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      Club Cell Secretory Protein (CCSP) is Reduced in Hospitalized Chronic Obstructive Pulmonary Disease (COPD) Exacerbations

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          Introduction Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) cause the majority of the morbidity, mortality, and health-care expenditure associated with COPD. The pathogenesis of AECOPD is complex, but oxidative stress has been implicated in AECOPD. Club cell secretory protein (CCSP), a molecule secreted by the non-ciliated bronchiolar Club cells, is thought to protect airways from oxidative stress and may be a therapeutic target in AECOPD.1 Previous studies have linked CCSP with COPD and lung function decline.2 However, no studies have investigated the association between CCSP levels and AECOPD. Our objective was to determine if CCSP levels correlate with AECOPD by measuring plasma CCSP levels at the time of AECOPD hospitalization, and recovery compared to stable outpatients. We used data from two multicenter clinical trials of patients at increased risk of AECOPD to test the hypothesis that plasma CCSP levels are reduced in AECOPD compared to stable COPD. Methods We performed a case–control study (ratio 1:2, matched on age, sex, tobacco pack-years, and FEV1% predicted) where cases were hospitalized AECOPD patients from the Zileuton to Treat Adults with Chronic Obstructive Pulmonary Disease (LEUKO) study. All participants in the LEUKO study with plasma samples obtained at both hospital day 0 and 30 days post-hospitalization were included in the analyses. Matched stable controls were outpatients at high risk for AECOPD, but without exacerbations in the 4 weeks prior to study entry and blood draw, in the Macrolide Azithromycin to Prevent Rapid Worsening of Symptoms Associated with Chronic Obstructive Pulmonary Disease (MACRO) study. Plasma CCSP levels at hospital day 0 and day 30 post-hospitalization for cases and at baseline for controls were quantified using commercially available ELISA kits (BioVendor, Candler, NC, USA). CCSP levels were transformed to a natural logarithmic scale to achieve normal distribution. To account for case–control matching, conditional logistic regression was used to determine the association between CCSP and case–control status. Serum creatinine was a covariate in adjusted models since CCSP levels are affected by kidney function and creatinine clearance predicts plasma CCSP levels.3 T-tests were used to compare CCSP means between cases at hospital day 0, day 30 post-hospitalization, and controls. Results We measured plasma CCSP levels in 30 cases and 60 controls. After exclusion of one case with extreme plasma CCSP levels (day 0: 125.56 ng/mL; day 30: 136.73 ng/mL) and the two matched controls for this case, we have 29 cases and 58 matched controls for analysis (Table 1). Median [interquartile range (IQR)] age of the cases was 61 [55–68] years, 45% were females, 35% were current smokers, median [IQR] smoking history of 40 [28–57] pack-years, mean FEV1% predicted was 28.8% and median [IQR] serum creatinine was 1.0 [0.8–1.1]. The controls had a median [IQR] age of 60 [56–68] years, 41% were female, 26% were current smokers, median [IQR] smoking history of 40 [30–50] pack-years, mean FEV1% predicted was 34.6%, and median [IQR] serum creatinine was 0.9 [0.8–1.1] mg/dL. Table 1 Baseline Characteristics Cases (n=29) Controls (n=58) Age, years (median [IQR]) 61 [55-68] 60 [56-68] Female, no. (%) 13 (45%) 24 (41%) Race or ethnic group, no. (%)  White 15 (52%) 42 (72%)  African-American 13 (45%) 10 (17%)  Other 1 (3%) 6 (10%) Current smoker, no. (%) 10 (35%) 15 (26%) Smoking history, pack-years (median [IQR]) 40 [28-57] 40 [30-50] Spirometry (mean±SD)  FEV1, L 0.8 ± 0.4 1.0 ± 0.5  FEV1% predicted 28.8 ± 13.1 34.6 ± 15.9  FVC, L 2.0 ± 0.6 2.5 ± 0.9  FEV1/FVC ratio 0.4 ± 0.1 0.4 ± 0.1 Inhaled therapies, no (%)  ICS 24 (83%) 43 (74%)  LABA 22 (76%) 43 (74%)  LAMA 17 (59%) 39 (67%) Serum creatinine, mg/dL (median [IQR]) 1.0 [0.8-1.1] 0.9 [0.8-1.1] Notes: Definitions: Cases, hospitalized acute exacerbation in COPD; controls, stable COPD. Abbreviations: FEV1, forced expiratory volume in one second; FVC, forced vital capacity; ICS, inhaled corticosteroid; LABA, long-acting beta2-agonist; LAMA, long-acting muscarinic antagonist; and SD, standard deviation. Hospitalized AECOPD (case) status was associated with reduced plasma CCSP levels compared to stable COPD (control) status, matched on age, sex, tobacco pack years, and FEV1% predicted. Each natural log unit