Inhibition of fatty acid synthase with C75 decreases organ injury after hemorrhagic shock

Background—Hemorrhagic shock is the primary cause of morbidity and mortality in the intensive care units in patients under the age of 35. Several organs including the lungs are seriously affected due to the hemorrhagic shock and inadequate resuscitation. Excess free fatty acids have shown to trigger inflammation in various disease conditions. C75 is a small compound that inhibits fatty acid synthase, a key enzyme in the control of fatty acid metabolism that also stimulates fatty acid oxidation. We hypothesized that C75 treatment would be protective against hemorrhagic shock. Methods—Adult, male, Sprague-Dawley rats were cannulated with a femoral artery catheter and subjected to controlled bleeding. Blood was shed to maintain a mean arterial pressure of 30 mm Hg for 90 min, then resuscitated over 30 min with a crystalloid volume equal to twice the volume of shed blood. Fifteen minutes into the 30 min resuscitation, the rats received either intravenous infusion of C75 (1 mg/kg BW) or vehicle (20% DMSO). Blood and tissue samples were collected 6 h after resuscitation (i.e., 7.5 h after hemorrhage) for analysis. Results—After hemorrhage and resuscitation, C75 treatment decreased the increase in serum free fatty acids by 48%, restored adenosine triphosphate (ATP) levels, and stimulated carnitine palmitoyl transferase-1 (CPT-1) activity. Administration of C75 decreased serum levels of markers of injury (AST, lactate, and LDH) by 38%, 32%, and 78%, respectively. Serum creatinine and blood urea nitrogen (BUN) were also significantly decreased by 38% and 40%, respectively. These changes correlated with decreases in neutrophil infiltration in the lung, evidenced by decreases in Gr-1-stained cells and myeloperoxidase activity and improved lung histology. Finally, administration of C75 decreased pulmonary mRNA levels of COX-2 and IL-6 by 87% and 65%, respectively. Please address correspondence, proofs, and reprint requests to: Ping Wang, MD, Professor and Vice Chairman for Research, Department of Surgery, Hofstra North Shore-LIJ School of Medicine, Head, Center for Translational Research, The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030, Tel: (516) 562-3411, Fax: (516) 562-2396, pwang@nshs.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HHS Public Access Author manuscript Surgery. Author manuscript; available in PMC 2017 February 01. Published in final edited form as: Surgery. 2016 February ; 159(2): 570–579. doi:10.1016/j.surg.2015.07.036. A uhor M anscript