CC16 Levels Research Articles

Blood Biomarkers of Sensitization and Asthma.

Biomarkers are essential to determine different phenotypes of childhood asthma, and for the prediction of response to treatments. In young preschool children with asthma, aeroallergen sensitization, and blood eosinophil count of 300/μL or greater may identify those who can benefit from the daily use of inhaled corticosteroids (ICS). We propose that every preschool child who is considered for ICS treatment should have these two features measured as a minimum before a decision is made on the commencement of long-term preventive treatment. In practice, IgE-mediated sensitization should be considered as a quantifiable variable, i.e., we should use the titer of sIgE antibodies or the size of skin prick test response. A number of other blood biomarkers may prove useful (e.g., allergen-specific IgG/IgE antibody ratios amongst sensitized individuals, component-resolved diagnostics which measures sIgE response to a large number of allergenic molecules, assessment of immune responses to viruses, level of serum CC16, etc.), but it remains unclear whether these can be translated into clinically useful tests. Going forward, a more integrated approach which takes into account multiple domains of asthma, from the pattern of symptoms and blood biomarkers to genetic risk and lung function measures, is needed if we are to move toward a stratified approach to asthma management.

Serum Clara Cell Protein (CC16) Levels and Multi-Detector Computed Tomography–Based Volumetric Assessment of Lung Parenchymal Injury in Isolated Blunt Thoracic Trauma Patients: a Prospective Observational Study

Numerous studies have been done for markers of lung injury especially in animal models and it remains relatively unexplored whether these biomarkers clinically correlate with the outcome of patients or with the extent of lung parenchymal injury as deduced by MDCT. This prospective study was conducted to assess the serum level of Clara cell secretory protein (CC16) and volume of the uninvolved lung by MDCT and to ascertain the correlation between levels of CC16 with the volume of the injured lung in the clinical outcome of patients of blunt thoracic trauma. Serum CC16 levels and mean uninvolved lung volumes of both lungs were compared in between groups of eventless recovery, need for mechanical ventilation and mortality with p value < 0.05 considered to be significant. Sixty-two patients of blunt chest trauma, age range from 18 to 60 years, were evaluated in our study. Out of them, 43 (69%) were male. Higher level (more than 100 ng/mL) of serum Clara cell protein was associated with the requirement of ventilator and mortality. Total mean uninvolved lung volume of 1075.71 ± 327.5 and 2329.23 ± 776.01 was significantly associated with the requirement of mechanical ventilation and eventless recovery of patients respectively. A mild negative correlation (− 0.4) between the remaining volume of the lung after injury and serum Clara cell protein levels were also noted. Serum CC16 levels may obviate the need of MDCT in the selected group of patients and thereby avoiding its radiation hazards.

Serum biomarkers and outcomes in patients with moderate COPD: a substudy of the randomised SUMMIT trial

RationaleSystemic levels of C reactive protein (CRP), surfactant protein D (SPD), fibrinogen, soluble receptor of activated glycogen end-product (sRAGE) and club cell protein 16 (CC-16) have been associated with chronic...

SERUM CLARA CELL PROTEIN (CC16) IN RELATION TO PULMONARY FUNCTIONS AMONG WORKERS EXPOSED TO NAPHTHALENE IN PVC MANUFACTURE

AbstractIntroduction: Naphthalene is a harmful environmental tox reduced in serum and/or airway lining fluid of patients with COPD, asthma, bronchopulmonary dysplasia, silicosis, and post-transplant rejection. Aim of work: This study was done to evaluate the use of serum CC16 level as a biological marker for occupational respiratory diseases in relation to pulmonary function tests among workers exposed to naphthalene in polyvinyl chloride (PVC) manufacture. Material and methods: The study included 33 exposed workers and 33 control subjects. The study groups were subjected to full history taking, clinical examination and pulmonary function testing. Serum levels of CC16 and naphthalene levels measured for both groups. Results: Pulmonary functions parameters (FVC, FEV1, FEV1/FVC, FEF 25%, FEF 50%, FEF 75%), were significantly decreased in the exposed group compared to the control and indicated obstructive ventilatory impairment among the exposed workers. Serum naphthalene was significantly higher, while serum CC16 was significantly lower among the exposed group compared to the control. Exposed smokers exhibited the highest serum naphthalene and the lowest serum CC16 among all study groups. The duration of naphthalene exposure positively correlated with the serum level of naphthalene and negatively correlated with pulmonary functions and the serum level of CC16. Also serum level of CC16 correlated negatively with the serum naphthalene level and smoking index.Conclusion: Occupational exposure to naphthalene in PVC manufacture is associated with obstructive ventilatory impairment, with corresponding decrease in the serumlevel of Clara cell protein (CC16), which can be used as a biomarker for respiratory system affection among workers exposed to naphthalene.

Association between Early Acute Respiratory Distress Syndrome after Living-Donor Liver Transplantation and Perioperative Serum Biomarkers: The Role of Club Cell Protein 16.

