Kasotakis George, Galvan Manuel, King Elizabeth, Sarkar Beda, Stucchi Arthur, Mizgerd Joseph P, Burke Peter A, Remick Daniel
From the Department of Surgery (G.K., M.G., E.K., B.S., A.S., P.A.B.), Departments of Medicine, Microbiology and Biochemistry, Pulmonary Center (J.P.M.), and Department of Pathology and Laboratory Medicine (D.R.), Boston University School of Medicine, Boston, Massachusetts.
J Trauma Acute Care Surg. 2017 Apr;82(4):758-765. doi: 10.1097/TA.0000000000001389.
Histone deacetylase inhibitors (HDACI) are members of a family of epigenetic modifying agents with broad anti-inflammatory properties. These anti-inflammatory properties may have important therapeutic implications in acute respiratory distress syndrome (ARDS). However, administration of HDACI may create an immunosuppressive environment conducive to bacterial growth. Accordingly, the aim of the current study is to investigate the effect of HDACI valproic acid (VPA) on host inflammatory response and bacterial burden in a murine model of Escherichia coli pneumonia-induced ARDS.
ARDS was induced in male C57BL6 mice (n = 24) by endotracheal instillation of 3 × 10 E. coli. VPA (250 mg/kg) was administered 30 minutes after E. coli instillation in the intervention group. Blood samples were collected at 3 and 6 hours, and animals were sacrificed at 6 hours. Bronchoalveolar lavage (BAL) was performed, and tissue specimens were harvested. Cytokine levels were measured in blood and BAL, and so was transalveolar protein transit. Cell counts and colony forming units were quantified in BAL fluid.
VPA reduced neutrophil influx into the lungs and local tissue destruction through decreased myeloperoxidase activity. It also ameliorated the pulmonary and systemic inflammatory response. This led to greater bacterial proliferation in the pulmonary parenchyma.
Administration of VPA in a clinically relevant bacterial model of murine ARDS mitigates the host inflammatory response, essentially preventing ARDS, but creates an immunosuppressive environment that favors bacterial overgrowth.
组蛋白去乙酰化酶抑制剂（HDACI）是一类具有广泛抗炎特性的表观遗传修饰剂。这些抗炎特性可能在急性呼吸窘迫综合征（ARDS）中具有重要的治疗意义。然而，给予HDACI可能会创造一个有利于细菌生长的免疫抑制环境。因此，本研究的目的是在大肠杆菌肺炎诱导的ARDS小鼠模型中，研究HDACI丙戊酸（VPA）对宿主炎症反应和细菌负荷的影响。
通过气管内注入3×10个大肠杆菌，在雄性C57BL6小鼠（n = 24）中诱导ARDS。在干预组中，在注入大肠杆菌后30分钟给予VPA（250 mg/kg）。在3小时和6小时采集血样，并在6小时处死动物。进行支气管肺泡灌洗（BAL），并采集组织标本。测量血液和BAL中的细胞因子水平，以及经肺泡蛋白转运情况。对BAL液中的细胞计数和菌落形成单位进行定量。
VPA通过降低髓过氧化物酶活性，减少了中性粒细胞向肺部的流入和局部组织破坏。它还改善了肺部和全身的炎症反应。这导致肺实质中细菌增殖增加。
在小鼠ARDS的临床相关细菌模型中给予VPA可减轻宿主炎症反应，从根本上预防ARDS，但会创造一个有利于细菌过度生长的免疫抑制环境。
