Inhalation of sphingosine kinase inhibitor attenuates airway inflammation in asthmatic mouse model

Nishiuma, Teruaki; Nishimura, Yoshihiro; Okada, Taro; Kuramoto, Emi; Kotani, Yoshikazu; Jahangeer, Saleem; Nakamura, Shun‐ichi

doi:10.1152/ajplung.00445.2007

Cited by 99 publications

(95 citation statements)

References 40 publications

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“…Interestingly, S1P, normalized to the BALF protein concentration (37.5 6 3.4 mg/ml in WT mice; 41.1 6 2.9 mg/ml in CF mice), was decreased in CF BALF (P , 0.01; Figure 6). These concentrations are comparable to those analyzed previously in the BALF of C57BL/6 mice by an enzymatic method and thin liquid chromatography (24,25).…”

Section: Cf Pulmonary Milieu Affects Maturation and Activation Of Dcssupporting

confidence: 88%

Low Sphingosine-1–Phosphate Impairs Lung Dendritic Cells in Cystic Fibrosis

Krause

Limberis

et al. 2013

Am J Respir Cell Mol Biol

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Dysfunction of the cystic fibrosis transmembrane regulator (CFTR) leads to chronic inflammation and infection of the respiratory tract. The role of CFTR for cells of the pulmonary immune system is only partly understood. The present study analyzes the phenotype and immune stimulatory capacity of lung dendritic cells (DCs) from CFTR knockout (CF) mice. Total numbers of conventional DCs, plasmacytoid DCs, and CD103-positive DCs were lower in CF mice compared with wild-type (WT) control mice, as was the expression of major histocompatibility complex class II molecules (MHCII), CD40, and CD86. After pulmonary infection with respiratory syncytial virus, DC numbers increased in WT mice but not in CF mice, and the T cellstimulatory capacity of CF DCs was impaired. The culture of CF lung DCs with bronchoalveolar lavage fluid (BALF) from WT mice increased the expression of MHCII, CD40, and CD86. The supplementation of CF BALF with sphingosine-1-phosphate (S1P), a mediator of immune cell migration and activation that is decreased in CF BALF, rescued the reduced expression of MHCII and CD40 in WT lung DCs and human blood DCs. These findings suggest that DCs are impaired in the CF lung, and that altered S1P affects lung DC function. These findings provide a novel link between defective CFTR and pulmonary innate immune dysfunction in CF.

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Section: Cf Pulmonary Milieu Affects Maturation and Activation Of Dcssupporting

confidence: 88%

Low Sphingosine-1–Phosphate Impairs Lung Dendritic Cells in Cystic Fibrosis

Krause

Limberis

et al. 2013

Am J Respir Cell Mol Biol

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“…The systemic treatments with SKI-II had no effect on the infiltration of inflammatory cells (D). (12), N,N-dimethylsphingosine (DMS) (11,35), and 2-(p-hydroxyanilino)-4-(p-chlorophenyl) thiazole (SK-I) (11). The in vivo AHR induced by antigen challenge was also attenuated in the sphingosine kinase-1 knockout mice (14).…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that sphingosine kinase inhibitors such as DMS (11,35) and SK-I (11) could attenuate antigen-induced airway inflammation. However, in the present study, the SKI-II treatments had no significant effect on the increase in BAL cells ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…The finding that S1P can act as a chemotactic agent for eosinophils further suggests an involvement of S1P in pathophysiology of asthma (10). Indeed, inhalation of inhibitors for sphingosine kinase, which produces S1P directly from sphingosine, attenuated antigen-induced airway inflammation in mice (11). In addition, S1P might have an ability to cause airway hyperresponsiveness (AHR) (12 -15).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2010

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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.

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“…Previous studies linking asthma to sphingolipids have been centered on inflammatory and allergic mechanisms related to the sphingolipid mediator S1P (48)(49)(50)(51)(52)(53). S1P is involved in mast cell degranulation and airway hyperresponsiveness in allergic asthma models (53)(54)(55)(56) and has been a focus on the development of sphingolipid-based anti-inflammatory agents (51,(57)(58)(59).…”

Section: Ormdl3 and Sphingolipidsmentioning

confidence: 99%