Footitt Joseph, Mallia Patrick, Durham Andrew L, Ho W Eugene, Trujillo-Torralbo Maria-Belen, Telcian Aurica G, Del Rosario Ajerico, Chang Cheng, Peh Hong-Yong, Kebadze Tatiana, Aniscenko Julia, Stanciu Luminita, Essilfie-Quaye Sarah, Ito Kazuhiro, Barnes Peter J, Elkin Sarah L, Kon Onn M, Wong W S Fred, Adcock Ian M, Johnston Sebastian L
Airway Disease Infection Section, National Heart and Lung Institute, Imperial College, London, England; Imperial College Healthcare NHS Trust, London, England; Centre for Respiratory Infection, Imperial College, London, England.
Airways Disease Section, National Heart and Lung Institute, Imperial College, London, England.
Chest. 2016 Jan;149(1):62-73. doi: 10.1378/chest.14-2637. Epub 2016 Jan 6.
Respiratory virus infections are commonly associated with COPD exacerbations, but little is known about the mechanisms linking virus infection to exacerbations. Pathogenic mechanisms in stable COPD include oxidative and nitrosative stress and reduced activity of histone deacetylase-2 (HDAC2), but their roles in COPD exacerbations is unknown. We investigated oxidative and nitrosative stress (O&NS) and HDAC2 in COPD exacerbations using experimental rhinovirus infection.
Nine subjects with COPD (Global Initiative for Chronic Obstructive Lung Disease stage II), 10 smokers, and 11 nonsmokers were successfully infected with rhinovirus. Markers of O&NS-associated cellular damage, and inflammatory mediators and proteases were measured in sputum, and HDAC2 activity was measured in sputum and bronchoalveolar macrophages. In an in vitro model, monocyte-derived THP-1 cells were infected with rhinovirus and nitrosylation and activity of HDAC2 was measured.
Rhinovirus infection induced significant increases in airways inflammation and markers of O&NS in subjects with COPD. O&NS markers correlated with virus load and inflammatory markers. Macrophage HDAC2 activity was reduced during exacerbation and correlated inversely with virus load, inflammatory markers, and nitrosative stress. Sputum macrophage HDAC2 activity pre-infection was inversely associated with sputum virus load and inflammatory markers during exacerbation. Rhinovirus infection of monocytes induced nitrosylation of HDAC2 and reduced HDAC2 activity; inhibition of O&NS inhibited rhinovirus-induced inflammatory cytokines.
O&NS, airways inflammation, and impaired HDAC2 may be important mechanisms of virus-induced COPD exacerbations. Therapies targeting these mechanisms offer potential new treatments for COPD exacerbations.
呼吸道病毒感染通常与慢性阻塞性肺疾病（COPD）急性加重相关，但病毒感染与急性加重之间的联系机制知之甚少。稳定期COPD的发病机制包括氧化应激和亚硝化应激以及组蛋白去乙酰化酶2（HDAC2）活性降低，但其在COPD急性加重中的作用尚不清楚。我们使用实验性鼻病毒感染研究了COPD急性加重期的氧化应激和亚硝化应激（O&NS）以及HDAC2。
9名COPD患者（慢性阻塞性肺疾病全球倡议II期）、10名吸烟者和11名非吸烟者成功感染鼻病毒。检测痰液中O&NS相关细胞损伤标志物、炎症介质和蛋白酶，并检测痰液和支气管肺泡巨噬细胞中的HDAC2活性。在体外模型中，用鼻病毒感染单核细胞衍生的THP-1细胞，检测HDAC2的亚硝化作用和活性。
鼻病毒感染导致COPD患者气道炎症和O&NS标志物显著增加。O&NS标志物与病毒载量和炎症标志物相关。急性加重期巨噬细胞HDAC2活性降低，且与病毒载量、炎症标志物和亚硝化应激呈负相关。感染前痰液巨噬细胞HDAC2活性与急性加重期痰液病毒载量和炎症标志物呈负相关。鼻病毒感染单核细胞可诱导HDAC2亚硝化并降低HDAC2活性；抑制O&NS可抑制鼻病毒诱导的炎性细胞因子。
O&NS、气道炎症和HDAC2功能受损可能是病毒诱导COPD急性加重的重要机制。针对这些机制的治疗方法为COPD急性加重提供了潜在的新治疗手段。
