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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Ceramide: a Key Signaling Molecule in a Guinea Pig Model of Allergic Asthmatic Response and Airway Inflammation

Department of Preclinical and Clinical Pharmacology (E.M., L.G., R.M.) and Anatomy, Histology and Forensic Medicine, Section of Histology (S.N., L.C.), University of Florence, Florence, Italy; Pathobiology, and Pulmonary, Critical Care Medicine, Cleveland Clinic, Cleveland, Ohio (W.X., S.A.A.C.); Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, and Department of Pharmacological and Physiological Sciences, St. Louis University School of Medicine, St. Louis, Missouri (D.L., G.M.M., D.S.); and Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Italy and Centro Neurolesi "Bonino-Pulejo", Messina, Italy (S.C.)

Although mechanisms involved in the pathogenesis of asthma remain unclear, roles for oxidative/nitrosative stress, epithelial cell apoptosis, and airway inflammation have been documented. Ceramide is a sphingolipid with potent proinflammatory and proapoptotic properties. This study aimed at determining whether increased formation of ceramide contributes to the development of airway inflammation and hyper-responsiveness, using a well characterized in vivo model of allergic asthmatic response and airway inflammation in ovalbumin-sensitized guinea pigs. Aerosol administration of ovalbumin increased ceramide levels and ceramide synthase activity in the airway epithelium associated with respiratory abnormalities, such as cough, dyspnea, and severe bronchoconstriction. These abnormalities correlated with nitrotyrosine formation in the airway epithelium and oxidative/nitrosative stress, epithelial cell apoptosis, and airway inflammation evident by the infiltration of neutrophils and eosinophils in lung tissues, mast cell degranulation, and release of prostaglandin D₂ and proinflammatory cytokines. Inhibition of de novo ceramide synthesis with the competitive and reversible inhibitor of ceramide synthase fumonisin B1 (0.25, 0.5 and 1 mg/kg b.wt.), given i.p. daily for 4 days before allergen challenge, attenuated nitrotyrosine formation and oxidative/nitrosative stress, epithelial cell apoptosis, and airway inflammation while improving the respiratory and histopathological abnormalities. These results implicate ceramide in the development of allergic asthmatic response and airway inflammation. Strategies aimed at reducing the levels of ceramide and downstream events should yield promising novel anti-asthmatic agents.

Address correspondence to: Prof. Emanuela Masini, Dept. Preclinical and Clinical Pharmacology, University of Florence. Viale G. Pieraccini 6, I-50139 Florence, Italy. E-mail: emanuela.masini{at}unifi.it

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