Sepsis is an acute inflammatory condition that can result in multiple organ failure and acute lung injury (ALI). Growth arrest-specific protein 6 (Gas6) is a broad regulator of the innate immune response involved with the NF-κB signaling pathway. We hypothesized that Gas6 could have a protective role in attenuating the severity of ALI and sepsis. Male mice were subjected to sepsis by cecal ligation and puncture (CLP) after which recombinant murine Gas6 (rmGas6; 5 μg/mouse) or normal saline (vehicle) was administered intravenously. Blood and lung tissues were collected at 20 h after CLP for various measurements. Treatment with rmGas6 significantly reduced serum levels of the injury markers AST, ALT and LDH as well as proinflammatory cytokines IL-6 and IL-17, compared to the vehicle group (P<0.05). The parenchyma of the lungs damaged by CLP was attenuated by rmGas6 treatment. Lung mRNA levels of TNF-α, IL-1β, IL-6, IL-17 and MIP-2 were decreased by 60%, 86%, 82%, 93% and 82%, respectively, with rmGas6 treatment as determined by real time RT-PCR (P<0.05). The degradation of IκB-α induced by CLP in the lungs was inhibited by rmGas6 treatment. The number of neutrophils and myeloperoxidase activity in the lungs were significantly reduced in the rmGas6 group. Moreover, rmGas6 reduced the in-vitro migration of differentiated human promyelocytic HL60 cells by 64%. Finally, the 10-day survival rate of mice subjected to CLP was increased from 31% in the vehicle group to 67% in the rmGas6 group (P<0.05). Thus, Gas6 has potential to be developed as a novel therapeutic agent to treat patients with sepsis and acute lung injury.

Background Renal injury caused by ischemia-reperfusion (I/R) often occurs following shock or transplantation. Growth arrest-specific protein 6 (Gas6) is a secreted protein that binds to the TAM-family tyrosine kinase receptors which modulate the inflammatory response and activate cell survival pathways. We hypothesized that Gas6 could have a protective role in attenuating the severity of renal injury after I/R. Materials and methods Adult mice were subjected to 45 min of bilateral renal ischemia. Recombinant mouse Gas6 (rmGas6, 5 μg/mouse) or normal saline (vehicle) was administered intraperitoneally 1 h before ischemia and all subjects were sacrificed at 23 h after I/R for blood and tissue analysis. The expression of protein and mRNA was assessed by Western blotting and qPCR, respectively. Results Treatment with rmGas6 significantly decreased serum levels of creatinine and BUN by 29% and 27%, respectively, improved the renal histological injury index and reduced the apoptosis in the kidneys, compared to the vehicle. Renal mRNA levels of IL-1β, IL-6, TNF-α, KC and MIP-2 were decreased significantly by 99%, 60%, 53%, 58%, and 43%, with rmGas6 treatment, respectively. After I/R, renal IκB-α levels were reduced by 40%, while they returned to sham levels with rmGas6 treatment. The mRNA levels of iNOS and COX-2 were reduced by 79% and 70%, respectively, while the expression of cyclin D1 was increased by 2.1-fold in the rmGas6-treated group, compared to the vehicle. Conclusions Gas6 suppresses the NF-κB pathway and promotes cell proliferation, leading to reduction of inflammation and protection of renal injury induced by I/R.

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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.