Ethyl pyruvate reduces mortality in an endotoxin-induced severe acute lung injury mouse model.
BACKGROUND
Ethyl pyruvate (EP) was recently identified as an experimental therapeutic agent in a wide variety of model systems for inflammation-mediated tissue and cellular injury.


OBJECTIVE
To evaluate the effect of ethyl EP on improving the survival in mice with LPS-induced acute lung injury (ALI).


METHODS
ALI was induced by administering lipopolysaccharide (LPS) intratracheally. The mice were treated intraperitoneally (i.p.) with 100, 50 and 10 mg/kg EP immediately before intratracheal instillation of LPS, and 100 mg/kg EP was administered 0, 12, 24 and 48 hours after induction of ALI. The mortality rate was recorded and analyzed by the Kaplan-Meier method. Serum tumor necrosis factor (TNF)-alpha, interleukin (IL) -6 and IL-1 beta were measured in bronchial alveolar lavage fluid using an enzyme-linked immunosorbent assay. High-mobility group box 1 levels were measured by Western immunoblotting.


RESULTS
Treatment with EP significantly inhibited the release of HMGB1, TNF-alpha, IL-6 and IL-1beta into bronchoalveolar lavage (BAL) fluids of ALI mice, and reduced the permeability index of the injured lung. High EP doses reduced the mortality from ALI and the permeability index (100 mg/kg and 50 mg/kg EP versus control; P < 0.0001). Early administration of high-dose EP significantly increased survival rate (0, 12 and 24 h versus control; P < 0.0001, P < 0.0001 and P = 0.01 respectively by log-rank test). There was no survival advantage when EP was initiated at 48 h.


CONCLUSIONS
Ethyl pyruvate improves survival and reduces the lung permeability index in mice with LPS-induced ALI.
Shang
Guan-Hong
GH
Department of Respiratory Medicine, Qilu Hospital, School of Medicine, Shandong University, Jinan 250012, PR China. shangguanhong0516@163.com
Lin
Dian-Jie
DJ
Xiao
Wei
W
Jia
Chong-Qi
CQ
Li
Yu
Y
Wang
Ai-Hua
AH
Dong
Liang
L
D055371:Acute Lung Injury / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D000818:Animals; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004797:Enzyme-Linked Immunosorbent Assay; D024243:HMGB1 Protein / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D007274:Injections, Intraperitoneal; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects* / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010539:Permeability; D011773:Pyruvates / Q000008:administration & dosage / Q000494:pharmacology*; D019141:Respiratory System Agents / Q000008:administration & dosage / Q000494:pharmacology*; D012720:Severity of Illness Index; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D024243:HMGB1 Protein; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D011773:Pyruvates; D019141:Respiratory System Agents; D014409:Tumor Necrosis Factor-alpha; C440499:lipopolysaccharide, Escherichia coli O111 B4; C046522:ethyl pyruvate