Lee Ji-Hae, Choi Chang Soon, Bae Il-Hong, Choi Jin Kyu, Park Young-Ho, Park Miyoung
Vital Beautie Research Institute, Amorepacific Corporation R&D Center, Yongin, Republic of Korea.
Medical Beauty QA Team, Aestura Corporation, Anseong, Republic of Korea.
J Dermatol Sci. 2018 Apr 30. doi: 10.1016/j.jdermsci.2018.04.017.
Although it is established that epidermal barrier disturbance and immune dysfunction resulting in IgE sensitization are critical factors in the development of cutaneous inflammation, the pathogenesis and targeted therapy of atopic dermatitis (AD)-specific pathways have still been unknown.
Taking into account the fact that Th2 cytokines in AD have both unique and overlapping functions including increased epidermal thickening, inflammation, and decreased expressing of the barrier proteins keratinocyte differentiation, we sought to clarify our hypothesis that TRPV1 antagonist plays a critical role in skin barrier function and can be a therapeutic target for AD.
AD-like dermatitis was induced in hairless mice by repeated oxazolone (Ox) challenges to hairless mice. The functional studies concerning skin barrier function, anti-inflammatory action, and molecular mechanism by TRPV1 antagonism were conducted by histopathological assays, ELISA, qPCR, western blotting, and skin blood flow measurement.
Topically administered TRPV1 antagonist, PAC-14028 (Asivatrep: CHFNOS), improved AD-like dermatitis and skin barrier functions, and restored the expression of epidermal differentiation markers. In addition, the PAC-14028 cream significantly inhibited cutaneous inflammation by decreasing the expression of serum IgE, and the epidermal expression of IL-4, and IL-13 in Ox-AD mice. These results may provide a novel insight into the molecular mechanism of PAC-14028 cream involved in anti-inflammatory effects and skin barrier functions by suppressing the multiple signaling pathways including IL-4/-13-mediated activation of JAK/STAT, TRPV1, and neuropeptides.
PAC-14028 cream can be a potential therapeutic tool for the treatment of chronic inflammation and disrupted barrier function in patients with AD.
虽然已经确定表皮屏障紊乱和导致IgE致敏的免疫功能障碍是皮肤炎症发展的关键因素，但特应性皮炎（AD）特异性途径的发病机制和靶向治疗仍然未知。
鉴于AD中的Th2细胞因子具有独特且重叠的功能，包括表皮增厚、炎症增加以及屏障蛋白角质形成细胞分化表达降低，我们试图阐明我们的假设，即TRPV1拮抗剂在皮肤屏障功能中起关键作用，并且可以成为AD的治疗靶点。
通过对无毛小鼠反复进行恶唑酮（Ox）激发诱导无毛小鼠发生类AD性皮炎。通过组织病理学检测、ELISA、qPCR、蛋白质印迹和皮肤血流测量，对TRPV1拮抗作用的皮肤屏障功能、抗炎作用和分子机制进行功能研究。
局部应用TRPV1拮抗剂PAC-14028（阿西曲普：CHFNOS）改善了类AD性皮炎和皮肤屏障功能，并恢复了表皮分化标志物的表达。此外，PAC-14028乳膏通过降低Ox-AD小鼠血清IgE的表达以及IL-4和IL-13的表皮表达，显著抑制了皮肤炎症。这些结果可能为PAC-14028乳膏通过抑制包括IL-4/-13介导的JAK/STAT、TRPV1和神经肽的多种信号通路参与抗炎作用和皮肤屏障功能的分子机制提供新的见解。
PAC-14028乳膏可能是治疗AD患者慢性炎症和屏障功能破坏的潜在治疗工具。
