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. Conclusions Administration of C75 after hemorrhage and resuscitation decreased the increase in serum FFA, decreased markers of tissue injury, downregulated the expression of inflammatory mediators, and decreased neutrophil infiltration and lung injury. Thus, the dual action of inhibiting fatty acid synthesis and stimulating fatty acid oxidation by C75 could be developed as a promising adjuvant therapy strategy to protect against hemorrhagic shock.

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