Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
J Eur Acad Dermatol Venereol. 2019 Apr;33(4):753-760. doi: 10.1111/jdv.15387. Epub 2019 Jan 1.
Trappin-2/pre-elafin is an endogenous inhibitor of human neutrophil elastase involved in inflammation, innate immunity and vascular remodelling, which consist of the complex pathological process of systemic sclerosis (SSc).
To clarify the potential role of trappin-2 in SSc.
Serum trappin-2 levels were determined by enzyme-linked immunosorbent assay in 51 SSc and 18 healthy subjects. Trappin-2 expression was evaluated in SSc lesional skin and cultured endothelial cells treated with FLI1 siRNA by immunohistochemistry, reverse transcription-real-time PCR and/or immunoblotting. Friend leukaemia virus integration 1 (Fli1) binding to the PI3 promoter was assessed by chromatin immunoprecipitation.
Since serum trappin-2 levels inversely correlated with estimated glomerular filtration rate in SSc patients with renal dysfunction, SSc patients with normal renal function were analysed. Although serum trappin-2 levels were comparable between diffuse cutaneous SSc, limited cutaneous SSc and control subjects, the prevalence of digital ulcers or elevated right ventricular systolic pressure (RVSP) was significantly higher in SSc patients with elevated serum trappin-2 levels than in those with normal levels. Furthermore, serum trappin-2 levels were significantly increased in SSc patients with digital ulcers or elevated RVSP compared to those without. Moreover, serum trappin-2 levels positively correlated with RVSP values in SSc patients. Importantly, trappin-2 expression was enhanced in small vessels of SSc lesional skin. In cultured endothelial cells, trappin-2 expression was elevated by gene silencing of FLI1 at mRNA and protein levels and Fli1 occupied the PI3 promoter.
Endothelial trappin-2 up-regulation partially due to Fli1 deficiency can be associated with the development of SSc vasculopathy.
Trappin-2/pre-elafin 是一种内源性人中性粒细胞弹性蛋白酶抑制剂，参与炎症、先天免疫和血管重塑，这些过程构成了系统性硬化症（SSc）的复杂病理过程。
阐明 trappin-2 在 SSc 中的潜在作用。
采用酶联免疫吸附试验检测 51 例 SSc 患者和 18 例健康对照者血清 trappin-2 水平。采用免疫组化、逆转录实时 PCR 和/或免疫印迹法检测 SSc 皮损皮肤和经 FLI1 siRNA 处理的培养内皮细胞中 trappin-2 的表达。采用染色质免疫沉淀法评估 Friend 白血病病毒整合 1（Fli1）与 PI3 启动子的结合。
由于 SSc 患者肾功能障碍时血清 trappin-2 水平与估计肾小球滤过率呈负相关，因此分析了肾功能正常的 SSc 患者。虽然弥漫性皮肤 SSc、局限性皮肤 SSc 和对照组患者的血清 trappin-2 水平无差异，但血清 trappin-2 水平升高的 SSc 患者中，发生手指溃疡或右心室收缩压（RVSP）升高的比例显著高于水平正常的患者。此外，与无手指溃疡或 RVSP 升高的患者相比，发生手指溃疡或 RVSP 升高的 SSc 患者的血清 trappin-2 水平显著升高。此外，血清 trappin-2 水平与 SSc 患者的 RVSP 值呈正相关。重要的是，trappin-2 在 SSc 皮损皮肤的小血管中表达增强。在培养的内皮细胞中，通过 FLI1 的基因沉默在 mRNA 和蛋白水平上均使 trappin-2 表达升高，且 Fli1 占据 PI3 启动子。
内皮细胞 trappin-2 的上调部分归因于 Fli1 的缺乏，这可能与 SSc 血管病变的发生有关。
