auy-954 and Pneumonia

Sphingosine-1-phosphate and its receptors have emerged as important modulators of the immune response. The sphingosine-1-phosphate prodrug 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol (FTY720) can alleviate experimental allergic airway inflammation. Nevertheless, the role of individual sphingosine-1-phosphate receptors in the regulation of allergic airway inflammation remains undefined. Using a newly characterized potent and selective sphingosine-1-phosphate receptor 1 (S1P₁) agonist with physical properties allowing airway delivery, we studied the contribution of S1P₁ signaling to eosinophilic airway inflammation induced in ovalbumin-immunized mice by airway challenges with ovalbumin. Airway delivery of receptor-nonselective sphingosine-1-phosphate prodrug significantly inhibits the sequential accumulation of antigen-presenting dendritic cells and CD4+ T cells in draining lymph nodes. This in turn suppressed by >80% the accumulation of CD4+ T cells and eosinophils in the airways. Systemic delivery of sphingosine-1-phosphate prodrug or of an S1P)₁-specific agonist at doses sufficient to induce lymphopenia did not inhibit eosinophil accumulation in the airways. In contrast, local airway delivery of S1P₁-specific agonist inhibited airways release of endogenous CCL5 and CCL17 chemokines, and significantly suppressed accumulation of activated T cells and eosinophils in the lungs. Specific S1P₁ agonism in lungs contributes significantly to anti-inflammatory activities of sphingosine-1-phosphate therapeutics by suppressing chemokine release in the airways, and may be of clinical relevance.

Topics: Allergens; Animals; beta-Alanine; Chemokines; Lung; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Ovalbumin; Pneumonia; Prodrugs; Receptors, Lysophospholipid; Receptors, Lysosphingolipid; Thiophenes

Sphingosine 1-phosphate (S1P) is a key endogenous regulator of the response to lung injury, maintaining endothelial barrier integrity through interaction with one of its receptors, S1P(1). The short-term administration of S1P or S1P(1) receptor agonists enhances endothelial monolayer barrier function in vitro, and attenuates injury-induced vascular leak in the lung and other organ systems in vivo. Although S1P(1) agonists bind to and activate S1P(1), several of these agents also induce receptor internalization and degradation, and may therefore act as functional antagonists of S1P(1) after extended exposure. Here we report on the effects of prolonged exposure to these agents in bleomycin-induced lung injury. We demonstrate that repeated administration of S1P(1) agonists dramatically worsened lung injury after bleomycin challenge, as manifested by increased vascular leak and mortality. Consistent with these results, prolonged exposure to S1P(1) agonists in vitro eliminated the ability of endothelial cell monolayers to respond appropriately to the barrier-protective effects of S1P, indicating a loss of normal S1P-S1P(1) signaling. As bleomycin-induced lung injury progressed, continued exposure to S1P(1) agonists also resulted in increased pulmonary fibrosis. These data indicate that S1P(1) agonists can act as functional antagonists of S1P(1) on endothelial cells in vivo, which should be considered in developing these agents as therapies for vascular leak syndromes. Our findings also support the hypothesis that vascular leak is an important component of the fibrogenic response to lung injury, and suggest that targeting the S1P-S1P(1) pathway may also be an effective therapeutic strategy for fibrotic lung diseases.

Topics: Animals; beta-Alanine; Bleomycin; Blood Coagulation; Endothelial Cells; Fibrosis; Fingolimod Hydrochloride; Humans; Lung Injury; Lysophospholipids; Male; Mice; Mice, Inbred C57BL; Oxadiazoles; Pneumonia; Propylene Glycols; Pulmonary Alveoli; Receptors, Lysosphingolipid; Signal Transduction; Sphingosine; Survival Analysis; Thiophenes; Vascular Diseases

It has been suggested that intratracheal administration of the immunomodulator, FTY720, could have anti-inflammatory effects without causing a decrease in blood lymphocyte counts. However, the receptor responsible for this effect has not been defined.. We have described, in a mouse model of allergen-induced inflammation, the use of proton magnetic resonance imaging to non-invasively assess lung fluid accumulation and inflammation. Here, we used this model to investigate the sphingosine-1-phosphate (S1P) receptor responsible for the anti-inflammatory effect of FTY720.. When given intranasally, FTY720 (3 and 10 microg.kg(-1)) inhibited by approximately 50% the allergen-induced accumulation of fluid in the lung detected by magnetic resonance imaging, but had no effect on the cellular inflammation in the airway space or on circulating blood lymphocytes. Inhibition of the infiltration of inflammatory cells into the airways was only observed at a dose of FTY720 that induced lymphopenia (100 microg.kg(-1)). Similar results were observed in S1P(3)-deficient mice. The effect of FTY720 was mimicked by intranasal treatment of wild-type mice with a S1P(1)-specific agonist, AUY954.. Thus, in contrast to previously published work, our results suggest that systemic exposure of FTY720 is necessary to obtain an airway anti-inflammatory effect. On the contrary, inhibition of the allergen-induced accumulation of fluid in the lung, via activation of the S1P(1) receptor, is obtainable without systemic effects.

Topics: Administration, Intranasal; Allergens; Animals; Anti-Asthmatic Agents; Anti-Inflammatory Agents; beta-Alanine; Budesonide; Capillary Permeability; Dose-Response Relationship, Drug; Female; Fingolimod Hydrochloride; Immunologic Factors; Lung; Magnetic Resonance Imaging; Mice; Mice, Inbred C57BL; Mice, Knockout; Pneumonia; Propylene Glycols; Pulmonary Edema; Receptors, Lysosphingolipid; Sphingosine; Sphingosine-1-Phosphate Receptors; Thiophenes