Department of Clinical Pharmacology, Medical University of Bialystok, Bialystok, Poland.
Adv Exp Med Biol. 2013;756:9-14. doi: 10.1007/978-94-007-4549-0_2.
Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation and chronic inflammation of airways and lung parenchyma. Our aim was to assess two important elements of intracellular signaling involved in regulation of inflammation in COPD in patients subjected to long-acting beta2-agonist or long-acting beta2-agonist plus long-acting antimuscarinic: peroxisome proliferator-activated receptor gamma (PPARγ) protein, which has antiinflammatory and immunomodulatory properties and cAMP response element binding protein (CREB) and activated (CREB-P) protein which has histone acetyltransferase activity and increases histone acetylation and transcriptional activation of chromatin. Twenty one stable COPD patients (18 males and 3 females, mean age 65 years) receiving 12 μg B.I.D formoterol were assayed before and after 3 month add-on therapy, consisting of 18 μg Q.D. tiotropium. In all patients, sputum induction, spirometry, lung volumes, and DLCO were performed before and after therapy. Sputum cells were isolated and processed to isolate cytosolic and nuclear fractions. PPARγ, CREB, or CREB-P proteins were quantified in subcellular fractions using Western blot. Tiotropium add-on therapy improved respiratory parameters: FEV1 and lung volumes. After therapy mean expression of PPARγ in cell nuclei was significantly increased by about 180%, while CREB and phosphorylated CREB levels in cytosol and nuclei were decreased by about 30%. Our data show that the mechanism whereby tiotropium reduces exacerbations may be associated not only with persistent increase in airway functions and reduced hyperinflation mediated by muscarinic receptors, but also with possible anti-inflammatory effects of the drug, involving increased PPARγ and decreased CREB signaling.
慢性阻塞性肺疾病（COPD）的特征是气流受限进行性加重和气道及肺实质的慢性炎症。我们的目的是评估 COPD 患者在长期使用β2 激动剂或长效β2 激动剂加长效抗毒蕈碱药物后，两种参与炎症调节的细胞内信号转导的重要因素：过氧化物酶体增殖物激活受体γ（PPARγ）蛋白，具有抗炎和免疫调节作用；cAMP 反应元件结合蛋白（CREB）和激活的（CREB-P）蛋白，具有组蛋白乙酰转移酶活性，增加组蛋白乙酰化和染色质的转录激活。21 例稳定的 COPD 患者（18 名男性和 3 名女性，平均年龄 65 岁）接受 12μg B.I.D 福莫特罗治疗 3 个月后，加用 18μg Q.D.噻托溴铵治疗。所有患者在治疗前后均进行了痰诱导、肺功能、肺容积和 DLCO 检测。分离痰液细胞并处理以分离细胞质和核部分。使用 Western blot 定量亚细胞部分的 PPARγ、CREB 或 CREB-P 蛋白。噻托溴铵加用治疗改善了呼吸参数：FEV1 和肺容积。治疗后，细胞核中 PPARγ 的平均表达增加了约 180%，而细胞质和细胞核中 CREB 和磷酸化 CREB 水平降低了约 30%。我们的数据表明，噻托溴铵减少加重的机制不仅与持续增加气道功能和减少由毒蕈碱受体介导的过度充气有关，而且可能与药物的抗炎作用有关，涉及增加 PPARγ 和减少 CREB 信号转导。
