Ludwig Boltzmann Institute for Lung Vascular Research, Neue Stiftingtalstrasse 6/VI, 8010, Graz, Austria.
Division of Endocrinology and Diabetology; Department of Internal Medicine, Medical University of Graz, Graz, Austria.
Respir Res. 2020 Jul 2;21(1):167. doi: 10.1186/s12931-020-01433-w.
Inhibitors of cyclin-dependent kinases 4/6 (CDK4/6) block cell cycle progression and are commonly used for treatment of several forms of cancer. Due to their anti-proliferative mode of action, we hypothesized that palbociclib could attenuate the development of bleomycin-induced lung fibrosis. In a preclinical setting, mice were treated with bleomycin and then co-treated with or without palbociclib. Lung function, collagen deposition and pulmonary inflammation were analysed after 14 days.Bleomycin treatment led to an increase of pulmonary fibrosis and inflammation, and concomitant decline of lung function. Palbociclib treatment significantly decreased collagen deposition in the lung after bleomycin treatment, but did not ameliorate lung function. Importantly, palbociclib augmented inflammatory cell recruitment (including macrophages and T cells) in the bronchoalveolar lavage fluid.This study supports the recent alert from the Food and Drug Administration (FDA) that use of CDK4/6 inhibitors, such as palbociclib, may have severe pulmonary adverse effects. Our study showing heightened pulmonary inflammation following palbociclib treatment highlights the risk of severe inflammatory adverse effects in the lung. This is of special interest in patients with known pulmonary risk factors and emphasizes the need of careful monitoring all patients treated with CDK4/6 inhibitors for signs of lung inflammation.
细胞周期蛋白依赖性激酶 4/6（CDK4/6）抑制剂可阻止细胞周期进程，常用于治疗多种癌症。由于其抗增殖作用模式，我们假设 palbociclib 可以减轻博来霉素诱导的肺纤维化的发展。在临床前环境中，用博来霉素处理小鼠，然后用或不用 palbociclib 共同处理。在 14 天后分析肺功能、胶原蛋白沉积和肺部炎症。博来霉素处理导致肺纤维化和炎症增加，同时肺功能下降。Palbociclib 治疗可显著减少博来霉素处理后的肺胶原蛋白沉积，但不能改善肺功能。重要的是，Palbociclib 增加了支气管肺泡灌洗液中的炎症细胞募集（包括巨噬细胞和 T 细胞）。本研究支持食品和药物管理局（FDA）最近的警告，即使用 CDK4/6 抑制剂（如 palbociclib）可能会产生严重的肺部不良反应。我们的研究表明，palbociclib 治疗后肺部炎症加剧，突出了肺部严重炎症不良反应的风险。对于已知存在肺部风险因素的患者，这一点尤其重要，强调需要仔细监测所有接受 CDK4/6 抑制剂治疗的患者的肺部炎症迹象。
