Pharmacologic ACE-Inhibition Mitigates Radiation-Induced Pneumonitis by Suppressing ACE-Expressing Lung Myeloid Cells
Radiation Pneumonitis
Pneumonitis
DOI:
10.1016/j.ijrobp.2022.01.023
Publication Date:
2022-01-29T10:59:58Z
AUTHORS (11)
ABSTRACT
Radiation-induced lung injury is a major dose-limiting toxicity for thoracic radiation therapy patients. In experimental models, treatment with angiotensin converting enzyme (ACE) inhibitors mitigates pneumonitis; however, the mechanism of action not well understood. Here, we evaluate direct role ACE inhibition on immune cells.ACE expression and activity were determined in cell compartment irradiated adult rats after either high dose fractionated to right (5 fractions × 9 Gy) or single 13.5 Gy partial body irradiation. Mitigation radiation-induced pneumonitis ACE-inhibitor lisinopril was evaluated rat irradiation model. During pneumonitis, characterized inflammation content lungs bronchoalveolar lavage fluid. vitro mechanistic studies performed using primary human monocytes monocytic THP-1 line.In both increased cells. Treatment improved survival during (P = .0004). Lisinopril abrogated increases fluid monocyte chemoattractant protein 1 (chemokine ligand 2) MIP-1a cytokine levels < .0001). reduced .006) frequency CD45+ CD11b+ myeloid cells .004). vitro, acutely .045) reactive oxygen species (ROS) generation .004) monocytes, whereas blocked ROS. ROS by pharmacologic NADPH oxidase 2 .012) type receptor .013).These data demonstrate activation within promotes pathogenesis while suppresses proinflammatory subsets. Mechanistically, our directly activates ACE/type pathway via 2.
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