Acid sphingomyelinase regulates T_H2 cytokine release and bronchial asthma

Abstract

Background Allergic diseases and especially allergic asthma are widespread diseases with high prevalence in childhood, but also in adults. Acid sphingomyelinase (ASM) is a key regulator of the sphingolipid pathway. Previous studies defined the association of ASM with the pathogenesis of TH1‐directed lung diseases like cystic fibrosis and acute lung injury. Here, we define the role of ASM in TH2‐regulated allergic bronchial asthma. Methods To determine the role of Asm under baseline conditions, wild‐type (WT) and Asm−/− mice were ventilated with a flexiVent setup and bronchial hyperresponsiveness was determined using acetylcholine. Flow cytometry and cytokine measurements in bronchoalveolar lavage fluid and lung tissue were followed by in vitro TH2 differentiations with cells from WT and Asm−/− mice and blockade of Asm with amitriptyline. As proof of principle, we conducted an ovalbumin‐induced model of asthma in WT‐ and Asm−/− mice. Results At baseline, Asm−/− mice showed better lung mechanics, but unaltered bronchial hyperresponsiveness. Higher numbers of Asm−/− T cells in bronchoalveolar lavage fluid released lower levels of IL‐4 and IL‐5, and these results were paralleled by decreased production of typical TH2 cytokines in Asm−/− T lymphocytes in vitro. This phenotype could be imitated by incubation of T cells with amitriptyline. In the ovalbumin asthma model, Asm−/− animals were protected from high disease activity and showed better lung functions and lower levels of eosinophils and TH2 cytokines. Conclusion Asm deficiency could induce higher numbers of TH2 cells in the lung, but those cells release decreased TH2 cytokine levels. Hereby, Asm−/− animals are protected from bronchial asthma, which possibly offers novel therapeutic strategies, for example, with ASM blockade.

Ceramide in apoptosis and oxidative stress in allergic inflammation and asthma

“…Acidic sphingomyelinase, which cleaves sphingomyelin to ceramide, has been implicated in bronchial asthma in mice. 45 However, in contrast to significant increases in ceramide and dihydroceramide levels, sphingomyelin levels were essentially unchanged after exposure to HDM (see Fig E5 in this article's Online Repository at www. jacionline.org), indicating that sphingomyelin degradation is not a major contributor to elevation of ceramide level.…”

Serum sphingolipid profile in asthma

“…In contrast to that in the healthy control group, the serum ASMase activity in the asthma group was significantly reduced, but there was no significant difference in induced sputum supernatant ASMase activity between the two groups (Table 3). ASMase is thought to convert SM into Cer in the pathogenesis of asthma 11,37,38 . In this study, the SM level was found to be decreased in asthma patients, and thus, we speculated that ASMase activity may be up‐regulated in asthma patients.…”

“…ASMase is thought to convert SM into Cer in the pathogenesis of asthma. 11,37,38 In this study, the SM level was found to be decreased in asthma patients, and thus, we speculated that ASMase activity may be up-regulated in asthma patients. However, the results showed that the serum ASMase activity in asthma patients was lower than that in healthy controls.…”

“…ASMase, a key enzyme that hydrolyzes SM to produce Cer, is the type most widely distributed in lung tissue 11,37 . In contrast to that in the healthy control group, the serum ASMase activity in the asthma group was significantly reduced, but there was no significant difference in induced sputum supernatant ASMase activity between the two groups (Table 3).…”

“…SM levels are maintained by catabolic action of neutral or acid sphingomyelinase (ASMase), releasing Cer and the corresponding head group, phosphorylcholine, or by anabolic action of sphingomyelin synthase (SMS), basing on Cers as substrate 10 . In addition, ASMase was found to be involved in the regulation of the typical T helper 2 phenotype 11 and was implicated in inflammatory diseases, such as acute lung injury 12 and rheumatoid disease 13 . However, the role of SM in asthma remains elusive.…”