Angiotensin-converting enzyme inhibitors (ACEIs) are used by millions of patients to treat hypertension, diabetic kidney disease, and heart failure. However, these patients are often at increased risk of infection. To evaluate the impact of ACEIs on immune responses to infection, we compared the effect of an ACEI versus an angiotensin receptor blocker (ARB) on neutrophil antibacterial activity. ACEI exposure reduced the ability of murine neutrophils to kill methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and Klebsiella pneumoniae in vitro. In vivo, ACEI-treated mice infected with MRSA had increased bacteremia and tissue bacteria counts compared to mice treated with an ARB or with no drug. Similarly, ACEIs, but not ARBs, increased the incidence of MRSA-induced infective endocarditis in mice with aortic valve injury. Neutrophils from ACE knockout (KO) mice or mice treated with an ACEI produced less leukotriene B4 (LTB4) upon stimulation with MRSA or lipopolysaccharide, whereas neutrophils overexpressing ACE produced more LTB4 compared to wild-type neutrophils. As a result of reduced LTB4 production, ACE KO neutrophils showed decreased survival signaling and increased apoptosis. In contrast, neutrophils overexpressing ACE had an enhanced survival phenotype. Last, in a cohort of human volunteers receiving the ACEI ramipril for 1 week, ACEI administration reduced neutrophil superoxide and reactive oxygen species production and neutrophils isolated from volunteers during ramipril treatment had reduced bactericidal activity. Together, these data demonstrate that ACEI treatment, but not ARB treatment, can reduce the bacterial killing ability of neutrophils.

血管紧张素转换酶抑制剂 (ACEI) 被数百万患者用于治疗高血压、糖尿病肾病和心力衰竭。然而，这些患者的感染风险往往增加。为了评估 ACEI 对感染免疫反应的影响，我们比较了 ACEI 与血管紧张素受体阻滞剂 (ARB) 对中性粒细胞抗菌活性的影响。ACEI 暴露降低了小鼠中性粒细胞在体外杀死耐甲氧西林金黄色葡萄球菌(MRSA)、铜绿假单胞菌和肺炎克雷伯菌的能力。在体内，与接受 ARB 治疗或不接受药物治疗的小鼠相比，接受 ACEI 治疗的感染 MRSA 的小鼠菌血症和组织细菌计数增加。同样，ACEIs（而非 ARB）会增加主动脉瓣损伤小鼠 MRSA 诱导的感染性心内膜炎的发生率。ACE 敲除 (KO) 小鼠或接受 ACEI 处理的小鼠的中性粒细胞在 MRSA 或脂多糖刺激后产生较少的白三烯 B4 (LTB4)，而与野生型中性粒细胞相比，过度表达 ACE 的中性粒细胞产生更多的 LTB4。由于 LTB4 产生减少，ACE KO 中性粒细胞表现出生存信号减少和细胞凋亡增加。相反，过度表达 ACE 的中性粒细胞具有增强的生存表型。最后，在一组接受 ACEI 雷米普利 1 周的人类志愿者中，ACEI 给药减少了中性粒细胞超氧化物和活性氧的产生，并且在雷米普利治疗期间从志愿者中分离出的中性粒细胞的杀菌活性降低。总之，这些数据表明 ACEI 治疗（而非 ARB 治疗）可以降低中性粒细胞的细菌杀灭能力。