Nucleic acids, lipids, and other cell components can be found within different types of extracellular vesicles (EVs), which include apoptotic bodies (ABs), large extracellular vesicles (LEVs), and small extracellular vesicles (SEVs). Release of LEVs from cells can be reduced by genetic or pharmacological inhibition of the enzyme acid sphinogomyelinase (aSMase), and indeed several studies have demonstrated a role for the clinically approved aSMase inhibitor imipramine in blocking LEV release, including in response to UVB exposure. Given that exposure of keratinocytes to UVB radiation results in the generation of UVR photoproducts in DNA that can subsequently be found in association with ABs and SEVs, we examined how imipramine impacts the release of extracellular DNA containing UVR photoproducts at an early time point after UVR exposure. Using several different model systems, including cultured keratinocytes in vitro, discarded human surgical skin ex vivo, and skin biopsies obtained from treated human subjects, these pilot studies suggest that imipramine treatment stimulates the release of CPD‐containing, SEV‐associated DNA. These surprising findings indicate that LEV and SEV generation pathways could be linked in UVB‐irradiated cells and that imipramine may exacerbate the systemic effects of extracellular UVR‐damaged DNA throughout the body.

中文翻译：

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酸性鞘磷脂酶抑制剂丙咪嗪可增强受 UVB 照射的人体皮肤小细胞外囊泡中含有 UV 光产物的 DNA 的释放

核酸、脂质和其他细胞成分存在于不同类型的细胞外囊泡 (EV) 中，其中包括凋亡小体 (AB)、大细胞外囊泡 (LEV) 和小细胞外囊泡 (SEV)。通过对酸性鞘磷脂酶 (aSMase) 进行遗传或药理学抑制，可以减少细胞中 LEV 的释放，事实上，多项研究已经证明了临床批准的 aSMase 抑制剂丙咪嗪在阻止 LEV 释放方面的作用，包括响应 UVB 暴露。鉴于角质形成细胞暴露于 UVB 辐射会导致 DNA 中产生 UVR 光产物，随后可以发现这些光产物与 AB 和 SEV 相关，我们研究了丙咪嗪如何在 UVR 暴露后的早期时间点影响含有 UVR 光产物的细胞外 DNA 的释放。这些初步研究使用几种不同的模型系统，包括体外培养的角质形成细胞、废弃的人体手术皮肤离体以及从接受治疗的人类受试者中获得的皮肤活检，表明丙咪嗪治疗刺激了含​​有 CPD 的 SEV 相关 DNA 的释放。这些令人惊讶的发现表明，LEV 和 SEV 生成途径可能在 UVB 照射的细胞中存在关联，并且丙咪嗪可能会加剧细胞外 UVR 损伤的 DNA 对整个身体的全身影响。