SKI-II, an Inhibitor of Sphingosine Kinase, Ameliorates Antigen-Induced Bronchial Smooth Muscle Hyperresponsiveness, but Not Airway Inflammation, in Mice

Abstract

Abstract. 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.

Sphingosine-1-Phosphate-Induced Airway Hyper-Reactivity in Rodents Is Mediated by the Sphingosine-1-Phosphate Type 3 Receptor

“…The role of endogenously produced S1P has been assessed in mouse models of asthma, and in all cases the airway hyper-reactivity was abrogated (Lai et al, 2008;Nishiuma et al, 2008;Haberberger et al, 2009;Chiba et al, 2010b). These data suggest that the increased S1P levels seen in the airways of asthmatic patients after provocation with allergen (Ammit et al, 2001) could drive the airway hyper-reactivity associated with this disease.…”

Asthmatic airway hyperresponsiveness: the ants in the tree

“…18,No. 11 challenged with ovalbumin is also enhanced, suggesting that other allergens, even without intrinsic proteolytic activity, may cause AHR by increasing the ability of the ASM to generate force.…”

“…18,No. 11 chain (smMHC) combined with actomyosin filamentogenesis and cellular hypertrophy by transforming growth factor (TGF) b1 [33] and cardiotrophin-1 [34] are good examples.…”

“…The house dust mite allergen Dermatophagoides pteronyssinus (Der p 1) also increases ASM force generation by a mechanism dependent on its cysteine protease activity [10]. Ex vivo contractility of bronchial rings derived from mice [11] or rats [12] sensitized and . Once stimulated to contract in response to a spasmogen, the muscle strives to shorten.…”

Activation of SphK1 by K6PC-5 Inhibits Oxygen–Glucose Deprivation/Reoxygenation-Induced Myocardial Cell Death

“…2B, C), indicating a role of SphK1 in OGD-mediated cell death. Furthermore, B-5354c (Kono et al, 2002) and SKI-II (Chiba et al, 2010;Li et al, 2014), two established SphK1 inhibitors, similarly aggravated H9c2 cell death by OGD/reoxygenation (Fig. 2D).…”