Treatment with a sphingosine-1-phosphate analog inhibits airway remodeling following repeated allergen exposure

AJP Lung Cellular and Molecular Physiology (Impact Factor: 4.08). 01/2012; 302:L736-L745.


Treatment with a sphingosine-1-phosphate analog inhibits airway remodeling
following repeated allergen exposure. Am J Physiol Lung Cell Mol
Physiol 302: L736–L745, 2012. First published January 27, 2012;
doi:10.1152/ajplung.00050.2011.—Sphingosine-1-phosphate (S1P) is
an immunomodulatory lipid mediator that plays an important role in
lymphocyte trafficking. Elevated levels of S1P are found in bronchoalveolar
lavage (BAL) fluid of patients with asthma; however, its
role in disease is not known. FTY720, a synthetic analog of S1P, has
been shown to abrogate allergic inflammation and airway hyperresponsiveness
following acute allergen challenge. However, its effects
on asthmatic airway remodeling induced by repeated allergen exposure
are unknown. Ovalbumin (OVA)-sensitized rats were challenged
on days 14, 19, and 24 after sensitization. FTY720 or vehicle (PBS)
therapy was administered 1 h prior to each challenge. BAL fluid and
quantitative histological analysis were performed 48 h after the last
challenge. FTY720 inhibited OVA-induced features of airway remodeling
including increased airway smooth muscle mass and bronchial
neovascularization, without affecting lymphocyte numbers in secondary
lymphoid organs. Furthermore, CD3� cells adjacent to airway
smooth muscle bundles were increased in OVA-challenged rats but
the increase was inhibited by FTY720. There was an expansion of
bronchus-associated lymphoid tissue following FTY720 treatment of
OVA-challenged animals. Real-time quantitative PCR revealed that
Th2-associated transcription factors were inhibited following FTY720
therapy. Airway remodeling is a cardinal feature of severe asthma.
These results demonstrate that allergen-driven airway remodeling can
be inhibited by FTY720, offering potential new therapies for the
treatment of severe asthma.

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