liver: role of mast cell degranulation, oxidative stress, proinflammatory cytokine, and inducible nitric oxide synthase.
Drug Des Devel Ther. 2015; 9:5237-46.DD

Abstract

Hepatic ischemia/reperfusion (ISCH/REP) is a major clinical problem that is considered to be the most common cause of postoperative liver failure. Recently, mast cells have been proposed to play an important role in the pathophysiology of ISCH/REP in many organs. In contrast, the role played by mast cells during ISCH/REP-induced liver damage has remained an issue of debate. This study aimed to investigate the protective role of mast cells in order to search for an effective therapeutic agent that could protect against fatal ISCH/REP-induced liver damage. A model of warm ISCH/REP was induced in the liver of rats. Four groups of rats were used in this study: Group I: SHAM (normal saline, intravenously [iv]); Group II: ISCH/REP; Group III: sodium cromoglycate + ISCH/REP (CROM + ISCH/REP), and Group IV: ketotifen (KET) + ISCH/REP (KET + ISCH/REP). Liver damage was assessed both histopathologically and biochemically. Mast cell degranulation was assessed histochemically. Lipid peroxidation (malondialdehyde [MDA]) as well as the levels of glutathione (GSH), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α), the formation of nitric oxide (NO), and the expression of inducible NO synthase (iNOS) were determined. The results of this study revealed increased mast cell degranulation in the liver during the acute phase of ISCH/REP. Moreover, CROM, but not KET, decreased the activity of alanine aminotransferase, aspartate aminotransferase, and lactic dehydrogenase and maintained normal liver tissue histology. Both CROM and KET protected against mast cell degranulation in the liver. In addition, both CROM and KET decreased IL-6 and TNF-α. However, CROM, but not KET, decreased MDA formation and increased GSH. Furthermore, KET, but not CROM, increased both NO formation and iNOS expression. In conclusion, this study clearly demonstrated mast cell degranulation in warm ISCH/REP in the liver of rats. More importantly, CROM, but not KET, ameliorated the effect of ISCH/REP-induced injury in rat liver. CROM may protect the liver through mast cell stabilization, inhibition of TNF-α, IL-6, MDA, and iNOS and increased GSH. KET may maintain ISCH/REP-induced liver injury through the NO/iNOS pathway.

Authors+Show Affiliations

Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia ; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt.Department of Pathology, Faculty of Medicine, Tanta University, Tanta, Egypt.

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26396497

Citation

El-Shitany, Nagla A., and Karema El-Desoky. "Cromoglycate, Not Ketotifen, Ameliorated the Injured Effect of Warm Ischemia/reperfusion in Rat Liver: Role of Mast Cell Degranulation, Oxidative Stress, Proinflammatory Cytokine, and Inducible Nitric Oxide Synthase." Drug Design, Development and Therapy, vol. 9, 2015, pp. 5237-46.
El-Shitany NA, El-Desoky K. Cromoglycate, not ketotifen, ameliorated the injured effect of warm ischemia/reperfusion in rat liver: role of mast cell degranulation, oxidative stress, proinflammatory cytokine, and inducible nitric oxide synthase. Drug Des Devel Ther. 2015;9:5237-46.
El-Shitany, N. A., & El-Desoky, K. (2015). Cromoglycate, not ketotifen, ameliorated the injured effect of warm ischemia/reperfusion in rat liver: role of mast cell degranulation, oxidative stress, proinflammatory cytokine, and inducible nitric oxide synthase. Drug Design, Development and Therapy, 9, 5237-46. https://doi.org/10.2147/DDDT.S88337
El-Shitany NA, El-Desoky K. Cromoglycate, Not Ketotifen, Ameliorated the Injured Effect of Warm Ischemia/reperfusion in Rat Liver: Role of Mast Cell Degranulation, Oxidative Stress, Proinflammatory Cytokine, and Inducible Nitric Oxide Synthase. Drug Des Devel Ther. 2015;9:5237-46. PubMed PMID: 26396497.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cromoglycate, not ketotifen, ameliorated the injured effect of warm ischemia/reperfusion in rat liver: role of mast cell degranulation, oxidative stress, proinflammatory cytokine, and inducible nitric oxide synthase. AU - El-Shitany,Nagla A, AU - El-Desoky,Karema, Y1 - 2015/09/16/ PY - 2015/9/24/entrez PY - 2015/9/24/pubmed PY - 2016/7/7/medline KW - inducible nitric oxide synthase KW - ischemia/reperfusion KW - ketotifen KW - liver KW - mast cells KW - nitric oxide KW - sodium cromoglycate SP - 5237 EP - 46 JF - Drug design, development and therapy JO - Drug Des Devel Ther VL - 9 N2 - Hepatic ischemia/reperfusion (ISCH/REP) is a major clinical problem that is considered to be the most common cause of postoperative liver failure. Recently, mast cells have been proposed to play an important role in the pathophysiology of ISCH/REP in many organs. In contrast, the role played by mast cells during ISCH/REP-induced liver damage has remained an issue of debate. This study aimed to investigate the protective role of mast cells in order to search for an effective therapeutic agent that could protect against fatal ISCH/REP-induced liver damage. A model of warm ISCH/REP was induced in the liver of rats. Four groups of rats were used in this study: Group I: SHAM (normal saline, intravenously [iv]); Group II: ISCH/REP; Group III: sodium cromoglycate + ISCH/REP (CROM + ISCH/REP), and Group IV: ketotifen (KET) + ISCH/REP (KET + ISCH/REP). Liver damage was assessed both histopathologically and biochemically. Mast cell degranulation was assessed histochemically. Lipid peroxidation (malondialdehyde [MDA]) as well as the levels of glutathione (GSH), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α), the formation of nitric oxide (NO), and the expression of inducible NO synthase (iNOS) were determined. The results of this study revealed increased mast cell degranulation in the liver during the acute phase of ISCH/REP. Moreover, CROM, but not KET, decreased the activity of alanine aminotransferase, aspartate aminotransferase, and lactic dehydrogenase and maintained normal liver tissue histology. Both CROM and KET protected against mast cell degranulation in the liver. In addition, both CROM and KET decreased IL-6 and TNF-α. However, CROM, but not KET, decreased MDA formation and increased GSH. Furthermore, KET, but not CROM, increased both NO formation and iNOS expression. In conclusion, this study clearly demonstrated mast cell degranulation in warm ISCH/REP in the liver of rats. More importantly, CROM, but not KET, ameliorated the effect of ISCH/REP-induced injury in rat liver. CROM may protect the liver through mast cell stabilization, inhibition of TNF-α, IL-6, MDA, and iNOS and increased GSH. KET may maintain ISCH/REP-induced liver injury through the NO/iNOS pathway. SN - 1177-8881 UR - https://www.unboundmedicine.com/medline/citation/26396497/Cromoglycate_not_ketotifen_ameliorated_the_injured_effect_of_warm_ischemia/reperfusion_in_rat_liver:_role_of_mast_cell_degranulation_oxidative_stress_proinflammatory_cytokine_and_inducible_nitric_oxide_synthase_ L2 - https://dx.doi.org/10.2147/DDDT.S88337 DB - PRIME DP - Unbound Medicine ER -