SulfanilamideおよびPhenacetinの毒性発現機構に関する研究

第1章 緒言 第2章 Sulfanilamide皮膚アレルギーの発現機序 第3章 Phenacetinとsulfanilamideの腎毒作用機序辞Made available in DSpace on 2012-06-27T04:09:37Z (GMT). No. of bitstreams: 1 eyanagi.pdf: 6706292 bytes, checksum: 1065bee7bf31bb31c5d5c2ab5663510b (MD5) Previous issue date: 1991-02-1

Acid sphingomyelinase inhibition suppresses lipopolysaccharide-mediated release of inflammatory cytokines from macrophages and protects against disease pathology in dextran sulphate sodium-induced colitis in mice

Lipopolysaccharide (LPS) and inflammatory cytokines cause activation of sphingomyelinases (SMases) and subsequent hydrolysis of sphingomyelin (SM) to produce a lipid messenger ceramide. The design of SMase inhibitors may offer new therapies for the treatment of LPS- and cytokine-related inflammatory bowel disease. We synthesized a series of difluoromethylene analogues of SM (SMAs). We report here the effects of the most potent SMase inhibitor, SMA-7, on the LPS-mediated release of tumour necrosis factor-α, interleukin-1β and interleukin-6 from THP-1 macrophages and the pathology of dextran sulphate sodium (DSS)-induced colitis in mice. SMA-7 suppressed the LPS-induced cytokine release and nuclear factor-κB activation. LPS stimulation caused a four-fold increase in acid SMase activation, but little increase in neutral SMase activity. The presence of 10 μm SMA-7 caused acid SMase to remain at the control levels and reduced the formation of ceramide. HT-29 cells had significantly decreased cell viability when incubated with media from LPS-stimulated THP-1 macrophages. However, incubating the colon cells in media from both SMA-7 and LPS-treated macrophages caused little decrease in viability, suggesting that ceramide has a role in the LPS-stimulated signalling that releases cytotoxic factors against colon cells. Oral administration of SMA-7 to mice with 2% DSS in the drinking water, for 10 or 21 consecutive days, reduced significantly the cytokine levels in the colon and the severity of colonic injury. These findings suggest a central role for acid SMase/ceramide signalling in the pathology of DSS-induced colitis in mice, indicating a possible preventive or therapeutic role for SMase inhibitor in inflammatory bowel disease