Low CC16 mRNA Expression Levels in Bronchial Epithelial Cells Are Associated with Asthma Severity

Li, Xingnan; Guerra, Stefano; Ledford, Julie G.; Kraft, Monica; Li, Huashi; Hastie, Annette T.; Castro, Mario; Denlinger, Loren C.; Erzurum, Serpil C.; Fahy, John V.; Gaston, Benjamin; Israel, Elliot; Jarjour, Nizar N.; Levy, Bruce D.; Mauger, David T.; Moore, Wendy C.; Zein, Joe; Kaminski, Naftali; Wenzel, Sally E.; Woodruff, Prescott G.; Meyers, Deborah A.; Bleecker, Eugene R.

doi:10.1164/rccm.202206-1230oc

Cited by 18 publications

(14 citation statements)

References 65 publications

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“…Decreased CC16 serum levels are rather characteristic in chronic lung diseases with high degrees of bronchial epithelial cell damage, as it was recently shown by Li et al. who demonstrated an association of CC16 mRNA expression levels and asthma susceptibility, severity and exacerbations ( 13 ).…”

Section: Discussionmentioning

confidence: 77%

Brief Research Report: Serum clara cell 16 kDa protein levels are increased in patients hospitalized for severe SARS-CoV-2 or sepsis infection

Rohmann¹,

Stürmer²,

Geisler³

et al. 2022

Front. Immunol.

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BackgroundClara cell 16 kDa protein (CC16) is a secretory protein primarily expressed in epithelial cells in the lungs. Previous studies show that CC16 exerts anti-inflammatory and immune-modulatory properties in both acute and chronic pulmonary diseases. However, despite the evidence of CC16’s high biomarker potential, evaluation of its role in infectious diseases is yet very limited.MethodsSerum CC16 concentrations were measured by ELISA and assessed in two different types of severe infections. Using a case-control study design, patients treated for either severe SARS-CoV-2 or severe non-pulmonary sepsis infection were compared to age- and sex-matched healthy human subjects.ResultsSerum CC16 was significantly increased in both types of infection (SARS-CoV-2: 96.22 ± 129.01 ng/ml vs. healthy controls: 14.05 ± 7.48 ng/ml, p = 0.022; sepsis: 35.37 ± 28.10 ng/ml vs. healthy controls: 15.25 ± 7.51 ng/ml, p = 0.032) but there were no distinct differences between infections with and without pulmonary focus (p = 0.089). Furthermore, CC16 serum levels were positively correlated to disease duration and inversely to the platelet count in severe SARS-CoV-2 infection.ConclusionsIncreased CC16 serum levels in both SARS-CoV-2 and sepsis reinforce the high potential as a biomarker for epithelial cell damage and bronchoalveolar−blood barrier leakage in pulmonary as well as non-pulmonary infectious diseases.

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Section: Discussionmentioning

confidence: 77%

Brief Research Report: Serum clara cell 16 kDa protein levels are increased in patients hospitalized for severe SARS-CoV-2 or sepsis infection

Rohmann¹,

Stürmer²,

Geisler³

et al. 2022

Front. Immunol.

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“…Low CC16 mRNA expression in bronchial epithelial cells was reported to involve in asthma susceptibility and severity. 28 The lower levels of serum CC16 were reported in those with COPD-asthma overlap having a positive BDR. 11 Allergen exposure-induced free eosinophil granules (e.g.…”

Section: Discussionmentioning

confidence: 94%

“…CC16 is a pneumoprotein secreted from terminal respiratory bronchioles in humans. Low CC16 mRNA expression in bronchial epithelial cells was reported to involve in asthma susceptibility and severity 28 . The lower levels of serum CC16 were reported in those with COPD‐asthma overlap having a positive BDR 11 .…”

