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

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Abstract

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 by 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 minutes, then resuscitated over 30 minutes with a crystalloid volume equal to twice the volume of shed blood. Fifteen minutes into the 30-minute resuscitation, the rats received either intravenous infusion of C75 (1 mg/kg body weight) or vehicle (20% dimethyl sulfoxide). Blood and tissue samples were collected 6 hours after resuscitation (ie, 7.5 hours after hemorrhage) for analysis.

Results.

After hemorrhage and resuscitation, C75 treatment decreased the increase in serum free fatty acids by 48%, restored adenosine triphosphate levels, and stimulated carnitine palmitoyl transferase-1 activity. Administration of C75 decreased serum levels of markers of injury (aspartate aminotransferase, lactate, and lactate dehydrogenase) by 38%, 32%, and 78%, respectively. Serum creatinine and blood urea nitrogen were also decreased significantly 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 cyclooxygenase-2 and interleukin-6 by 87% and 65%, respectively.

Conclusion.

Administration of C75 after hemorrhage and resuscitation decreased the increase in serum free fatty acids, 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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