Department of Leukocyte Biology, Imperial College, London, UK.
Crit Care Med. 2013 Jul;41(7):1627-36. doi: 10.1097/CCM.0b013e31827c0c8d.
Benzodiazepines are used for treating anxiety, epilepsy, muscle spasm, alcohol withdrawal, palliation, insomnia, and sedation as they allosterically modulate γ-amino-butyric acid type A (GABAA) receptors. Despite widespread use, the importance and mechanism of their immune side-effects are poorly understood. Herein we sought to elucidate the impact and mechanism of benzodiazepine-induced susceptibility to infection at anxiolytic doses in mice.
Animal randomized controlled trial.
Laboratory.
Adult female C57BL/6 and BALB/c mice.
The effect of a subsedative, anxiolytic dose of diazepam (2 mg kg intraperitoneal) was investigated in a murine Streptococcus pneumoniae pneumonia model.
Mortality, bacterial and cytokine load, cell recruitment, and intracellular pH were measured. Diazepam treatment did not affect immune homeostasis in the lung. However, diazepam increased mortality and bacterial load from S. pneumoniae pneumonia. The increases in mortality and bacterial load were reversed by a GABAA antagonist, bicuculline, indicating dependence on GABAA receptor signaling. While cell recruitment was unaltered by diazepam, the cytokine response to infection was affected, suggesting that local responses to the pathogen were perturbed. Macrophage and monocytes expressed benzodiazepine sensitive (α1-γ2) GABAA receptors. Interestingly macrophage GABAA receptor expression was regulated by bacterial toll-like receptor agonists and cytokines indicating an endogenous role in the immune response. Functionally diazepam appeared to counteract the endogenous down-regulation of GABAA signaling during infection. Consistent with augmented GABAA signaling, diazepam provoked intracellular acidosis in macrophage, leading to impaired cytokine production, bacterial phagocytosis and killing. In contrast, selective benzodiazepines that do not target the α1 GABAA subunit did not affect macrophage function ex vivo or increase susceptibility to pneumonia in vivo.
Our data highlight the regulation of macrophage function by GABAA receptor signaling and the potential harm of benzodiazepine exposure during pneumonia. Therapeutically, selective drugs may improve the safety profile of benzodiazepines.
苯二氮䓬类药物通过变构调节γ-氨基丁酸 A 型 (GABAA) 受体，用于治疗焦虑、癫痫、肌肉痉挛、酒精戒断、缓解疼痛、失眠和镇静。尽管它们被广泛使用，但它们免疫副作用的重要性和机制仍了解甚少。在此，我们试图阐明在焦虑剂量下苯二氮䓬类药物对感染易感性的影响和机制。
动物随机对照试验。
实验室。
成年雌性 C57BL/6 和 BALB/c 小鼠。
研究了亚镇静、抗焦虑剂量的地西泮（2mg/kg 腹腔内注射）对肺炎链球菌肺炎小鼠模型的影响。
测量了死亡率、细菌和细胞因子负荷、细胞募集和细胞内 pH。地西泮治疗不会影响肺部的免疫稳态。然而，地西泮增加了肺炎链球菌肺炎的死亡率和细菌负荷。GABAA 拮抗剂荷包牡丹碱逆转了死亡率和细菌负荷的增加，表明这依赖于 GABAA 受体信号。虽然地西泮不影响细胞募集，但感染后的细胞因子反应受到影响，表明局部对病原体的反应受到干扰。巨噬细胞和单核细胞表达苯二氮䓬敏感的 (α1-γ2) GABAA 受体。有趣的是，细菌 toll 样受体激动剂和细胞因子调节巨噬细胞 GABAA 受体的表达，表明其在免疫反应中有内源性作用。功能上，地西泮似乎抵消了感染期间 GABAA 信号的内源性下调。与增强的 GABAA 信号一致，地西泮在巨噬细胞中引起细胞内酸中毒，导致细胞因子产生、细菌吞噬和杀伤受损。相比之下，选择性不针对 α1 GABAA 亚基的苯二氮䓬类药物不会影响体外巨噬细胞功能，也不会增加体内肺炎易感性。
我们的数据强调了 GABAA 受体信号对巨噬细胞功能的调节，以及在肺炎期间接触苯二氮䓬类药物的潜在危害。在治疗上，选择性药物可能会改善苯二氮䓬类药物的安全性。
