Ethyl pyruvate reduces hepatic mitochondrial swelling and dysfunction in a rat model of sepsis.
Sepsis causes mitochondrial oxidative injury and swelling. Ethyl pyruvate (EP) is a cytoprotective agent, while aquaporin-8 (AQP8) is a mitochondrial water channel that can induce mitochondrial swelling. We assessed whether EP protects mitochondria during sepsis, and whether AQP8 contributes to the underlying mechanisms. A cecal ligation and puncture (CLP) sepsis model was established in Sprague-Dawley rats, randomized to 3 groups: sham (n=20), CLP (n=59) and CLP+EP (n=51). All rats received postoperative intraperitoneal fluid resuscitation (30 ml/kg); the CLP+EP group also received intraperitoneal EP (100 mg/kg). Survival was assessed at 24 hours. Hepatic mitochondrial ultrastructure was characterized by electron microscopy. The membrane potential of isolated hepatic mitochondria was determined using JC-1 and flow cytometry. Mitochondrial AQP8 expression and cytochrome C (Cyt C) release were measured by Western blotting (values normalized to ß-actin). Survival in the sham, CLP and CLP+EP groups was 100%, 21% and 41%, respectively. Mitochondrial cross-sectional area was smaller in the CLP+EP group than in the CLP group (0.231±0.110 vs. 0.641±0.460 µm(2); P<0.001), with a tendency for a lower form factor (a measure of contour irregularity) in the CLP+EP group. Mitochondrial depolarization by CLP was inhibited by EP. Mitochondrial Cyt C release was higher in the CLP group than in the sham (1.211±0.24 vs. 0.48±0.03) or CLP+EP (0.35±0.39) groups. AQP8 expression was similar between groups, with a trend for lower expression in the CLP+EP group compared with the CLP group. EP improves sepsis outcome by targeting the mitochondrion, possibly through modulation of AQP8 expression.
Department of Surgical Intensive Care Unit, The First Affiliated Hospital of Sun Yat-sen University Guangzhou, Guangdong, China.
Zhiyi
Z
Jiang
Department of Surgical Intensive Care Unit, The Dongguan People's Hospital Dongguan, Guangdong, China.
Xiaoyue
X
Li
Department of Surgical Intensive Care Unit, The First Affiliated Hospital of Sun Yat-sen University Guangzhou, Guangdong, China.
Zongqin
Z
Lin
Department of Surgical Intensive Care Unit, The First Affiliated Hospital of Sun Yat-sen University Guangzhou, Guangdong, China.
Juan
J
Chen
Department of Surgical Intensive Care Unit, The First Affiliated Hospital of Sun Yat-sen University Guangzhou, Guangdong, China.
Xiangdong
X
Guan
Department of Surgical Intensive Care Unit, The First Affiliated Hospital of Sun Yat-sen University Guangzhou, Guangdong, China.
Minying
M
Chen
D000818:Animals; D020346:Aquaporins / Q000235:genetics / Q000378:metabolism; D001562:Benzimidazoles / Q000494:pharmacology*; D002232:Carbocyanines / Q000494:pharmacology*; D004195:Disease Models, Animal; D006801:Humans; D008099:Liver / Q000187:drug effects; D008107:Liver Diseases / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D008297:Male; D008930:Mitochondria, Liver / Q000378:metabolism; D008933:Mitochondrial Swelling / Q000187:drug effects*; D011773:Pyruvates / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D020346:Aquaporins; D001562:Benzimidazoles; D002232:Carbocyanines; D011773:Pyruvates; C108330:aquaporin 8; C046522:ethyl pyruvate; C068624:5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine
Sepsis; aquaporin 8; ethyl pyruvate; mitochondrial swelling; rat; ultrastructure