Alkaline sphingomyelinase deficiency impairs intestinal mucosal barrier integrity and reduces antioxidant capacity in dextran sulfate sodium-induced colitis

BACKGROUND Ulcerative colitis is a chronic inflammatory disease of the colon with an unknown etiology.Alkaline sphingomyelinase(alk-SMase)is specifically expressed by intestinal epithelial cells,and has been reported to play an anti-inflammatory role.However,the underlying mechanism is still unclear.AIM To explore the mechanism of alk-SMase anti-inflammatory effects on intestinal barrier function and oxidative stress in dextran sulfate sodium(DSS)-induced colitis.METHODS Mice were administered 3%DSS drinking water,and disease activity index was determined to evaluate the status of colitis.Intestinal permeability was evaluated by gavage administration of fluorescein isothiocyanate dextran,and bacterial translocation was evaluated by measuring serum lipopolysaccharide.Intestinal epithelial cell ultrastructure was observed by electron microscopy.Western blotting and quantitative real-time reverse transcription-polymerase chain reaction were used to detect the expression of intestinal barrier proteins and mRNA,respectively.Serum oxidant and antioxidant marker levels were analyzed using commercial kits to assess oxidative stress levels.RESULTS Compared to wild-type(WT)mice,inflammation and intestinal permeability in alk-SMase knockout(KO)mice were more severe beginning 4 d after DSS induction.The mRNA and protein levels of intestinal barrier proteins,including zonula occludens-1,occludin,claudin-3,claudin-5,claudin-8,mucin 2,and secretory immunoglobulin A,were significantly reduced on 4 d after DSS treatment.Ultrastructural observations revealed progressive damage to the tight junctions of intestinal epithelial cells.Furthermore,by day 4,mitochondria appeared swollen and degenerated.Additionally,compared to WT mice,serum malondialdehyde levels in KO mice were higher,and the antioxidant capacity was significantly lower.The expression of the transcription factor nuclear factor erythroid 2-related factor 2(Nrf2)in the colonic mucosal tissue of KO mice was significantly decreased after DSS treatment.mRNA levels of Nrf2-regulated downstream antioxidant enzymes were also decreased.Finally,colitis in KO mice could be effectively relieved by the injection of tertiary butylhydroquinone,which is an Nrf2 activator.CONCLUSION Alk-SMase regulates the stability of the intestinal mucosal barrier and enhances antioxidant activity through the Nrf2 signaling pathway.

Alkaline sphingomyelinase(NPP7) in hepatobiliary diseases: A field that needs to be closely studied

Alkaline sphingomyelinase cleaves phosphocholine from sphingomyelin, platelet-activating factor, lysophosphatidylcholine, and less effectively phosphatidyl-choline. The enzyme shares no structure similarities with acid or neutral sphingomyelinase but belongs to ectonucleotide pyrophosphatase/phosphodiesterase(NPP) family and therefore is also called NPP7 nowadays. The enzyme is expressed in the intestinal mucosa in many species and additionally in human liver. The enzyme in the intestinal tract has been extensively studied but not that in human liver. Studies on intestinal alkaline sphingomyelinase show that it inhibits colonic tumorigenesis and inflammation, hydrolyses dietary sphingomyelin, and stimulates cholesterol absorption. The review aims to summarize the current knowledge on liver alkaline sphingomyelinase in human and strengthen the necessity for close study on this unique human enzyme in hepatobiliary diseases.