Cyclic AMP-regulating agents inhibit endotoxin-mediated cartilage degradation.
Cyclic AMP-regulating agents inhibit endotoxin-mediated cartilage degradation.
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环AMP调节剂抑制内毒素介导的软骨降解。
DOI：
10.1042/bj2440063
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发表时间：
1987
期刊：
影响因子：
--
通讯作者：
Sledge,CB
中科院分区：
文献类型：
--
作者：
Bednar,MS;Hubbard,JR;Steinberg,JJ;Broner,FA;Sledge,CB
用磷酸二酯酶抑制剂[茶碱和3-异丁基-1-甲基黄嘌呤(IBMX)]、Forsklin(激活腺苷环化酶催化亚单位)和环AMP类似物(二丁酰基和8-溴)研究了环磷酸腺苷对软骨降解的影响。通过量化释放到8天牛鼻中隔软骨培养上清液中的蛋白多糖来评估破损情况。茶碱(1-20 mM)、IBMX(0.01-2 mM)和二丁酰环AMP(0.1-2 mM)对非刺激(无内毒素)软骨蛋白多糖的释放速率影响很小或没有影响。8-溴环状AMP(0.5-2 mM)和福司可林(50-75微克/毫升)的崩解率略有增加，但可检测到。为了检测这些药物的潜在抑制作用，将环状AMP调节剂加入到伤寒沙门氏菌内毒素(12-25微克/毫升)处理的培养物中，伤寒沙门氏菌内毒素是一种有效的软骨降解刺激剂。3种环状AMP调节剂均能显著抑制内毒素引起的3-4倍刺激作用。10-20 mM-茶碱、1-2 mM-IBMX、50-75微克/ml福司可林、2 mM-二丁酰环腺苷、2 mM-8-溴环腺苷抑制效果最好。抑制被证明是可逆的，表明软骨在治疗后是存活的。琼脂糖凝胶CL-2B层析从处理软骨释放的蛋白多糖产物表明，内毒素刺激的向低平均MR的转变被环状AMP类似物和磷酸二酯酶抑制剂显著阻止。总之，这些结果表明，增加环状AMP的药物抑制了内毒素介导的软骨降解的数量和质量方面。
The influence of cyclic AMP on cartilage degradation was investigated by using phosphodiesterase inhibitors [theophylline and 3-isobutyl-1-methylxanthine (IBMX)], forskolin (which activates the catalytic subunit of adenylate cyclase) and cyclic AMP analogues (dibutyryl and 8-bromo). Breakdown was assessed by quantification of proteoglycans released into the media of 8-day bovine nasal-septum cartilage cultures. Theophylline (1-20 mM), IBMX (0.01-2 mM) and dibutyryl cyclic AMP (0.1-2 mM) had little or no influence on the rate of proteoglycan release from unstimulated (no-endotoxin) cartilages. A small but detectable increase in breakdown was observed with 8-bromo cyclic AMP (0.5-2 mM) and forskolin (50-75 micrograms/ml). To examine potential inhibitory influences of these agents, the cyclic AMP modulators were added to cultures simultaneously treated with Salmonella typhosa endotoxin (12-25 micrograms/ml), a potent stimulator of cartilage degradation. The 3-4-fold stimulation of breakdown by endotoxin was strikingly inhibited by all three classes of cyclic AMP regulators. Optimal inhibition was found at 10-20 mM-theophylline, 1-2 mM-IBMX, 50-75 micrograms of forskolin/ml, 2 mM-dibutyryl cyclic AMP and 2 mM-8-bromo cyclic AMP. Inhibition was shown to be reversible, indicating that cartilages were viable after treatment. Sepharose CL-2B chromatography of proteoglycan products released from treated cartilages showed that the endotoxin-stimulated shift to lower average Mr was significantly prevented by cyclic AMP analogues and phosphodiesterase inhibitors. Together, these results show that agents which increase cyclic AMP inhibit both quantitative and qualitative aspects of endotoxin-mediated cartilage degradation.