TY - JOUR
T1 - Sphingosine 1-phosphate rescues canine LPS-induced acute lung injury and alters systemic inflammatory cytokine production in vivo
AU - Szczepaniak, William S.
AU - Zhang, Yingze
AU - Hagerty, Sarah
AU - Crow, Michael T.
AU - Kesari, Priya
AU - Garcia, Joe G.N.
AU - Choi, Augustine M.K.
AU - Simon, Brett A.
AU - McVerry, Bryan J.
PY - 2008/11
Y1 - 2008/11
N2 - S1P has been demonstrated to protect against the formation of lipopolysaccharide (LPS)-induced lung edema when administered concomitantly with LPS. In the current study, we sought to determine the effectiveness of S1P to attenuate lung injury in a translationally relevant canine model of ALI when administered as rescue therapy. Secondarily, we examined whether the attenuation of LPS-induced physiologic lung injury after administration of S1P was, at least in part, caused by an alteration in local and/or systemic inflammatory cytokine expression. We examined 18, 1-year-old male beagles prospectively in which we instilled bacterial LPS (2-4 mg/kg) intratracheally followed in 1 h with intravenous S1P (85 μg/kg) or vehicle and 8 h of high-tidal-volume mechanical ventilation. S1P attenuated the formation of Qs/Qt (32%), and both the presence of protein (72%) and neutrophils (95%) in BAL fluid compared with vehicle controls. Although lung tissue inflammatory cytokine production was found to vary regionally throughout the LPS-injured lung, S1P did not alter the expression pattern. Similarly, BAL cytokine production was not altered significantly by intravenous S1P in this model. Interestingly, S1P potentiated the LPS-induced systemic production of 3 inflammatory cytokines, TNF-α (6-fold), KC (1.2-fold), and IL-6 (3-fold), without resulting in end-organ dysfunction. In conclusion, intravenous S1P reduces inflammatory lung injury when administered as rescue therapy in our canine model of LPS-induced ALI. This improvement is observed in the absence of changes in local pulmonary inflammatory cytokine production and an augmentation of systemic inflammation.
AB - S1P has been demonstrated to protect against the formation of lipopolysaccharide (LPS)-induced lung edema when administered concomitantly with LPS. In the current study, we sought to determine the effectiveness of S1P to attenuate lung injury in a translationally relevant canine model of ALI when administered as rescue therapy. Secondarily, we examined whether the attenuation of LPS-induced physiologic lung injury after administration of S1P was, at least in part, caused by an alteration in local and/or systemic inflammatory cytokine expression. We examined 18, 1-year-old male beagles prospectively in which we instilled bacterial LPS (2-4 mg/kg) intratracheally followed in 1 h with intravenous S1P (85 μg/kg) or vehicle and 8 h of high-tidal-volume mechanical ventilation. S1P attenuated the formation of Qs/Qt (32%), and both the presence of protein (72%) and neutrophils (95%) in BAL fluid compared with vehicle controls. Although lung tissue inflammatory cytokine production was found to vary regionally throughout the LPS-injured lung, S1P did not alter the expression pattern. Similarly, BAL cytokine production was not altered significantly by intravenous S1P in this model. Interestingly, S1P potentiated the LPS-induced systemic production of 3 inflammatory cytokines, TNF-α (6-fold), KC (1.2-fold), and IL-6 (3-fold), without resulting in end-organ dysfunction. In conclusion, intravenous S1P reduces inflammatory lung injury when administered as rescue therapy in our canine model of LPS-induced ALI. This improvement is observed in the absence of changes in local pulmonary inflammatory cytokine production and an augmentation of systemic inflammation.
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U2 - 10.1016/j.trsl.2008.09.002
DO - 10.1016/j.trsl.2008.09.002
M3 - Article
C2 - 19010292
AN - SCOPUS:56049110035
SN - 1931-5244
VL - 152
SP - 213
EP - 224
JO - Translational Research
JF - Translational Research
IS - 5
ER -