title: Sphingosine 1-phosphate rescues canine LPS-induced acute lung injury and alters systemic inflammatory cytokine production in vivo.
abstract: 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 microg/kg) or vehicle and 8 h of high-tidal-volume mechanical ventilation. S1P attenuated the formation of Q(s)/Q(t) (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-alpha (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.
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: William S
authors.initials: WS
authors.lastname: Szczepaniak
authors.forename: Yingze
authors.initials: Y
authors.lastname: Zhang
authors.forename: Sarah
authors.initials: S
authors.lastname: Hagerty
authors.forename: Michael T
authors.initials: MT
authors.lastname: Crow
authors.forename: Priya
authors.initials: P
authors.lastname: Kesari
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
authors.forename: Augustine M K
authors.initials: AM
authors.lastname: Choi
authors.forename: Brett A
authors.initials: BA
authors.lastname: Simon
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: McVerry
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D016207:Cytokines / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000276:immunology; D008246:Lysophospholipids / Q000494:pharmacology*; D008297:Male; D009504:Neutrophils / Q000276:immunology; D012121:Respiration, Artificial; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; D013110:Sphingosine