Inhalation of sphingosine kinase inhibitor attenuates airway inflammation in asthmatic mouse model.
Sphingosine 1-phosphate (S1P) produced by sphingosine kinase (SPHK) is implicated in acute immunoresponses, however, mechanisms of SPHK/S1P signaling in the pathogenesis of bronchial asthma are poorly understood. In this study, we hypothesized that SPHK inhibition could ameliorate lung inflammation in ovalbumin (OVA)-challenged mouse lungs. Six- to eight-week-old C57BL/6J mice were sensitized and exposed to OVA for 3 consecutive days. Twenty-four hours later, mice lungs and bronchoalveolar lavage (BAL) fluid were analyzed. For an inhibitory effect, either of the two different SPHK inhibitors, N,N-dimethylsphingosine (DMS) or SPHK inhibitor [SK-I; 2-(p-hydroxyanilino)-4-(p-chlorophenyl) thiazole], was nebulized for 30 min before OVA inhalation. OVA inhalation caused S1P release into BAL fluid and high expression of SPHK1 around bronchial epithelial walls and inflammatory areas. DMS or SK-I inhalation resulted in a decrease in S1P amounts in BAL fluid to basal levels, accompanied by decreased eosinophil infiltration and peroxidase activity. The extent of inhibition caused by DMS inhalation was higher than that caused by SK-I. Like T helper 2 (Th2) cytokine release, OVA inhalation-induced increase in eotaxin expression was significantly suppressed by DMS pretreatment both at protein level in BAL fluid and at mRNA level in lung homogenates. Moreover, bronchial hyperresponsiveness to inhaled methacholine and goblet cell hyperplasia were improved by SPHK inhibitors. These data suggest that the inhibition of SPHK affected acute eosinophilic inflammation induced in antigen-challenged mouse model and that targeting SPHK may provide a novel therapeutic tool to treat bronchial asthma.
Nishiuma
Teruaki
T
Division of Respiratory Medicine, Deptartment of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan. nishiuma@med.kobe-u.ac.jp
Nishimura
Yoshihiro
Y
Okada
Taro
T
Kuramoto
Emi
E
Kotani
Yoshikazu
Y
Jahangeer
Saleem
S
Nakamura
Shun-ichi
S
D000280:Administration, Inhalation; D000814:Aniline Compounds / Q000627:therapeutic use*; D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000188:drug therapy*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002478:Cells, Cultured; D019742:Chemokines, CC / Q000096:biosynthesis; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D020397:Goblet Cells / Q000473:pathology; D006801:Humans; D006965:Hyperplasia; D007378:Interleukins / Q000502:physiology; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D020545:Respiratory Mucosa / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000627:therapeutic use; D013844:Thiazoles / Q000627:therapeutic use*; D000099157:Sphingosine Kinase
D000814:Aniline Compounds; D019742:Chemokines, CC; D004791:Enzyme Inhibitors; D007378:Interleukins; D008246:Lysophospholipids; D010047:Ovalbumin; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D013844:Thiazoles; D000099157:Sphingosine Kinase; C530150:2-(4-hydroxyanilino)-4-(4-chlorophenyl)thiazole; C060506:sphingosine 1-phosphate; C061800:N,N-dimethylsphingosine