Pharmacologic ACE-Inhibition Mitigates Radiation-Induced Pneumonitis by Suppressing ACE-Expressing Lung Myeloid Cells.
Pharmacologic ACE-Inhibition Mitigates Radiation-Induced Pneumonitis by Suppressing ACE-Expressing Lung Myeloid Cells.
复制标题
药理学ACE抑制通过抑制表达ACE的肺髓样细胞减轻放射诱导的肺炎。
DOI：
10.1016/j.ijrobp.2022.01.023
复制
发表时间：
2022-05-01
影响因子：
7
通讯作者：
Himburg, Heather A.
中科院分区：
文献类型：
--
作者：
Sharma, Guru Prasad;Fish, Brian L.;Frei, Anne C.;Narayanan, Jayashree;Gasperetti, Tracy;Scholler, Dana;Pierce, Lauren;Szalewski, Nathan;Blue, Noah;Medhora, Meetha;Himburg, Heather A.
辐射引起的肺损伤是胸部放疗患者的主要剂量限制性毒性。在实验模型中，血管紧张素转换酶（ACE）抑制剂治疗可减轻放射性肺炎；然而，其作用机制尚不清楚。在这里，我们评估ACE抑制对肺免疫细胞的直接作用。研究了大鼠右肺高剂量分次放射治疗（5次× 9 Gy）和单次13.5 Gy部分体照射（PBI）后肺免疫细胞室中ACE的表达和活性。在13.5 Gy大鼠PBI模型中评估ace抑制剂赖诺普利对辐射性肺炎的缓解作用。在肺炎期间，我们描述了肺和支气管肺泡灌洗液（BALF）中的炎症和免疫细胞含量。使用原代人单核细胞和人单核THP-1细胞系进行体外机制研究。在PBI和分级RT模型中，辐射增加了肺免疫细胞的ACE活性。赖诺普利治疗可提高放射性肺炎患者的生存率（p=0.0004）。赖诺普利消除了辐射引起的BALF MCP-1 （CCL2）和MIP-1α细胞因子水平的升高（p < 0.0001）。赖诺普利治疗降低了ACE表达（p=0.006）和CD45+CD11b+肺髓样细胞频率（p=0.004）。在体外，辐射损伤急性增加了人单核细胞的ACE活性（p=0.045）和活性氧（ROS）的产生（p=0.004），而赖诺普利治疗可阻断辐射诱导的ACE和ROS的增加。有趣的是，通过药物抑制NADPH氧化酶2 (NOX2) （p=0.012）或1型血管紧张素受体（AGTR1） （p=0.013），可以阻断辐射诱导的ROS生成。这些数据表明，辐射诱导的免疫室内ACE激活促进了放射性肺炎的发病机制，而ACE抑制抑制了促炎免疫细胞亚群的激活。在机制上，我们的体外数据表明，辐射直接激活免疫细胞中的ACE/AGTR1途径，并通过Nox2促进ROS的产生。
Radiation-induced lung injury is a major dose-limiting toxicity for thoracic radiotherapy patients. In experimental models, treatment with angiotensin converting enzyme (ACE) inhibitors mitigates radiation pneumonitis; however, the mechanism of action is not well understood. Here, we evaluate the direct role of ACE inhibition on lung immune cells. ACE expression and activity were determined in the lung immune cell compartment of irradiated adult rats following either high dose fractionated radiation therapy (RT) to the right lung (5 fractions × 9 Gy) or a single dose of 13.5 Gy partial body irradiation (PBI). Mitigation of radiation-induced pneumonitis with the ACE-inhibitor lisinopril was evaluated in the 13.5 Gy rat PBI model. During pneumonitis, we characterized inflammation and immune cell content in the lungs and bronchoalveolar lavage fluid (BALF). In vitro mechanistic studies were performed using primary human monocytes and the human monocytic THP-1 cell line. In both the PBI and fractionated RT models, radiation increased ACE activity in lung immune cells. Treatment with lisinopril improved survival during radiation pneumonitis (p=0.0004). Lisinopril abrogated radiation-induced increases in BALF MCP-1 (CCL2) and MIP-1α cytokine levels (p < 0.0001). Treatment with lisinopril reduced both ACE expression (p=0.006) and frequency of CD45+CD11b+ lung myeloid cells (p=0.004). In vitro, radiation injury acutely increased ACE activity (p=0.045) and reactive oxygen species (ROS) generation (p=0.004) in human monocytes, whereas treatment with lisinopril blocked radiation-induced increases in both ACE and ROS. Interestingly, radiation-induced ROS generation was blocked by pharmacological inhibition of either NADPH oxidase 2 (NOX2) (p=0.012) or the type 1 angiotensin receptor (AGTR1) (p=0.013). These data demonstrate radiation-induced ACE activation within the immune compartment promotes the pathogenesis of radiation pneumonitis, while ACE inhibition suppresses activation of pro-inflammatory immune cell subsets. Mechanistically, our in vitro data demonstrate radiation directly activates the ACE/AGTR1 pathway in immune cells and promotes generation of ROS via Nox2.
登录
查看更多内容
对辐射引起的肺损伤进行建模：从整个胸腔照射中学到的经验教训。
影响因子：
2.6
作者：
Beach TA;Groves AM;Williams JP;Finkelstein JN
通讯作者：
Finkelstein JN
DOI：
10.3109/0284186x.2010.521192
发表时间：
2011-01
期刊：
Acta oncologica (Stockholm, Sweden)
影响因子：
--
作者：
Huang EX;Hope AJ;Lindsay PE;Trovo M;El Naqa I;Deasy JO;Bradley JD
通讯作者：
Bradley JD
影响因子：
8
作者：
Duan M;Steinfort DP;Smallwood D;Hew M;Chen W;Ernst M;Irving LB;Anderson GP;Hibbs ML
通讯作者：
Hibbs ML
DOI：
10.1016/j.ijrobp.2014.03.048
发表时间：
2014-07-15
影响因子：
7
作者：
Mahmood, Javed;Jelveh, Salomeh;Zaidi, Asif;Doctrow, Susan R.;Medhora, Meetha;Hill, Richard P.
通讯作者：
Hill, Richard P.
影响因子：
9.6
作者：
Hanania, Alexander N.;Mainwaring, Walker;Ludwig, Michelle
通讯作者：
Ludwig, Michelle