白杨素抑制核因子-κB通路并减轻大鼠失血性休克模型中的肺损伤。
Apocynin suppressed the nuclear factor-κB pathway and attenuated lung injury in a rat hemorrhagic shock model.
作者信息
Choi Seok Ho, Suh Gil Joon, Kwon Woon Yong, Kim Kyung Su, Park Min Ji, Kim Taegyun, Ko Jeong In
机构信息
From the Trauma Center (S.H.C.), Dankook University Hospital, Cheonan-si, Chungnam, Republic of Korea; and Department of Emergency Medicine (G.J.S., W.Y.K., K.S.K., M.J.P., T.K., J.I.K.), Seoul National University College of Medicine, Seoul, Republic of Korea.
出版信息
J Trauma Acute Care Surg. 2017 Mar;82(3):566-574. doi: 10.1097/TA.0000000000001337.
BACKGROUND
The aim of this study was to investigate whether a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) inhibitor, apocynin, reduces reactive oxygen species (ROS) production, suppresses the nuclear factor κB (NF-κB) pathway, attenuates lung injury, and improves survival in rat hemorrhagic shock (HS) model.
METHODS
Blood was drawn from male Sprague-Dawley rats (290-340 g) to maintain a mean arterial pressure of 20-25 mm Hg for 40 minutes. The rats were resuscitated with the drawn blood, and a vehicle (HS), a low dose of apocynin (20 mg/kg, LD-Apo), or a high dose of apocynin (40 mg/kg, HD-Apo) was administered intraperitoneally. The survival of the rats was observed for 72 hours. Then, a separated set of rats was euthanized at 6 hours post-HS induction. We measured gp91-phox (Nox2) expression, Nox activity, cytoplasmic phosphorylated inhibitor κB-α (p-IκB-α) expression, NF-κB p65 DNA-binding activity, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) gene expressions, malondialdehyde (MDA) level, myeloperoxidase (MPO) activity, and histological damage in the lung tissues.
RESULTS
The survival rates of the sham, HS, HS + LD-Apo, and HS + HD-Apo groups were 100% (5/5), 30% (3/10), 40% (4/10), and 70% (7/10), respectively. A high dose of apocynin decreased gp91-phox expression, Nox activity, and MDA level in the lung tissues during HS and resuscitation. It also decreased p-IκB-α expression, NF-κB p65 DNA-binding activity, TNF-α and IL-6 gene expressions, and MPO activity in the lung tissues and attenuated histological lung injuries. However, a low dose of apocynin failed to show these benefits.
CONCLUSIONS
The administration of a high dose of apocynin inhibited Nox2 expression and Nox activity, reduced lipid peroxidation, suppressed the NF-κB pathway and subsequent pro-inflammatory cytokines transcription in the lung tissues, and attenuated lung injury during HS and resuscitation in rats.
背景
本研究旨在探讨烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶（Nox）抑制剂白杨素是否能减少活性氧（ROS）生成、抑制核因子κB（NF-κB）通路、减轻肺损伤并提高大鼠失血性休克（HS）模型的生存率。
方法
从雄性Sprague-Dawley大鼠（290 - 340 g）采血，维持平均动脉压在20 - 25 mmHg 40分钟。大鼠用采得的血液进行复苏，并腹腔注射溶剂（HS组）、低剂量白杨素（20 mg/kg，LD-Apo组）或高剂量白杨素（40 mg/kg，HD-Apo组）。观察大鼠72小时的生存率。然后，在HS诱导后6小时处死另一组大鼠。我们检测了肺组织中gp91-phox（Nox2）表达、Nox活性、细胞质磷酸化抑制蛋白κB-α（p-IκB-α）表达、NF-κB p65 DNA结合活性、肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）基因表达、丙二醛（MDA）水平、髓过氧化物酶（MPO）活性以及肺组织的组织学损伤。
结果
假手术组、HS组、HS + LD-Apo组和HS + HD-Apo组的生存率分别为100%（5/5）、30%（3/10）、40%（4/10）和70%（7/10）。高剂量白杨素在HS及复苏过程中降低了肺组织中gp91-phox表达、Nox活性和MDA水平。它还降低了肺组织中p-IκB-α表达、NF-κB p65 DNA结合活性、TNF-α和IL-6基因表达以及MPO活性，并减轻了肺组织学损伤。然而，低剂量白杨素未显示出这些益处。
结论
高剂量白杨素给药可抑制大鼠HS及复苏过程中肺组织Nox2表达和Nox活性，减少脂质过氧化，抑制NF-κB通路及随后的促炎细胞因子转录，并减轻肺损伤。
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