A群鏈球菌（Group A Streptococcus, Streptococcus pyogenes）是人類致病的重要病原菌之一，可導致危及生命的侵襲性疾病，包括壞死性筋膜炎和鏈球菌毒性休克症候群（streptococcal toxic shock syndrome）。活性氧化物質（reactive oxygen species）在抵禦外來病菌中扮演重要調控功能。細胞中活性氧化物質的生成來源之一為NADPH氧化酶（NADPH oxidase），除了宿主防禦的角色外，也參與在細胞訊息傳遞以及基因表現的調控中。然而，過量的活性氧化物質對細胞有害，由活性氧化物質引起的氧化壓力已被報導與許多生理功能失調及疾病相關。在本研究中，我們探討了氧化壓力與A群鏈球菌疾病嚴重程度之間的相關性，並探討抗氧化劑對嚴重A群鏈球菌感染的保護作用。在我們臨床病人檢體檢測結果顯示，非侵襲性和侵襲性症狀GAS患者血清中，硫氧還蛋白(thioredoxin)含量明顯高於健康對照組。並在A群鏈球菌感染引起的壞死性筋膜炎患者組織切片發現環氧合酶-2(cyclooxygenase-2)在血管中表現。這些結果顯示氧化壓力與A群鏈球菌疾病的嚴重程度具相關性。我們進一步利用細胞模式研究A群鏈球菌感染所誘導的氧化壓力在內皮細胞中扮演的角色。實驗發現，在A群鏈球菌感染下引起了大量的活性氧化物質產生進而誘導NF-κB活化。另一方面，A群鏈球菌感染會誘導HMEC-1細胞中環氧合酶-2(cyclooxygenase-2)的表現量增加。在感染前加入夾竹桃麻素(apocynin)、右旋美沙酚(dextromethorphan)和重組硫氧還蛋白(thioredoxin)可顯著減弱A群鏈球菌感染細胞中活性氧化物質的產生並抑制NF-κB活化。此外，在這些抗氧化劑處理後，A群鏈球菌感染誘導的內皮活化指標細胞內黏附分子(ICAM)、血管細胞黏附分子(VCAM)和誘導型一氧化氮酶(iNOS)的表現量降低。而在重組硫氧還蛋白(thioredoxin)作用下，可抑制感染細胞中環氧合酶-2(cyclooxygenase-2)的表現。總結而言，在細胞實驗中發現夾竹桃麻素(apocynin)、右旋美沙酚(dextromethorphan)和重組硫氧還蛋白(thioredoxin)可在GAS感染中作為抗發炎調節劑。

Group A Streptococcus (GAS), as known as Streptococcus pyogenes, is an important human pathogen that leads to life-threatening invasive diseases, including necrotizing fasciitis and streptococcal toxic shock syndrome (STSS). Oxygen-derived free radicals, collectively termed reactive oxygen species (ROS), play important roles in host defenses. The key producers of ROS in cells are the family of NADPH oxidases (NOX), which could regulate host defense, cellular signaling and gene expression. However, excess ROS are lethal to cells. ROS-mediated stress has been implicated in various dysfunctions and diseases. In this study, correlation between oxidative stress and severity of GAS disease and the protective role of antioxidant against severe GAS infections were explored. Clinical results showed that serum levels of thioredxoin (Trx) in GAS patients including non-invasive and invasive symptoms were significantly higher than the healthy control. Tissue sections from GAS infected-patients with necrotizing fasciitis revealed that cyclooxygenase-2 (COX-2) expressed in vascular. These results suggested that oxidative stress was associated with severity of GAS disease. We further studied the roles of GAS infection-induced oxidative stress in vitro, GAS infection effectively caused abundant ROS production followed by NF-κB activation. On the other hand, GAS infection induced increased expression of COX-2. Treatments with apocynin (APO), dextromethorphan (DM) and recombinant Trx notably attenuated ROS production in GAS-infected cells and inhibited NF-κB activation. Furthermore, the expression of endothelial activation marker and iNOS decreased after these anti-oxidant treatments. Recombinant Trx also attenuated the expression of COX-2 in GAS infected-cells. Taken together, NOX inhibitor, DM and trx could inhibit the oxidative stress in GAS-infected cells and reduce the inflammation to serve as anti-inflammatory modulators.

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