Song Dongmei, Song Geng, Niu Yinghao, Song Wei, Wang Jiantao, Yu Lei, Yang Jianwang, Lv Xin, Steinberg Harry, Liu Shu Fang, Wang Baoshan
Department of Allergy and Otolaryngology, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
Br J Pharmacol. 2014 Oct;171(19):4399-412. doi: 10.1111/bph.12780. Epub 2014 Sep 5.
Ulinastatin (UTI), a serine protease inhibitor, was recently found to have an anti-inflammatory action. However, the mechanisms mediating this anti-inflammatory effect are not well understood. This study tested the hypothesis that UTI suppresses allergic inflammation by inducing the expression of haem oxygenase 1 (HO1).
Control mice and mice sensitized (on days 1, 9 and 14) and challenged (on days 21 to 27) with ovalbumin (OVA) were treated with UTI. The effects of UTI on basal expression of HO1 and that induced by OVA challenge were examined. The involvement of UTI-induced HO1 expression in anti-inflammatory and antioxidant effects of UTI was also evaluated.
UTI markedly increased basal HO1 protein expression in lungs of control mice in a time- and dose-dependent manner, and augmented HO1 protein expression induced by OVA. The up-regulation of HO1 mediated by UTI in sensitized and OVA-challenged mice was associated with reduced airway inflammation, alleviated tissue injury, reduced oxidant stress and enhanced antioxidant enzyme activities. Inhibition of HO1 activity using HO1 inhibitor, zinc protoporphyrin, attenuated inhibitory effects of UTI on inflammation and oxidant stress, and its stimulant effects on antioxidant enzyme activities. Mechanistic analysis showed that UTI increased nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2), stimulated Nrf2 DNA binding activity and concomitantly up-regulated HO1 mRNA expression.
UTI is a potent and naturally occurring inducer of HO1 expression. HO1 up-regulation contributes significantly to the anti-inflammatory and organ-protective effects of UTI, which has important research and therapeutic implications.
乌司他丁（UTI）是一种丝氨酸蛋白酶抑制剂，最近发现它具有抗炎作用。然而，介导这种抗炎作用的机制尚不完全清楚。本研究检验了UTI通过诱导血红素加氧酶1（HO1）表达来抑制过敏性炎症的假说。
用UTI处理对照小鼠以及用卵清蛋白（OVA）致敏（第1、9和14天）并激发（第21至27天）的小鼠。检测UTI对HO1基础表达以及OVA激发诱导的HO1表达的影响。还评估了UTI诱导的HO1表达在UTI抗炎和抗氧化作用中的参与情况。
UTI以时间和剂量依赖性方式显著增加对照小鼠肺组织中HO1蛋白的基础表达，并增强OVA诱导的HO1蛋白表达。UTI介导的致敏和OVA激发小鼠中HO1的上调与气道炎症减轻、组织损伤缓解、氧化应激降低以及抗氧化酶活性增强有关。使用HO1抑制剂锌原卟啉抑制HO1活性可减弱UTI对炎症和氧化应激的抑制作用及其对抗氧化酶活性的刺激作用。机制分析表明，UTI增加了核因子红细胞2相关因子2（Nrf2）的核转位，刺激了Nrf2的DNA结合活性，并同时上调了HO1 mRNA表达。
UTI是HO1表达的一种强效天然诱导剂。HO1上调对UTI的抗炎和器官保护作用有显著贡献，具有重要的研究和治疗意义。
