Abstract
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.
Footnotes
-
This work was supported by St. Louis University Seed Funds PPG PO1 081064 and by funds from the University of Florence (Florence, Italy).
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
doi:10.1124/jpet.107.131565.
-
ABBREVIATIONS: S1P, sphingosine 1-phosphate; TNF, tumor necrosis factor; OVA, ovalbumin; NBT, nitro blue tetrazolium; FB1, fumonisin B1; PBS, phosphate-buffered saline; SOD, superoxide dismutase; DTT, dithiothreitol; MBP, major basic protein; PAO, pressure at the airway opening; Ac-DEVD-AMC, Ac-Asp-Glu-Val-Asp-AMC; 8-OHdG, 8-hydroxy-2′-deoxyguanosine; IL, interleukin; PARP, poly(ADP-ribose)polymerase; S1Pr, sphingosine 1-phosphate receptor; TdT, terminal deoxynucleotidyl transferase; TUNEL, TdT-mediated dUTP nick-end labeling; PGD2, prostaglandin D2.
- Received September 12, 2007.
- Accepted November 26, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|