Elsevier

Translational Research

Volume 152, Issue 5, November 2008, Pages 213-224
Translational Research

Original article
Sphingosine 1-phosphate rescues canine LPS-induced acute lung injury and alters systemic inflammatory cytokine production in vivo

https://doi.org/10.1016/j.trsl.2008.09.002Get rights and content

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.

Section snippets

Methods

Animal protocols were approved by the University of Pittsburgh and the Johns Hopkins University Institutional Animal Care and Use Committees.

Experimental groups

Eighteen 1-year-old male beagles (10–15 kg) received intrabronchial instillation of LPS (2–4 mg/kg) under direct bronchoscopic visualization. The animals then received either iv S1P (85 μg/kg) or vehicle (saline) 1 h after LPS instillation (n, 9 each group).

Intrabronchial LPS induces severe lung injury in vehicle-treated animals

In the 9 animals who received intrabronchial LPS followed by vehicle, PaO2/FiO2 declined throughout the duration of the experiment (from 561.0 ± 15.3 to 294.0 ± 31.3; Table I). Qs/Qt increased rapidly and progressively throughout the

Discussion

Using a translationally relevant large animal model of inflammatory ALI, we recently demonstrated that iv S1P (85 μg/kg) administered concomitantly with intratracheal LPS reduced shunt formation, attenuated alveolar protein accumulation, and decreased regional alveolar edema formation in beagles compared with animals injured with LPS alone.17 The current study has extended these findings to demonstrate that iv S1P reduces physiologic lung injury when administered subsequent to injury induction

References (42)

  • C.H. Goss et al.

    Incidence of acute lung injury in the United States

    Crit Care Med

    (2003)
  • G.D. Rubenfeld et al.

    Incidence and outcomes of acute lung injury

    N Engl J Med

    (2005)
  • L.B. Ware et al.

    The acute respiratory distress syndrome

    N Engl J Med

    (2000)
  • Y. Oba et al.

    Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network

    N Engl J Med

    (2000)
  • J.G. Garcia et al.

    Sphingosine 1-phosphate promotes endothelial cell barrier integrity by Edg-dependent cytoskeletal rearrangement

    J Clin Invest

    (2001)
  • X. Peng et al.

    Protective effects of sphingosine 1-phosphate in murine endotoxin-induced inflammatory lung injury

    Am J Respir Crit Care Med

    (2004)
  • W.S. Szczepaniak et al.

    Sphingosine 1-phosphate induces dose-dependent pulmonary vascoconstriction in the intact mouse lung

    Am J Respir Crit Care Med

    (2007)
  • K.L. Schaphorst et al.

    Role of sphingosine-1 phosphate in the enhancement of endothelial barrier integrity by platelet-released products

    Am J Physiol Lung Cell Mol Physiol

    (2003)
  • K.L. Schaphorst et al.

    Sphingosine 1-phosphate increases F-actin/adherens junction linkage and enhances barrier protection

    Amer J Resp Crit Care Med

    (2001)
  • S. Mandala et al.

    Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists

    Science

    (2002)
  • S. Salomone et al.

    Analysis of sphingosine 1-phosphate receptors involved in constriction of isolated cerebral arteries with receptor null mice and pharmacological tools

    Br J Pharmacol

    (2008)
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    Supported by grants from the NHLBI F32 HL74569, P50 HL073994, P01 HL 58604, and K08 HL083101.

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