Departments of Physiology (M.J.T., J.W.H.) and Pediatrics (N.D.) and Cystic Fibrosis Translational Research Centre (M.J.T., L.C.L., J.W.H), McGill University, Montréal, Québec, Canada; Pediatric Respiratory Medicine, Montreal Children's Hospital, Montréal, Québec, Canada (N.D., L.C.L.); Research Institute - McGill University Health Centre, Montréal, Québec, Canada (L.C.L., J.W.H.); Department of Internal, Respiratory Translational Laboratory, Respiratory and Critical Care Medicine, Philipps-University of Marburg, Marburg, Germany (N.D.); and Faculty of Medicine and Healthcare, al-Farabi Kazakh National University, Almaty, Kazakhstan (N.D.)
Departments of Physiology (M.J.T., J.W.H.) and Pediatrics (N.D.) and Cystic Fibrosis Translational Research Centre (M.J.T., L.C.L., J.W.H), McGill University, Montréal, Québec, Canada; Pediatric Respiratory Medicine, Montreal Children's Hospital, Montréal, Québec, Canada (N.D., L.C.L.); Research Institute - McGill University Health Centre, Montréal, Québec, Canada (L.C.L., J.W.H.); Department of Internal, Respiratory Translational Laboratory, Respiratory and Critical Care Medicine, Philipps-University of Marburg, Marburg, Germany (N.D.); and Faculty of Medicine and Healthcare, al-Farabi Kazakh National University, Almaty, Kazakhstan (N.D.).
J Pharmacol Exp Ther. 2020 Dec;375(3):414-429. doi: 10.1124/jpet.120.000080. Epub 2020 Oct 4.
Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel that impair airway salt and fluid secretion. Excessive release of proinflammatory cytokines and chemokines by CF bronchial epithelium during airway infection leads to chronic inflammation and a slow decline in lung function; thus, there is much interest in finding safe and effective treatments that reduce inflammation in CF. We showed previously that the cyclic nucleotide phosphodiesterase (PDE) inhibitor ensifentrine (RPL554; Verona Pharma) stimulates the channel function of CFTR mutants with abnormal gating and also those with defective trafficking that are partially rescued using a clinically approved corrector drug. PDE inhibitors also have known anti-inflammatory effects; therefore, we examined whether ensifentrine alters the production of proinflammatory cytokines in CF bronchial epithelial cells. Ensifentrine reduced the production of monocyte chemoattractant protein-1 and granulocyte monocyte colony-stimulating factor (GM-CSF) during challenge with interleukin-1 Comparing the effect of ensifentrine with milrinone and roflumilast, selective PDE3 and PDE4 inhibitors, respectively, demonstrated that the anti-inflammatory effect of ensifentrine was mainly due to inhibition of PDE4. Beneficial modulation of GM-CSF was further enhanced when ensifentrine was combined with low concentrations of the -adrenergic agonist isoproterenol or the corticosteroid dexamethasone. The results indicate that ensifentrine may have beneficial anti-inflammatory effects in CF airways particularly when used in combination with -adrenergic agonists or corticosteroids. SIGNIFICANCE STATEMENT: Airway inflammation that is disproportionate to the burden of chronic airway infection causes much of the pathology in the cystic fibrosis (CF) lung. We show here that ensifentrine beneficially modulates the release of proinflammatory factors in well differentiated CF bronchial epithelial cells that is further enhanced when combined with β-adrenergic agonists or low-concentration corticosteroids. The results encourage further clinical testing of ensifentrine, alone and in combination with β-adrenergic agonists or low-concentration corticosteroids, as a novel anti-inflammatory therapy for CF.
囊性纤维化（CF）是由囊性纤维化跨膜电导调节因子（CFTR）阴离子通道突变引起的，该突变损害气道盐和液体分泌。CF 支气管上皮细胞在气道感染期间过度释放促炎细胞因子和趋化因子，导致慢性炎症和肺功能缓慢下降；因此，人们非常关注寻找安全有效的治疗方法，以减轻 CF 中的炎症。我们之前曾表明，环核苷酸磷酸二酯酶（PDE）抑制剂 ensifentrine（RPL554；Verona Pharma）可刺激具有异常门控的 CFTR 突变体的通道功能，还可刺激部分使用临床批准的校正药物挽救的功能障碍转运的 CFTR 突变体的通道功能。PDE 抑制剂也具有已知的抗炎作用；因此，我们检查了 ensifentrine 是否会改变 CF 支气管上皮细胞中促炎细胞因子的产生。在白细胞介素-1 刺激期间，ensifentrine 降低了单核细胞趋化蛋白-1 和粒细胞-单核细胞集落刺激因子（GM-CSF）的产生。将 ensifentrine 的作用与米力农和罗氟司特进行比较，米力农和罗氟司特分别是选择性 PDE3 和 PDE4 抑制剂，结果表明 ensifentrine 的抗炎作用主要归因于 PDE4 的抑制。当 ensifentrine 与低浓度的β-肾上腺素能激动剂异丙肾上腺素或皮质类固醇地塞米松联合使用时，对 GM-CSF 的有益调节作用得到进一步增强。结果表明，ensifentrine 可能对 CF 气道具有有益的抗炎作用，特别是在与β-肾上腺素能激动剂或皮质类固醇联合使用时。意义声明：与慢性气道感染负担不成比例的气道炎症是 CF 肺部病理学的主要原因。我们在这里表明，ensifentrine 可有益地调节在分化良好的 CF 支气管上皮细胞中促炎因子的释放，当与β-肾上腺素能激动剂或低浓度皮质类固醇联合使用时，这种作用会进一步增强。结果鼓励进一步临床测试 ensifentrine，单独使用或与β-肾上腺素能激动剂或低浓度皮质类固醇联合使用，作为 CF 的新型抗炎治疗方法。