Section: Discussionmentioning

confidence: 99%

Role of club cell 16‐kDa secretory protein in asthmatic airways

Jung

Cao

Quoc

et al. 2023

Clin Experimental Allergy

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Background Club cell 16‐kDa secretory protein (CC16) is a pneumoprotein and functions as an anti‐inflammatory or antioxidant protein. However, altered levels of serum CC16 as well as their effect on airways inflammation have not been fully evaluated. Methods We recruited 63 adult asthmatics on maintenance medications and 61 healthy controls (HCs). The asthmatic subjects were divided into two groups according to the result of bronchodilator responsiveness (BDR) test: the present BDR (n = 17) and absent BDR (n = 46) groups. Serum CC16 levels were measured by ELISA. As an in vitro study, the effect of Dermatophagoides pteronyssinus antigen 1 (Der p1) on the production of CC16 in airways epithelial cells (AECs) according to a time‐dependent manner was assessed; the effects of CC16 protein on oxidative stress system, airways inflammation and remodelling were tested. Results Serum CC16 levels showed significantly higher in the asthmatics than in the HCs (p < .001) with a positive correlation with FEV1% (r = .352, p = .005). The present BDR group had significantly lower levels of serum CC16, FEV1% and MMEF%, but showed higher level of FeNO than the absent BDR group. Serum CC16 levels (below 496.0 ng/mL) could discriminate the present BDR group from the absent BDR group (area under the curve = 0.74, p = .004). In vitro testing demonstrated that Der p1 exposure significantly induced CC16 release from AECs for 1 h, which was progressively decreased after 6 h and followed by MMP‐9 and TIMP‐1 production. These findings were associated with oxidant/antioxidant disequilibrium and restored by CC16 treatment (but not dexamethasone). Conclusion Decreased CC16 production contributes to persistent airways inflammation and lung function decline. CC16 may be a potential biomarker for asthmatics with BDR.

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“…found that CC16 mRNA expression levels were negatively correlated with expression levels of Th2 genes, and CC16 could decrease sputum eosinophils through downregulating IL-5 and IL1RL1. 61 Though these findings were found in allergic respiratory diseases like asthma and ECRS, it provided possible explanation biologically for the link between CC16 and eosinophilic COPD.…”

Section: Discussionmentioning

confidence: 95%

CC16 as an Inflammatory Biomarker in Induced Sputum Reflects Chronic Obstructive Pulmonary Disease (COPD) Severity

Chen¹,

Xu²,

He³

et al. 2023

COPD

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The progression of an abnormal inflammatory response plays a crucial role in the lung function decline of chronic obstructive pulmonary disease (COPD) patients. Compared to serum biomarkers, inflammatory biomarkers in induced sputum would be a more reliable reflection of inflammatory processes in the airways. Patients and Methods: A total of 102 COPD participants were divided into a mild-to-moderate group (FEV1%pred≥ 50%, n=57) and a severe-to-very-severe group (FEV1%pred<50%, n=45). We measured a series of inflammatory biomarkers in induced sputum and analyzed their association with lung function and SGRQ in COPD patients. To evaluate the relationship between inflammatory biomarkers and the inflammatory phenotype, we also analyzed the correlation between biomarkers and airway eosinophilic phenotype. Results: We found increased mRNA levels of MMP9, LTB4R, and A1AR and decreased levels of CC16 mRNA in induced sputum in the severe-to-very-severe group. After adjustment for age, sex and other biomarkers, CC16 mRNA expression was positively associated with FEV1%pred (r=0.516, p=0.004) and negatively correlated with SGRQ scores (r=−0.3538, p=0.043). As previously known, decreased CC16 was related to the migration and aggregation of eosinophils in airway. It was also found that CC16 had a moderate negative correlation with the eosinophilic inflammation in airway (r=−0.363, p=0.045) in our COPD patients. Conclusion: Low CC16 mRNA expression levels in induced sputum were associated with low FEV1%pred and a high SGRQ score in COPD patients. Sputum CC16 as a potential biomarker for predicting COPD severity in clinical practice might attribute to the involvement of CC16 in airway eosinophilic inflammation.

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Low CC16 mRNA Expression Levels in Bronchial Epithelial Cells Are Associated with Asthma Severity

Cited by 18 publications

References 65 publications

Brief Research Report: Serum clara cell 16 kDa protein levels are increased in patients hospitalized for severe SARS-CoV-2 or sepsis infection

Brief Research Report: Serum clara cell 16 kDa protein levels are increased in patients hospitalized for severe SARS-CoV-2 or sepsis infection

Role of club cell 16‐kDa secretory protein in asthmatic airways

CC16 as an Inflammatory Biomarker in Induced Sputum Reflects Chronic Obstructive Pulmonary Disease (COPD) Severity

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