Milk fat globule EGF factor 8 attenuates sepsis-induced apoptosis and organ injury in alcohol-intoxicated rats.
BACKGROUND
Despite advances in our understanding of excessive alcohol-intake-related tissue injury and modernization of the management of septic patients, high morbidity and mortality caused by infectious diseases in alcohol abusers remain a prominent challenge. Our previous studies have shown that milk fat globule epidermal growth factor-factor VIII (MFG-E8), a protein required to opsonize apoptotic cells for phagocytosis, is protective in inflammation. However, it remains unknown whether MFG-E8 ameliorates sepsis-induced apoptosis and organ injury in alcohol-intoxicated rats. The purpose of this study was to determine whether recombinant murine MFG-E8 (rmMFG-E8) attenuates organ injury after acute alcohol exposure and subsequent sepsis.


METHODS
Acute alcohol intoxication was induced in male adult rats by a bolus injection of intravenous alcohol at 1.75 g/kg BW, followed by an intravenous infusion of 300 mg/kg BW/h of alcohol for 10 hours. Sepsis was induced at the end of 10-hour alcohol infusion by cecal ligation and puncture (CLP). rmMFG-E8 or vehicle (normal saline) was administered intravenously 3 times (i.e., at the beginning of alcohol injection, the beginning of CLP, and 10 hours post-CLP) at a dose of 20 microg/kg BW each. Blood and tissue samples were collected 20 hours after CLP in alcoholic animals for various measurements.


RESULTS
Acute alcohol exposure per se did not affect the production of MFG-E8; however, it primed the animal and enhanced sepsis-induced MFG-E8 downregulation in the spleen. Administration of rmMFG-E8 reduces alcohol/sepsis-induced apoptosis in the spleen, lungs, and liver. In addition, administration of rmMFG-E8 after alcohol exposure and subsequent sepsis decreases circulating levels of TNF-alpha and interleukin-6 and attenuates organ injury.


CONCLUSIONS
rmMFG-E8 attenuates sepsis-induced apoptosis and organ injury in alcohol-intoxicated rats.
Wu
Rongqian
R
Department of Surgery, The Feinstein Institute for Medical Research, North Shore University Hospital and Long Island Jewish Medical Center, Manhasset, New York 11030, USA.
Chaung
Wayne W
WW
Zhou
Mian
M
Ji
Youxin
Y
Dong
Weifeng
W
Wang
Zhimin
Z
Qiang
Xiaoling
X
Wang
Ping
P
D000435:Alcoholic Intoxication / Q000097:blood / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D015850:Interleukin-6 / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008297:Male; D008894:Milk Proteins / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology*; D018805:Sepsis / Q000097:blood / Q000378:metabolism / Q000473:pathology*; D013154:Spleen / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D000954:Antigens, Surface; D015850:Interleukin-6; C490919:Mfge8 protein, mouse; D008894:Milk Proteins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha