title: The lipoxin A4agonist BML-111 attenuates acute hepatic dysfunction induced by cecal ligation and puncture in rats.
abstract: Sepsis is a systemic inflammatory response associating severe infection leading to multi-organ failure, such as hepatic dysfunction. This study investigates the possible hepatoprotective effect of the lipoxin A4agonist (BML-111) in cecal ligation and puncture (CLP) model in rats. Pretreatment with BML-111 (1 mg/kg, i.p., 1 h before CLP) protected against CLP-induced mortality after 24 h. BML-111 prevented marked inflammatory cells in liver tissues and decreased elevation in serum hepatic biomarkers [alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TB), gamma-glutamyl transferase (γ-GT)] induced by CLP. Additionally, BML-111 attenuated elevated serum level of interleukin-6 (IL-6) and downregulated hepatic IL-6 mRNA expression. Meanwhile, BML-111 further increased serum IL-10 and upregulated hepatic IL-10 mRNA expression, while it downregulated hepatic mRNA expression of nuclear factor inhibitory protein kappa-B alpha (NFκBia), toll-like receptor-4 (TLR-4), and 5-lipooxygenase (5-LOX). Moreover, BML-111 prevented NF-κB/p65 nuclear translocation and activation. In conclusion, BML-111 attenuated CLP-induced acute hepatic dysfunction through its anti-inflammatory effect by decreasing NF-κB activity, TLR-4, and 5-LOX expression with subsequent decrease in pro-inflammatory IL-6 and elevation in anti-inflammatory IL-10.
authors.affiliation: Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt.
authors.forename: Ghada S
authors.initials: GS
authors.lastname: El-Tanbouly
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt. mohamshh@yahoo.com.
authors.forename: Mohammed S
authors.initials: MS
authors.lastname: El-Awady
authors.affiliation: Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
authors.forename: Nermeen A
authors.initials: NA
authors.lastname: Megahed
authors.affiliation: Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt.|Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
authors.forename: Hassan A
authors.initials: HA
authors.lastname: El-Kashef
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
authors.forename: Hatem A
authors.initials: HA
authors.lastname: Salem
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D002432:Cecum / Q000293:injuries / Q000601:surgery; D006538:Heptanoic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D016753:Interleukin-10 / Q000097:blood / Q000235:genetics; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics; D008026:Ligation; D044045:Lipoxins / Q000819:agonists*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D051197:Toll-Like Receptor 4 / Q000235:genetics; D005723:gamma-Glutamyltransferase / Q000097:blood
chemical_list: C530770:5(S),6(R)-7-trihydroxyheptanoic acid, methyl ester; D006538:Heptanoic Acids; D015850:Interleukin-6; D044045:Lipoxins; D016328:NF-kappa B; D020011:Protective Agents; D012333:RNA, Messenger; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; C040527:lipoxin A4; D016753:Interleukin-10; D001094:Arachidonate 5-Lipoxygenase; D005723:gamma-Glutamyltransferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D001663:Bilirubin
keywords: BML-111; Cecal ligation and puncture; Hepatic dysfunction; IL-10; IL-6; LXA4; NF-κB