Abstract
Background Sphingosine-1-phosphate (S1P) is a biologically active lysophospholipid mediator involved in modulating inflammatory process. We investigated the effects of FTY720, a structural analogue of S1P after phosphorylation, on lung injury induced by hindlimb ischemia reperfusion (IR) in rats. Methods Fifty Sprague-Dawley rats were divided into groups SM, IR, F3, F5, and F10. Group SM received sham operation, and bilateral hindlimb IR was established in group IR. The rats in groups F3, F5, and F10 were pretreated with 3, 5, and 10 mg/kg/d FTY720 for 7 days before IR. S1P lyase (S1PL), sphingosine kinase (SphK) 1, and SphK2 mRNA expressions, wet/dry weight (W/D), and polymorphonuclear/alveolus (P/A) in lung tissues were detected, and the lung injury score was evaluated. Results W/D, P/A, and mRNA expressions of S1PL, SphK1, and SphK2 were higher in group IR than in group SM, while these were decreased in both groups F5 and F10 as compared to IR (p < 0.05). The lung tissue presented severe lesions in group IR, which were attenuated in groups F5 and F10 with lower lung injury scores than in group IR (p < 0.05). Conclusions FTY720 pretreatment could attenuate lung injury induced by hindlimb IR by modulating S1P metabolism and decreasing pulmonary neutrophil infiltration.
Highlights
Limb ischemia reperfusion (IR) injury is commonly presented in restoration of blood flow to previously hypoxic extremities following severe crush injury, vessel damage, or some surgical procedures
Sphingosine-1-phosphate (S1P) is a biologically active lysophospholipid that is primarily produced by both sphingosine kinase 1 (SphK1) and sphingosine kinase 2 (SphK2) from sphingosine in response to various cellular stimuli [7], while its degradation is mainly mediated by S1P lyase (S1PL)
At the end of reperfusion, pH, PaO2, and base excess (BE) were significantly lower (p < 0 05), whereas PaCO2 was higher in group IR than in group SM (p < 0 05; Table 1)
Summary
Limb ischemia reperfusion (IR) injury is commonly presented in restoration of blood flow to previously hypoxic extremities following severe crush injury, vessel damage, or some surgical procedures. Strategies for limiting pulmonary PMN sequestration could serve as a promising alternative therapy to attenuate lung injury induced by limb IR. Sphingosine-1-phosphate (S1P) is a biologically active lysophospholipid that is primarily produced by both sphingosine kinase 1 (SphK1) and sphingosine kinase 2 (SphK2) from sphingosine in response to various cellular stimuli [7], while its degradation is mainly mediated by S1P lyase (S1PL). We investigated the effects of FTY720, a structural analogue of S1P after phosphorylation, on lung injury induced by hindlimb ischemia reperfusion (IR) in rats. S1P lyase (S1PL), sphingosine kinase (SphK) 1, and SphK2 mRNA expressions, wet/dry weight (W/D), and polymorphonuclear/alveolus (P/A) in lung tissues were detected, and the lung injury score was evaluated. FTY720 pretreatment could attenuate lung injury induced by hindlimb IR by modulating S1P metabolism and decreasing pulmonary neutrophil infiltration
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