title: Betulinic acid attenuates lung injury by modulation of inflammatory cytokine response in experimentally-induced polymicrobial sepsis in mice.
abstract: Sepsis commonly progresses to acute lung injury (ALI), an inflammatory lung disease with high morbidity and mortality. Septic ALI is characterized by excessive production of proinflammatory mediators. It remained refractory to present therapies and new therapies need to be developed to improve further clinical outcomes. Betulinic acid (BA), a pentacyclic lupane group triterpenoid has been shown to have anti-inflammatory activities in many studies. However, its therapeutic efficacy in polymicrobial septic ALI is yet unknown. Therefore, we investigated the effects of BA on septic ALI using cecal ligation and puncture (CLP) model in mice. Vehicle or BA (3, 10, and 30mg/kg) was administered intraperitoneally, 3 times (0, 24 and 48h) before CLP and CLP was done on 49(th)h of the study. Survival rate was observed till 120h post CLP. Lung tissues were collected for analysis by sacrificing mice 18h post CLP. BA at 10 and 30mg/kg dose significantly reduced sepsis-induced mortality and lung injury as implied by attenuated lung histopathological changes, decreased protein and neutrophils infiltration. BA also decreased lung NF-κB expression, cytokine, intercellular adhesion molecule-1, monocyte chemoattractant protein-1 and matrix metalloproteinase-9 levels. These evidences suggest that, the protective effects of BA on lungs are associated with defending action against inflammatory response and BA could be a potential modulatory agent of inflammation in sepsis-induced ALI.
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, Bareilly, U.P. 243 122, India.
authors.forename: Madhu Cholenahalli
authors.initials: MC
authors.lastname: Lingaraju
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, Bareilly, U.P. 243 122, India.
authors.forename: Nitya Nand
authors.initials: NN
authors.lastname: Pathak
authors.affiliation: Division of Bacteriology and Mycology, Indian Veterinary Research Institute, Izatnagar, Bareilly, U.P. 243 122, India.
authors.forename: Jubeda
authors.initials: J
authors.lastname: Begum
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, Bareilly, U.P. 243 122, India.
authors.forename: Venkanna
authors.initials: V
authors.lastname: Balaganur
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, Bareilly, U.P. 243 122, India.
authors.forename: Rafia Ahmad
authors.initials: RA
authors.lastname: Bhat
authors.affiliation: Division of Animal Biotechnology, Indian Veterinary Research Institute, Izatnagar, Bareilly, U.P. 243 122, India.
authors.forename: Harish Darasaguppe
authors.initials: HD
authors.lastname: Ramachandra
authors.affiliation: Division of Pathology, Indian Veterinary Research Institute, Izatnagar, Bareilly, U.P. 243 122, India.
authors.forename: Anjaneya
authors.initials: A
authors.lastname: Ayanur
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, Bareilly, U.P. 243 122, India.
authors.forename: Mahendra
authors.initials: M
authors.lastname: Ram
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, Bareilly, U.P. 243 122, India.
authors.forename: Vishakha
authors.initials: V
authors.lastname: Singh
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, Bareilly, U.P. 243 122, India.
authors.forename: Dhirendra
authors.initials: D
authors.lastname: Kumar
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, Bareilly, U.P. 243 122, India.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Kumar
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, Bareilly, U.P. 243 122, India. Electronic address: sktandan@ivri.res.in.
authors.forename: Surendra Kumar
authors.initials: SK
authors.lastname: Tandan
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy* / Q000628:therapy; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000627:therapeutic use*; D002432:Cecum; D060085:Coinfection / Q000188:drug therapy* / Q000382:microbiology; D016207:Cytokines / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000473:pathology / Q000648:ultrastructure; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D053978:Pentacyclic Triterpenes; D018805:Sepsis / Q000188:drug therapy* / Q000382:microbiology / Q000628:therapy; D014315:Triterpenes / Q000008:administration & dosage / Q000627:therapeutic use*; D000094062:Betulinic Acid
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D016328:NF-kappa B; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D018799:Intercellular Adhesion Molecule-1; D020780:Matrix Metalloproteinase 9; D000094062:Betulinic Acid
keywords: Cecal ligation and puncture; Cytokines; Inflammatory pulmonary insult; Matrix metalloproteinase (MMP)-9; Triterpenoid