Kesimer Mehmet, Ford Amina A, Ceppe Agathe, Radicioni Giorgia, Cao Rui, Davis C William, Doerschuk Claire M, Alexis Neil E, Anderson Wayne H, Henderson Ashley G, Barr R Graham, Bleecker Eugene R, Christenson Stephanie A, Cooper Christopher B, Han MeiLan K, Hansel Nadia N, Hastie Annette T, Hoffman Eric A, Kanner Richard E, Martinez Fernando, Paine Robert, Woodruff Prescott G, O'Neal Wanda K, Boucher Richard C
From the Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill (M.K., A.A.F., A.C., G.R., R.C., C.W.D., C.M.D., N.E.A., W.H.A., A.G.H., W.K.O., R.C.B.), and the Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem (E.R.B., A.T.H.) - both in North Carolina; the Department of Medicine, Columbia University Medical Center, and the Department of Epidemiology, Mailman School of Public Health at Columbia University (R.G.B.), and the Department of Medicine, Weill Cornell Medical College (F.M.), New York; the Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Department of Medicine, University of California San Francisco Medical Center, San Francisco (S.A.C., P.G.W.); the Department of Medicine and Physiology, David Geffen School of Medicine, University of California, Los Angeles (C.B.C.); the Division of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor (M.K.H.); the Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore (N.N.H.); the Department of Radiology, Division of Physiologic Imaging, University of Iowa Hospitals and Clinics, Iowa City (E.A.H.); and the Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Utah, Veterans Affairs Medical Center, Salt Lake City (R.E.K., R.P.).
N Engl J Med. 2017 Sep 7;377(10):911-922. doi: 10.1056/NEJMoa1701632.
Chronic obstructive pulmonary disease (COPD) is characterized by chronic bronchitic and emphysematous components. In one biophysical model, the concentration of mucin on the airway surfaces is hypothesized to be a key variable that controls mucus transport in healthy persons versus cessation of transport in persons with muco-obstructive lung diseases. Under this model, it is postulated that a high mucin concentration produces the sputum and disease progression that are characteristic of chronic bronchitis.
We characterized the COPD status of 917 participants from the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) using questionnaires administered to participants, chest tomography, spirometry, and examination of induced sputum. Total mucin concentrations in sputum were measured with the use of size-exclusion chromatography and refractometry. In 148 of these participants, the respiratory secreted mucins MUC5AC and MUC5B were quantitated by means of mass spectrometry. Data from chronic-bronchitis questionnaires and data on total mucin concentrations in sputum were also analyzed in an independent 94-participant cohort.
Mean (±SE) total mucin concentrations were higher in current or former smokers with severe COPD than in controls who had never smoked (3166±402 vs. 1515±152 μg per milliliter) and were higher in participants with two or more respiratory exacerbations per year than in those with zero exacerbations (4194±878 vs. 2458±113 μg per milliliter). The absolute concentrations of MUC5B and MUC5AC in current or former smokers with severe COPD were approximately 3 times as high and 10 times as high, respectively, as in controls who had never smoked. Receiver-operating-characteristic curve analysis of the association between total mucin concentration and a diagnosis of chronic bronchitis yielded areas under the curve of 0.72 (95% confidence interval [CI], 0.65 to 0.79) for the SPIROMICS cohort and 0.82 (95% CI, 0.73 to 0.92) for the independent cohort.
Airway mucin concentrations may quantitate a key component of the chronic bronchitis pathophysiologic cascade that produces sputum and mediates disease severity. Studies designed to explore total mucin concentrations in sputum as a diagnostic biomarker and therapeutic target for chronic bronchitis appear to be warranted. (Funded by the National Heart, Lung, and Blood Institute and others.).
慢性阻塞性肺疾病（COPD）的特征为慢性支气管炎和肺气肿成分。在一个生物物理模型中，气道表面粘蛋白的浓度被假定为一个关键变量，它控制着健康人黏液的运输，而在黏液阻塞性肺部疾病患者中则控制着运输的停止。在这个模型下，推测高粘蛋白浓度会导致慢性支气管炎特有的痰液和疾病进展。
我们通过向慢性阻塞性肺疾病研究（SPIROMICS）的917名参与者发放问卷、进行胸部断层扫描、肺功能测定以及诱导痰检查，来确定他们的COPD状态。痰液中的总粘蛋白浓度通过尺寸排阻色谱法和折射法进行测量。在这些参与者中的148名中，通过质谱法定量呼吸道分泌的粘蛋白MUC5AC和MUC5B。还在一个独立的94名参与者队列中分析了慢性支气管炎问卷数据和痰液中总粘蛋白浓度数据。
重度COPD的现吸烟者或既往吸烟者的平均（±标准误）总粘蛋白浓度高于从未吸烟的对照组（3166±402 vs. 1515±152微克/毫升），每年有两次或更多次呼吸道加重的参与者的总粘蛋白浓度高于无加重的参与者（4194±878 vs. 2458±113微克/毫升）。重度COPD的现吸烟者或既往吸烟者中MUC5B和MUC5AC的绝对浓度分别约为从未吸烟的对照组的3倍和10倍。对总粘蛋白浓度与慢性支气管炎诊断之间的关联进行的受试者工作特征曲线分析显示，SPIROMICS队列的曲线下面积为0.72（95%置信区间[CI]，0.65至0.79），独立队列的曲线下面积为0.82（95%CI，0.73至0.92）。
气道粘蛋白浓度可能量化了慢性支气管炎病理生理级联反应中产生痰液并介导疾病严重程度的关键成分。旨在探索痰液中总粘蛋白浓度作为慢性支气管炎诊断生物标志物和治疗靶点的研究似乎是有必要的。（由美国国立心肺血液研究所等资助。）
