To determine if endogenously generated
sphingosine-1-phosphate (S1P) is involved in the development of allergic
bronchial asthma, the effects of systemic treatments with SKI-II, a specific inhibitor of
sphingosine kinase, on
antigen-induced bronchial smooth muscle (BSM) hyperresponsiveness and airway
inflammation were examined in mice. Male BALB/c mice were actively sensitized with
ovalbumin (OA)
antigen and were repeatedly challenged with aerosolized
antigen. Animals also received
intraperitoneal injections with SKI-II (50 mg/kg) 1 h prior to each
antigen challenge. The
acetylcholine (ACh)-induced contraction of BSM isolated from the repeatedly
antigen-challenged mice was significantly augmented, that is, BSM hyperresponsiveness, as compared with that from the control animals (P < 0.05). The BSM hyperresponsiveness induced by
antigen exposure was ameliorated by the systemic treatment with SKI-II, whereas the treatments had no effect on BSM responsiveness to ACh in control animals. On the other hand, the systemic treatments with SKI-II had no effect on
antigen-induced inflammatory signs, such as increase in cell counts in bronchoalveolar lavage fluids (BALFs) and change in airway histology; upregulation of BALF
cytokines, such as
interleukin-4 (IL-4) and
IL-13; and elevation of total and OA-specific
immunoglobulin E (
IgE) in sera. These findings suggest that
sphingosine kinase inhibitors such as SKI-II have an ability to prevent the development of BSM hyperresponsiveness, but not of allergic airway
inflammation. The endogenously generated S1P might be one of the exacerbating factors for the
airway hyperresponsiveness, one of the characteristic features of allergic
bronchial asthma.