Chemically modified tetracyclines inhibit inducible nitric oxide synthase expression and nitric oxide production in cultured rat mesangial cells.
Chemically modified tetracyclines inhibit inducible nitric oxide synthase expression and nitric oxide production in cultured rat mesangial cells.
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化学修饰的四环素抑制培养的大鼠系膜细胞中诱导型一氧化氮合酶的表达和一氧化氮的产生。
DOI：
10.1006/bbrc.1996.1787
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发表时间：
1996
期刊：
影响因子：
--
通讯作者：
Amin,AR
中科院分区：
文献类型：
--
作者：
Trachtman,H;Futterweit,S;Greenwald,R;Moak,S;Singhal,P;Franki,N;Amin,AR
四环素类药物抑制基质金属蛋白酶（MMP），并在多种人类和动物疾病中减弱结缔组织降解。已经合成了化学修饰的四环素（CMT），其中抗菌效力已经被消除，但其中抗MMP功效被保留。一氧化氮（NO）可调节体外培养的系膜细胞MMP的合成和活性，因此，本实验观察CMT是否抑制培养的大鼠系膜细胞iNOS基因和蛋白的表达以及NO的产生。将系膜细胞在含有IFN-γ和LPS的培养基中维持24-72 h。试验培养基不含其他添加剂或含有浓度为1、2.5、5和10 μg/ml的CMT-1、3、5或8。采用Griess反应检测iNOS基因和蛋白表达及NO生成。CMT-3和CMT-8对肾小球系膜细胞NO产生的抑制作用呈时间和剂量依赖性，在5 μg/ml浓度时，抑制作用最强（<20%）。添加CMT-1具有适度（40%）的抑制作用，CMT-5没有改变NO的产生。CMT对NO产生的影响与其作为胶原酶抑制剂的效力直接相关。此外，CMT诱导的NO合成变化与稳态iNOS mRNA丰度和蛋白表达的平行改变相关。这些药物可用于改善NO依赖性肾小球炎症。
Tetracyclines inhibit matrix metalloproteinases (MMP) and attenuate connective tissue degradation in a wide variety of human and animal disorders. Chemically modified tetracyclines (CMT) have been synthesized in which the antibacterial potency has been eliminated but in which the anti-MMP efficacy is retained. Nitric oxide (NO) modulates MMP synthesis and activity in mesangial cellsin vitro.Therefore, we examined whether CMT inhibit iNOS gene and protein expression and NO production in cultured rat mesangial cells. Mesangial cells were maintained in media containing IFN-γ and LPS for 24–72 h. Test media contained either no further additives or CMT-1, 3, 5, or 8 at concentrations of 1, 2.5, 5, and 10 μg/ml. iNOS gene and protein expression were assessed and NO production was determined by the Griess reaction. Incubation of mesangial cells with CMT-3 and CMT-8 resulted in time- and dose-dependent inhibition of NO production that was maximal at 48 h (<20% of control) and at a drug concentration of 5 μg/ml (P<0.05). Addition of CMT-1 had a modest (40%) inhibitory effect and CMT-5 did not alter NO production. The impact of CMT on NO production was directly related to their potency as collagenase inhibitors. Moreover, CMT-induced changes in NO synthesis were associated with parallel alterations in steady-state iNOS mRNA abundance and protein expression. These agents may be useful to ameliorate NO-dependent glomerular inflammation.