increase in plasma CCSP was associated with a decreased odds for hospitalized AECOPD status in both unadjusted (odds ratio [OR] 0.347, 95% confidence interval [CI]: 0.121 to 0.998, p=0.0495) and adjusted models that included serum creatinine as a covariate (adjusted OR 0.269, 95% CI: 0.089 to 0.811, p=0.0197) (Table 2). The plasma CCSP (mean±standard deviation) at day 0 (1.53±0.62 ng/mL) vs controls (1.79±0.51 ng/mL) (p=0.041) were significantly different, while day 0 vs day 30 (1.64±0.60 ng/mL) (p=0.229) and day 30 vs controls were not significantly different (p=0.495). Table 2 Conditional Logistic Regression Analyses for Predicting Hospitalized Acute Exacerbation in COPD (AECOPD) Case vs Matched Stable COPD Control Status Hospitalized AECOPD Cases (n=29) Stable COPD Controls (n=58) Unadjusted OR (95% CI) Adjusted OR (95% CI) Plasma CCSP (mean±SD) 1.53±0.62 1.79±0.51 0.347 (0.121, 0.998) p=0.0495 0.269 (0.089, 0.811) p=0.0197 Notes: Cases and controls were matched on age, sex, tobacco pack-years, and FEV1% predicted. Plasma CCSP levels in ng/mL are in natural logarithmic scale. Adjusted model includes creatinine as a covariate. Abbreviations: CCSP, club cell secretory protein; SD, standard deviation; CI, confidence interval. Discussion To our knowledge, this study is the first to evaluate plasma CCSP during an AECOPD. We found that lower plasma CCSP is associated with higher odds of hospitalized AECOPD status relative to matched stable COPD and that plasma CCSP levels 30 days following hospitalization are similar to stable controls. CCSP is produced by the small airway club cell and is thought to protect airways from oxidative stress.1 Therefore, a reduction in CCSP levels during an AECOPD would result in increased susceptibility to oxidative stress, which could contribute to AECOPD severity. The increasing trend in plasma CCSP 30 days later, though not significantly different from hospitalization day 0, is suggestive of airway epithelial cells recovery following an AECOPD. We excluded one case with extreme plasma CCSP levels. This patient had a serum creatinine of 12.1 mg/dL indicating renal failure. Because plasma CCSP levels are affected by kidney function,3 it is likely that this extreme elevation in plasma CCSP levels is due to renal failure. Therefore, we accounted for renal function in our adjusted model. CCSP has been evaluated in several COPD cohorts. Bernard et al found that bronchoalveolar lavage fluid CCSP levels were reduced in stable COPD compared to non-smoker controls.4 In the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study, a 3-year multicentre prospective observational cohort of 2747 participants with COPD, Lomas et al found that median serum CCSP was lowest in COPD participants (5.9 ng/mL) compared to smoker (6.3 ng/mL) and non-smoker controls (7.5 ng/mL) without COPD.5 The median serum CCSP level among COPD participants in the ECLIPSE cohort is similar to our stable COPD control group (5.50 ng/mL), consistent with CCSP deficiency in patients with COPD. Low serum CCSP levels have been associated with accelerated lung function decline,2 which brings into question the possible role of CCSP augmentation therapy in COPD. Pre-clinical models of CCSP augmentation have demonstrated protective effects in both cellular and animal models.6 An ongoing clinical trial in premature infants with respiratory distress syndrome has shown that recombinant human CCSP can be safely delivered intratracheally, and a single dose reduces pulmonary inflammatory markers.7 Our findings support assessment of therapies targeting restoration of CCSP levels in COPD, specifically during an acute exacerbation or as a sustained, maintenance therapy in exacerbation-prone COPD patients. Our study has limitations including a modest sample size and being observational, thus we are unable to establish causality. Whether reduction in CCSP levels is a risk factor for versus a consequence of AECOPD will need to be addressed in larger longitudinal and mechanistic studies. We did not have baseline plasma CCSP levels prior to hospitalization, which could have helped determine if levels at 30 days return to baseline, but because we were able to match on age, sex, tobacco pack-years, and FEV1% predicted, we theorize that our matched controls reflect baseline, pre-hospitalization plasma CCSP levels among exacerbation-prone COPD patients. Conclusion In conclusion, lower plasma CCSP is associated with hospitalized AECOPD. Clinical studies are needed to evaluate the efficacy of CCSP as a novel treatment for COPD, especially in AECOPD.

