Serotonin exerts important functions in several liver pathophysiological processes. In this study, we investigated the role of serotonin in concanavalin A (Con A)-induced liver fibrosis (LF) in mice and the underlying mechanisms. To establish the mouse model of LF, mice of wild-type (WT) and tryptophan hydroxylase 1 (Tph1) knockout (serotonin depletion) received Con A for 8 successive weeks. Degree of fibrosis was assessed by Sirius red staining, as well as the measurements of alpha smooth muscle actin (α- SMA), hydroxyproline (Hyp) and type I collagen in liver tissues. To elucidate the potential mechanisms, we assessed the effect of serotonin depletion on inflammatory, oxidative stress as well as TGF-β1/Smads signaling pathway. We found that serotonin depletion significantly inhibited collagen deposition as evaluated by less collagenous fiber in Sirus Red staining and reduced contents of Hyp and type I collagen. In addition, the absence of serotonin significantly inhibited the release of several inflammatory cytokines, including interleukin-6 (IL-6), interferon-gamma (IFN-γ), tumor necrosis-alpha (TNF-α), and transforming growth factor β1 (TGF-β1). Oxidative stress was also largely mitigated in LF mice with serotonin deficiency as manifested by the decreases of oxidative stress markers (malonaldehyde (MDA) and myeloperoxidase (MPO)), as well as the increases of antioxidant stress indicators (glutathione (GSH), and GSH-px, catalase (CAT), superoxide dismutase (SOD)) in liver tissues. Moreover, the lack of serotonin may provide an antifibrotic role by inhibiting the intrahepatic expressions of TGF-β1, phosphorylated-smad2 (p-smad2), and phosphorylated-smad3 (p-smad3). These results indicated that, serotonin depletion attenuates Con A-induced LF through the regulation of inflammatory response, oxidative stress injury, and TGF-β1/Smads signaling pathway.

中文翻译：

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血清素的消耗通过抑制炎症、氧化应激和 TGF-β1/Smads 信号通路缓解刀豆蛋白 A 诱导的小鼠肝纤维化

血清素在几种肝脏病理生理过程中发挥重要作用。在这项研究中，我们研究了血清素在伴刀豆球蛋白 A (Con A) 诱导的小鼠肝纤维化 (LF) 中的作用及其潜在机制。为了建立 LF 小鼠模型，野生型 (WT) 和色氨酸羟化酶 1 (Tph1) 敲除（血清素消耗）小鼠连续 8 周接受 Con A。通过天狼星红染色以及肝组织中α平滑肌肌动蛋白（α-SMA）、羟脯氨酸（Hyp）和I型胶原蛋白的测量来评估纤维化程度。为了阐明潜在的机制，我们评估了血清素消耗对炎症、氧化应激以及 TGF-β1/Smads 信号通路的影响。我们发现血清素消耗显着抑制了胶原沉积，如 Sirus Red 染色中较少的胶原纤维和降低的 Hyp 和 I 型胶原含量所评估的那样。此外，血清素的缺失显着抑制了几种炎性细胞因子的释放，包括白介素 6 (IL-6)、干扰素-γ (IFN-γ)、肿瘤坏死-α (TNF-α) 和转化生长因子 β1 (TGF-β1)。5-羟色胺缺乏的LF小鼠的氧化应激也大大减轻，表现为氧化应激标志物（丙二醛（MDA）和髓过氧化物酶（MPO））的减少，以及抗氧化应激指标（谷胱甘肽（GSH）和GSH的增加） -px、过氧化氢酶 (CAT)、超氧化物歧化酶 (SOD)) 在肝组织中。而且，血清素的缺乏可能通过抑制 TGF-β1、磷酸化-smad2 (p-smad2) 和磷酸化-smad3 (p-smad3) 的肝内表达来提供抗纤维化作用。这些结果表明，血清素消耗通过调节炎症反应、氧化应激损伤和 TGF-β1/Smads 信号通路减弱了 Con A 诱导的 LF。