Kasotakis George, Galvan Manuel D, Osathanugrah Paw, Dharia Neerav, Bufe Lauren, Breed Zachary, Mizgerd Joseph P, Remick Daniel G
Department of Surgery, Boston University School of Medicine, Boston, Massachusetts.
Department of Surgery, Boston University School of Medicine, Boston, Massachusetts.
J Surg Res. 2017 Dec;220:206-212. doi: 10.1016/j.jss.2017.06.088. Epub 2017 Jul 31.
Acute lung injury and respiratory distress syndrome is characterized by uncontrolled inflammation of the lungs after a severe inflammatory stimulus. We have previously demonstrated an ameliorated syndrome and improved survival in mice with early administration of valproic acid (VPA), a broad-spectrum histone deacetylase inhibitor, while studies in humans have shown no benefit when anti-inflammatories are administered late. The current study tested the hypothesis that early treatment would improve outcomes in our gram-negative pneumonia-induced acute lung injury.
Mice (C57BL/6) had 50 × 10 Escherichia coli (strain 19,138) instilled endotracheally and VPA (250 mg/kg) administered intraperitoneally 3, 4, 6, and 9 h (n = 12/group) later. Six hours after VPA administration, the animals were sacrificed, and bronchoalveolar lavage (BAL) fluid interleukin-6 (IL-6), tumor necrosis factor, neutrophils and macrophages as well as the E coli colony-forming units were quantified. Plasma IL-6 was also measured. A separate group of mice (n = 12/group) were followed prospectively for 7 days to assess survival.
BAL IL-6 and tumor necrosis factor as well as plasma IL-6 were significantly lower in the animals administered VPA within 3 h (P < 0.05) but not when administered later (4, 6, 9 h). There was no difference in the BAL E coli colony-forming units, macrophage, or neutrophil numbers at any time point. Survival improved only when VPA was administered within 3 h.
A narrow therapeutic window exists in this murine model of gram-negative pneumonia-induced acute lung injury and likely explains the lack of response in studies with late administration of anti-inflammatory therapies in clinical studies.
急性肺损伤和呼吸窘迫综合征的特征是在严重炎症刺激后肺部出现不受控制的炎症。我们之前已经证明，早期给予丙戊酸（VPA，一种广谱组蛋白脱乙酰酶抑制剂）可改善小鼠的综合征并提高生存率，而在人类中的研究表明，晚期给予抗炎药并无益处。本研究检验了早期治疗可改善革兰氏阴性菌肺炎诱导的急性肺损伤患者预后的假设。
将50×10的大肠杆菌（菌株19,138）经气管内滴注到小鼠（C57BL/6）体内，并在3、4、6和9小时后腹腔注射VPA（250mg/kg）（每组n = 12）。给予VPA 6小时后，处死动物，对支气管肺泡灌洗（BAL）液中的白细胞介素-6（IL-6）、肿瘤坏死因子、中性粒细胞和巨噬细胞以及大肠杆菌集落形成单位进行定量。还测量了血浆IL-6。另一组小鼠（每组n = 12）进行前瞻性随访7天以评估生存率。
在3小时内给予VPA的动物中，BAL中的IL-6和肿瘤坏死因子以及血浆IL-6显著降低（P < 0.05），但在4、6、9小时后给予时则没有降低。在任何时间点，BAL中的大肠杆菌集落形成单位、巨噬细胞或中性粒细胞数量均无差异。只有在3小时内给予VPA时，生存率才会提高。
在这种革兰氏阴性菌肺炎诱导的急性肺损伤小鼠模型中存在一个狭窄的治疗窗，这可能解释了临床研究中晚期给予抗炎治疗缺乏反应的原因。