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          Most cited references 7

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          Number and proliferation of clara cells in normal human airway epithelium.

          Experimental pathologic studies suggest that Clara cells are one of the types of airway stem cells but the proliferation of Clara cells in human lungs has not yet been examined. The purpose of this study was to assess in conducting airways of normal human lungs: (1) the number of Clara cells; and (2) the contribution of Clara cells to the proliferation compartment. Samples of histologic normal tissue were taken from seven lungs obtained by autopsy. A triple sequential (immuno)histochemical staining was performed, using MIB-1 as a proliferation marker and anti-CC10 for the identification of Clara cells; subsequently, a PAS stain was carried out as a marker for goblet cells, as these cells were reported to be CC10-immunoreactive in an unknown proportion. Clara cells were virtually absent in the proximal airway epithelium. The number of Clara cells in the terminal bronchioles was 11 +/- 3% (mean +/- SD) and in respiratory bronchioles 22 +/- 5%. The overall proliferation compartment of the conducting airway epithelium was 0.83 +/- 0.47%; the contribution of Clara cells was 9%. In the terminal bronchioles 15% of proliferating airway epithelial cells were Clara cells, and in the respiratory bronchioles this number increased to 44%. The contribution of Clara cells to the proliferation compartment of normal human tracheobronchial epithelium is substantial, demonstrating a role of the Clara cell in the maintenance of the normal epithelium of the distal conducting airways in humans.
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            Evaluation of serum CC-16 as a biomarker for COPD in the ECLIPSE cohort.

            Circulating levels of Clara cell secretory protein-16 (CC-16) have been linked to Clara cell toxicity. It has therefore been suggested that this protein may be a useful marker of chronic obstructive pulmonary disease (COPD). Serum CC-16 levels were measured in 2083 individuals aged 40-75 years with COPD and a smoking history of >or=10 pack-years, 332 controls with a smoking history of >or=10 pack-years and normal lung function and 237 non-smoking controls. Serum CC-16 had a coefficient of repeatability of 2.90 over 3 months in a pilot study of 267 individuals. The median serum CC-16 level was significantly reduced in a replication group of 1888 current and former smokers with COPD compared with 296 current and former smokers without airflow obstruction (4.9 and 5.6 ng/ml, respectively; p<0.001) and 201 non-smokers (6.4 ng/ml; p<0.001). Serum levels of CC-16 were lower in current than in former smokers with GOLD stage II and III COPD but were not different in individuals with stage IV disease. Former, but not current smokers, with COPD had lower serum CC-16 levels with increasing severity of COPD (GOLD II vs GOLD IV COPD: 5.5 and 5.0 ng/ml, p = 0.006; r = 0.11 with forced expiratory volume in 1 s, p<0.001) and had significantly higher levels if they also had reversible airflow obstruction (p = 0.034). Serum CC-16 was affected by gender and age (r = 0.35; p<0.001) in subjects with COPD but not by body mass index or the presence of either chronic bronchitis or emphysema. Serum CC-16 levels are reduced in individuals with COPD and there is a weak correlation with disease severity in former smokers.
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              Clara cell protein in serum and bronchoalveolar lavage.

              The 10 kDa Clara cell protein was measured in serum and bronchoalveolar lavage (BAL) from 39 healthy subjects (14 smokers, 25 nonsmokers) and from 41 patients with respiratory disease (chronic obstructive pulmonary disease (COPD), sarcoidosis, lung cancer). Clara cell protein appears as one of the most abundant respiratory tract derived proteins, with values averaging 7% of the total protein content of lung lavages from healthy nonsmokers. A significant reduction of Clara cell protein was found in BAL from smokers and patients with COPD or lung cancer. The same pattern of change was found in the concentrations of Clara cell protein in serum. Pulmonary sarcoidosis did not affect absolute values of Clara cell protein in lung lavages but was associated with elevated levels in serum. Changes in lung lavage Clara cell protein differed from that of albumin, beta 2-microglobulin or the secretory component, since the latter were unaffected by smoking or COPD but increased in sarcoidosis and lung cancer. These results indicate that Clara cell protein in BAL or serum might serve as a sensitive indicator of nonciliated bronchial cell dysfunction.

                Author and article information

                Int J Chron Obstruct Pulmon Dis
                Int J Chron Obstruct Pulmon Dis
                International Journal of Chronic Obstructive Pulmonary Disease
                09 October 2020
                : 15
                : 2461-2464
                [1 ]Pulmonary, Allergy, Critical Care, and Sleep Medicine, Minneapolis VA Health Care System , Minneapolis, MN, USA
                [2 ]Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Minnesota , Minneapolis, MN, USA
                [3 ]Division of Biostatistics, School of Public Health, University of Minnesota , Minneapolis, MN, USA
                [4 ]APCBio Innovations, Inc ., Rockville, MD, USA
                Author notes
                Correspondence: Arianne K Baldomero Pulmonary, Allergy, Critical Care, and Sleep Medicine, Minneapolis VA Health Care System , 1 Veterans Drive, Post Code: Pulmonary 111N, Minneapolis, MN, USATel +1920-203-5517 Email
                © 2020 Baldomero et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (

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                Research Letter

                Respiratory medicine


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