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首页> 外文期刊>Journal of dermatological science >Sorafenib stimulates human skin type mast cell degranulation and maturation
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Sorafenib stimulates human skin type mast cell degranulation and maturation

机译：索拉非尼刺激人体皮肤型肥大细胞脱粒和成熟

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Highlights ? Sorafenib stimulates skin-type mast cell maturation and induces degranulation. ? Sorafenib also increases SCF expression within the epidermis. ? The effect of sorafenib on mast cell maturation is mediated via PI3K signaling. ? PI3K mediated signaling or SCF could be a new target for sorafenib-induced itch. Abstract Background Sorafenib is a multi-kinase inhibitor for treating advanced hepatocellular and renal cell carcinomas by targeting various types of receptors and signaling molecules, including vascular endothelial growth factor receptors, platelet-derived growth factor receptor, and Raf-1. Sorafenib may cause diverse cutaneous adverse reactions, including hand-foot reaction, facial and scalp eruptions, alopecia and pruritus. However, the mechanism of these adverse effects has not been well-investigated. Objective Mast cells (MCs) are reported to be associated with various types of skin diseases. To investigate the mechanism of sorafenib-induced cutaneous adverse effects, we focused on MCs in situ . Methods We evaluated skin samples of organ cultured normal human skin treated with sorafenib using c-Kit, tryptase, and stem cell factor (SCF), Ki-67, and TUNEL immunohistochemistry as well as quantitative real-time polymerase chain reaction to evaluate MC number, degranulation, proliferation, and apoptosis in situ . Results Sorafenib significantly increased the number and degranulation of skin-type MCs compared with the vehicle-treated control group in situ . However, sorafenib did not affect MC proliferation and apoptosis, suggesting that it stimulated MC maturation from resident precursors. Furthermore, sorafenib increased SCF expression in situ . The increase in MC number by sorafenib was abrogated by co-administration of SCF neutralizing antibody or the phosphoinositide 3-kinase (PI3K) inhibitor, wortmannin, but not the mitogen-activated protein kinase (MAPK)/extracellular signal–regulated kinase (ERK) kinase (MEK) inhibitor, PD98059. This suggests that SCF is involved in sorafenib-induced MC maturation. In addition, the compensatory upregulation of PI3K-signaling from inhibition of MAPK signaling by sorafenib might stimulate MC maturation in situ . We also evaluated MCs within the skin samples from patients with drug eruptions by sorafenib administration. The total and degranuated MCs number as well as SCF expression was significantly increased compared to healthy individuals. Conclusion Our results contribute to a better understanding of the mechanism by which sorafenib induces adverse cutaneous reactions via activation of skin-type MC degranulation and maturation. This activation appears to be related to PI3K signaling and SCF production, which could be a new targets for treating sorafenib-induced adverse reactions.
机译：强调 ？索拉非尼刺激皮肤型肥大细胞成熟，并诱导脱粒。还索拉非尼还增加了表皮内的SCF表达。还Sorafenib对肥大细胞成熟的影响通过PI3K信号传导介导。还PI3K介导的信号传导或SCF可能是Sorafenib诱导的瘙痒的新靶标。摘要背景Sorafenib是一种用于通过靶向各种类型的受体和信号分子治疗晚期肝细胞和肾细胞癌的多激酶抑制剂，包括血管内皮生长因子受体，血小板衍生的生长因子受体和RAF-1。索拉非尼可能导致不同的皮肤不良反应，包括手足反应，面部和头皮喷发，脱发和瘙痒。然而，这些不利影响的机制尚未得到良好研究。据报道，客观肥大细胞（MCS）与各种类型的皮肤疾病有关。为了探讨索拉非尼诱发的皮肤不利影响的机制，我们以MCS为原位。方法使用C-kit，胰蛋白酶和干细胞因子（SCF），KI-67和TUNEL免疫组化以及定量实时聚合酶链反应，评估用Sorafenib治疗的器官培养正常人体皮肤的皮肤样品。以及定量实时聚合酶链反应，以评估MC号原位，脱脂，增殖和细胞凋亡。结果索拉非尼与原位车辆处理的对照组相比显着增加了皮肤型MCS的数量和脱粒。然而，Sorafenib不影响MC增殖和凋亡，表明它刺激了驻留前体的MC成熟。此外，Sorafenib原位增加了SCF表达。通过共和SCF中和抗体或磷酸阳性3-激酶（PI3K）抑制剂，Wortmannin，但不是丝裂剂活化蛋白激酶（MAPK）/细胞外信号调节激酶（ERK）的磷酰基亚磷酸酯（PI3K）抑制剂的增加而删除了MC号的增加。激酶（MEK）抑制剂，PD98059。这表明SCF涉及Sorafenib诱导的MC成熟。此外，Sorafenib从MAPK信号传导抑制的PI3K信号传导的补偿上调可能刺激MC成熟原位。我们还通过Sorafenib施用的药物喷发患者评估了皮肤样本内的MCS。与健康个体相比，总数和脱脂的MCS号以及SCF表达显着增加。结论我们的结果有助于更好地理解Sorafenib通过激活皮肤型MC脱粒和成熟来诱导不良皮肤反应的机制。这种激活似乎与PI3K信号传导和SCF生产有关，这可能是治疗索拉非尼诱导的不良反应的新靶标。

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