Sildenafil Reduces Expression and Release of IL-6 and IL-8 Induced by Reactive Oxygen Species in Systemic Sclerosis Fibroblasts
Sildenafil Reduces Expression and Release of IL-6 and IL-8 Induced by Reactive Oxygen Species in Systemic Sclerosis Fibroblasts
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DOI：
10.3390/ijms21093161
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发表时间：
2020-05-01
影响因子：
5.6
通讯作者：
Antinozzi, Cristina
中科院分区：
文献类型：
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作者：
Di Luigi, Luigi;Sgro, Paolo;Antinozzi, Cristina
与血管损伤相关的氧化应激在系统性硬化症（SSc）的发病机制中起重要作用。事实上，雷诺现象（RP）患者甲襞毛细血管镜检查时的血管损伤是SSc发展的主要风险因素，同时存在特异性自身抗体。在这里，我们研究了磷酸二酯酶5型抑制剂（PDE 5i）西地那非，目前用于管理RP，在体外调节皮肤成纤维细胞对氧化应激的促炎反应的影响。在存在或不存在西地那非（1 μ M）的情况下，将从SSc患者和健康对照中分离的人成纤维细胞暴露于外源性活性氧（ROS）（100 μ M H2 O2）。西地那非治疗显著降低了真皮成纤维细胞基因表达和细胞释放的IL-6，已知在SSc和IL-8的组织损伤的发病机制中发挥核心作用，直接由ROS诱导。这种减少与STAT 3-、ERK-、NF-κ B-和PKB/AKT依赖性通路的抑制有关。我们的研究结果支持了这样的观点，即在RP的管理中使用PDE 5i可以探索其在体内调节氧化应激诱导的真皮成纤维细胞促炎活化中的功效，并可能最终有助于预防SSc引起的组织损伤。
Oxidative stress linked to vascular damage plays an important role in the pathogenesis of systemic sclerosis (SSc). Indeed, vascular damage at nailfold capillaroscopy in patients with Raynaud's Phenomenon (RP) is a major risk factor for the development of SSc together with the presence of specific autoantiobodies. Here, we investigated the effects of the phosphodiesterase type 5 inhibitor (PDE5i) sildenafil, currently used in the management of RP, in modulating the proinflammatory response of dermal fibroblasts to oxidative stress in vitro. Human fibroblasts isolated from SSc patients and healthy controls were exposed to exogenous reactive oxygen species (ROS) (100 mu M H2O2), in the presence or absence of sildenafil (1 mu M). Treatment with sildenafil significantly reduced dermal fibroblast gene expression and cellular release of IL-6, known to play a central role in the pathogenesis of tissue damage in SSc and IL-8, directly induced by ROS. This reduction was associated with suppression of STAT3-, ERK-, NF-kappa B-, and PKB/AKT-dependent pathways. Our findings support the notion that the employment of PDE5i in the management of RP may be explored for its efficacy in modulating the oxidative stress-induced proinflammatory activation of dermal fibroblasts in vivo and may ultimately aid in the prevention of tissue damage caused by SSc.