Article

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

AJP Lung Cellular and Molecular Physiology (Impact Factor: 4.04). 01/2012; 302:L736-L745.

ABSTRACT 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.

Download full-text

Full-text

Available from: Sana Siddiqui, Aug 25, 2015
0 Followers
 · 
128 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid produced by mast cells (MCs) on cross-linking of their high-affinity receptors for IgE by antigen that can amplify MC responses by binding to its S1P receptors. An acute MC-dependent allergic reaction can lead to systemic shock, but the early events of its development in lung tissues have not been investigated, and S1P functions in the onset of allergic processes remain to be examined. We used a highly specific neutralizing anti-S1P antibody (mAb) and the sphingosine-1-phosphate receptor 2 (S1PR2) antagonist JTE-013 to study the signaling contributions of S1P and S1PR2 to MC- and IgE-dependent airway allergic responses in mice within minutes after antigen challenge. Allergic reaction was triggered by a single intraperitoneal dose of antigen in sensitized mice pretreated intraperitoneally with anti-S1P, isotype control mAb, JTE-013, or vehicle before antigen challenge. Kinetics experiments revealed early pulmonary infiltration of mostly T cells around blood vessels of sensitized mice 20 minutes after antigen exposure. Pretreatment with anti-S1P mAb inhibited in vitro MC activation, as well as in vivo development of airway infiltration and MC activation, reducing serum levels of histamine, cytokines, and the chemokines monocyte chemoattractant protein 1/CCL2, macrophage inflammatory protein 1α/CCL3, and RANTES/CCL5. S1PR2 antagonism or deficiency or MC deficiency recapitulated these results. Both in vitro and in vivo experiments demonstrated MC S1PR2 dependency for chemokine release and the necessity for signal transducer and activator of transcription 3 activation. Activation of S1PR2 by S1P and downstream signal transducer and activator of transcription 3 signaling in MCs regulate early T-cell recruitment to antigen-challenged lungs through chemokine production. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
    Journal of Allergy and Clinical Immunology 12/2014; 135(4). DOI:10.1016/j.jaci.2014.10.044 · 11.25 Impact Factor