MicroRNAs in Skin Inflammation and Wounding by Mustard Vesicants.

硫磺芥末(SM)是使用最广泛的化学战剂，氮芥末(NM)是最强的 烷化剂导致DNA损伤和氧化损伤，导致几种 分子途径。潜伏期过后，它们的作用是炎症反应，表皮细胞死亡和 皮肤组织中的剧烈水泡和溃疡，这是主要的靶器官。基于 暴露剂量和持续时间，这些影响可能会导致长期的皮肤并发症，如干燥，红斑和 皮肤色素沉着随着伤口愈合时间的延长而改变，造成医疗负担，影响生活质量。 有太多关于暴露于发泡剂后的皮肤病理的信息； 然而，导致急性暴露所致慢性皮肤损伤的复杂分子机制仍然存在。 值得商榷。我们在SKH-1无毛小鼠身上完成的研究表明，急性皮肤发泡剂暴露 可导致氧化应激、DNA损伤、信号通路激活和炎症的表达 和蛋白水解性介质，包括细胞因子，促进皮肤炎症，水泡形成，和 伤口愈合延迟。此外，我们还发现NM诱导的基质金属蛋白酶-9的变化，炎性 小鼠皮肤中成纤维细胞生长因子2、肿瘤坏死因子-α、白介素1β和血管内皮生长因子等细胞因子伴随着皮肤微结构的改变。 MiR-155、miR-203a和miR-21。值得注意的是，这些miRNA与慢性皮肤炎症有关， 免疫反应和纤维化(miR-155)，通过靶向致炎基因的细胞因子信号转导 细胞因子，如皮肤组织中的肿瘤坏死因子-α(miR-203a)和皮肤伤口愈合和胶原沉积(miR-21)。 本申请建立在这些初步发现的基础上，并将详细调查SM和NM的影响 暴露在miRNA上会改变皮肤组织。我们的假设是，改变后的miRNA与 炎症、伤口愈合和纤维化可以靶向基因表达指导分子 起泡剂暴露引起慢性皮肤损伤的途径改变。使用NM和NM- 并在已建立的丹参致小鼠皮肤损伤模型上建立慢性皮损皮肤组织，具体目的为：1) 确定与炎症、伤口愈合和纤维化相关的miRNA，并分析miRNA靶标 以及通过miRNA靶标和途径分析程序的相关分子途径；以及2)确认 确定与发泡剂引起的皮肤损伤最相关的miRNA靶分子，并比较结果 NM和SM引起的皮肤损伤之间的差异。拟议的研究预计将于 识别独特的miRNAs，驱动SKH-1无毛小鼠观察到的分子途径改变 在SM和NM暴露之后。预计结果将建立miRNA签名， 它们可以作为新的诊断生物标志物，并开辟了miRNA靶向治疗的新途径 SM和NM暴露后皮肤并发症的发生率。

Sulfur mustard (SM), the most widely used chemical warfare agent, and nitrogen mustard (NM) are strong alkylating agents causing DNA damage as well as oxidative damage leading to the activation of several molecular pathways. After a latent period, their effect is an inflammatory response, epidermal cell death and excruciating vesication and ulcerations in the skin tissue, which is the main target organ. Based on the exposure dose and duration, these effects can lead to long-term skin complications like xerosis, erythema and pigmentation changes with a long wound healing tenure causing medical burden and affecting the life quality. There is plethora of information available on the skin pathology following exposure to vesicating agents; however, the complex molecular mechanisms that lead to chronic skin lesions from acute exposures are still debatable. Our completed studies in SKH-1 hairless mice have shown that acute cutaneous vesicant exposure can lead to oxidative stress, DNA damage, activation of signaling pathways, and expression of inflammatory and proteolytic mediators including cytokines, contributing to the skin inflammation, blister formation, and delayed wound healing. Furthermore, we also found that NM-induced changes in MMP-9, inflammatory cytokines like FGF2, TNF-α and IL-1β and VEGF in mouse skin were accompanied with alterations in micro- RNAs miR-155, miR-203a and miR-21. Notably, these mi-RNAs are connected to chronic skin inflammation, immune response and fibrosis (miR-155), cytokine signaling by targeting genes encoding pro-inflammatory cytokines like TNF-α in the skin tissue (miR-203a) and skin wound healing and collagen deposition (miR-21). This application is built upon these preliminary findings, and will investigate in detail the effect of SM and NM exposure on miRNA changes in the skin tissue. Our hypothesis is that altered miRNAs related to inflammation, wound healing and fibrosis could target the gene expression directing molecular pathway alterations to cause chronic skin injury from vesicating agents’ exposure. Employing both NM- and SM-induced skin tissues with chronic lesions in established mouse skin injury models, specific aims are: 1) to determine miRNAs associated with inflammation, wound healing and fibrosis, and analyze miRNA targets as well as related molecular pathways via miRNA target and pathway analysis programs; and 2) to confirm the identified miRNA target molecules most relevant to vesicant-induced skin injury, and compare the outcomes between both the NM- and SM-induced skin injuries. Completion of the proposed studies is anticipated to identify unique miRNAs driving the molecular pathway alterations observed in SKH-1 hairless mice following both SM- and NM-exposures. Outcomes are anticipated to establish miRNA signatures, which can serve as novel diagnostic biomarkers and open a new avenue of miRNA-targeted treatment of skin complications following SM and NM exposure.