Department of Intensive Care Unit, The First Hospital of China Medical University, Nanjing Bei Street 155, Shenyang 110001, Liaoning Province, PR China.
Department of Intensive Care Unit, The First Hospital of China Medical University, Nanjing Bei Street 155, Shenyang 110001, Liaoning Province, PR China.
Thromb Res. 2017 Feb;150:59-64. doi: 10.1016/j.thromres.2016.12.020. Epub 2016 Dec 24.
In the pathogenesis of sepsis-induced acute lung injury (ALI), the crosstalk between inflammation and coagulation plays a pivotal role. The aim of this study was to investigate the role of Rho kinase (ROCK) inhibitor in alleviating pulmonary inflammation and coagulation in lipopolysaccharide (LPS)-induced acute lung injury (ALI) models.
In the in vivo study, mice were randomized to four different groups: Control, Y-27632 (Y), LPS, and LPS+Y-27632 (LPS+Y). ALI was induced by intranasally administering LPS (10μg in 50μL PBS). Y-27632 (10mg/kg body weight,) was injected intraperitoneally at 18h and 1h before LPS challenge. Mice were euthanized at 3h or 8h post LPS challenge (N=8 per group). In the in vitro study, human pulmonary microvascular endothelial cells (HPMECs) were incubated with LPS alone (1μg/mL) or in combination with 10μM Y-27632 or 50μM BAY11-7082. Cells were pretreated with the inhibitors 30min before exposure to LPS. Three hours later, cells were isolated for subsequent analysis.
The myeloperoxidase (MPO) activity and fibrinogen deposits in the lung tissue significantly decreased and the lung damage in ALI mouse was attenuated. Pretreatment with Y-27632 markedly reduced the LPS-induced expression of interleukins 1β and 6, and the activation of nuclear factor (NF)-κB. Furthermore, ROCK inhibitor treatment antagonized the expression of tissue factor (TF) and plasminogen activator inhibitor (PAI)-1 in lung tissue and HPMECs.
ROCK inhibition protects against the endotoxin-induced pulmonary inflammation and coagulation via NF-kappaB pathway modulation.
在脓毒症诱导的急性肺损伤（ALI）的发病机制中，炎症和凝血的相互作用起着关键作用。本研究旨在探讨 Rho 激酶（ROCK）抑制剂在减轻脂多糖（LPS）诱导的急性肺损伤（ALI）模型中肺炎症和凝血中的作用。
在体内研究中，将小鼠随机分为四组：对照组、Y-27632（Y）组、LPS 组和 LPS+Y-27632（LPS+Y）组。通过鼻腔给予 LPS（10μg 在 50μLPBS 中）诱导 ALI。Y-27632（10mg/kg 体重）在 LPS 攻击前 18 小时和 1 小时经腹腔注射。在 LPS 攻击后 3 小时或 8 小时处死小鼠（每组 8 只）。在体外研究中，将人肺微血管内皮细胞（HPMEC）单独孵育 LPS（1μg/mL）或与 10μMY-27632 或 50μMBAY11-7082 联合孵育。抑制剂孵育 30min 后，细胞暴露于 LPS。3 小时后，分离细胞进行后续分析。
肺组织髓过氧化物酶（MPO）活性和纤维蛋白原沉积明显减少，ALI 小鼠的肺损伤减轻。Y-27632 预处理显著降低了 LPS 诱导的白细胞介素 1β和 6 的表达和核因子（NF）-κB 的激活。此外，ROCK 抑制剂处理拮抗了肺组织和 HPMEC 中组织因子（TF）和纤溶酶原激活物抑制剂（PAI）-1 的表达。
ROCK 抑制通过 NF-κB 通路调节减轻内毒素诱导的肺炎症和凝血。