Background Acute respiratory distress syndrome (ARDS) after living-donor liver transplantation (LDLT) is not uncommon, but it lacks the biomarkers for early detection. Club cell protein 16 (CC16), high-motility group box 1 protein (HMGB1), interleukin-1β (IL-1β), and IL-10 have been reported as relevant to the development of ARDS. However, they have not been investigated during LDLT. Methods Seventy-three consecutive recipients undergoing LDLT were enrolled and received the same perioperative care plan. Perioperative serum CC16, HMGB1, IL-1β, and IL-10 levels were measured at the pretransplant state, 30 minutes after reperfusion, postoperative day 1 (POD1), and POD3. ARDS was diagnosed according to the 2012 Berlin definition. Results Of the 73 recipients, 13 developed ARDS with significantly longer durations of mechanical ventilation and intensive care unit stay. Serum CC16 levels on POD1 increased significantly from the pretransplant state in the ARDS group but not in the non-ARDS group. Pretransplant serum CC16 levels were also higher in the ARDS group. The area under the receiver operating characteristic curves for POD1 serum CC16 levels used to discriminate ARDS was 0.803 (95% confidence interval: 0.679 to 0.895; p < 0.001). By comparison, HMGB1, IL-1β, and IL-10 were not associated with ARDS after LDLT. Conclusion The higher pretransplant serum CC16 level and its increased level on POD1 were associated with the development of early ARDS after LDLT. This trial is registered with NCT01936545, 27 August 2013.

Ultrafine CB-induced small airway obstruction in CB-exposed workers and mice

The potential threat of superfine carbon black (CB) particles to human health has received attention, but there are few human toxicological data available. The purpose of this study was to investigate the relationships between serum CC16 and SP-A with small airway related pulmonary functions in CB workers. Ninety-nine male CB packers and 115 non-CB-exposed healthy male workers were recruited. Serum CC16 and/or SP-A and pulmonary function tests were evaluated, and the relationship between them were also analyzed. To further assess pulmonary damage induced by CB particles in target organs, an animal inhalation exposure study was conducted. Male C57BL/6 mice were exposed to 15 and 30 mg/m3 CB for 6 h per day for 28 days. Levels of CC16 and SP-A were evaluated by ELISA and immunohistochemical staining (IHC). The results showed a 20% decreased in median CC16 and a 15% increase in median SP-A among CB-exposed workers. FEV1%, FEV/FVC, MMEF%, FEF25%, and FEF75% were also decreased in CB-exposed workers (P < 0.05). A significant positive correlation was observed between serum CC16 concentration and FEV1/FVC, although a negative correlation was found between serum SP-A concentration and FEV1/FVC. Serum CC16 was significantly reduced by 72% in mice with high CB-exposure, and serum SPA was 1.65x and 1.17x higher than CB-unexposed control mice in low and high CB-exposed mice, respectively. Lung CC16 and serum CC16 levels were positively correlated in mice (P = 0.024). Long-term exposure to ultrafine CB particles is associated with a decrease in CC16 and an increase in SP-A in the peripheral blood of CB-exposed workers. In conclusion, superfine CB particles have the potential to cause small airway obstruction.

Adipose-Derived Mesenchymal Stem Cells Can Ameliorate Airway Remodelling and Improve Oxidative Stress: An Open Label and Randomized Clinical Trial Study on Sulfur Mustard Exposed Patients

Background: Lung is a primary target for sulfur mustard (SM) toxicity. Here, we investigated the potential efficacy and safety of adipose derived mesenchymal stem cell (AdMSC) on respiratory quality, lung regeneration, oxidative stress, and airway remodelling in patients with mustard lung. Methods: In this clinical trial study, 10 patients received 100x106 cells every 20 days for 4 injections over 8 weeks. The pulmonary function tests (PFT), chronic obstructive pulmonary disease (COPD) Assessment Test (CAT), Borg Scale Dyspnea Assessment (BSDA), and 6 Minute Walk Test (6MWT) were evaluated. Total antioxidant capacity (TAC), malondialdehyde (MDA) and glutathione (GSH) were measured in the sputum of all samples. Changes in expression of metallothionein 3 (MT3), glutathione reductase (GR), glutathione peroxidase (GPX), and lacto peroxidase (LPO), as well as matrix metallopeptidase 2 (MMP2), matrix metallopeptidase 9 (MMP9), transforming growth factor-b1 (TGF-b), vascular endothelial growth factor (VEGF), metallopeptidase inhibitor 1 (TIMP1), and metallopeptidase inhibitor 2 (TIMP2) were assessed using real-time PCR. Clara cell protein 16 (CC16) and Mucin-1 protein (KL-6) were measured in the sputum all samples as biomarkers of lung injury using enzyme immunoassay method. This study is registered with ClinicalTrials.gov (NCT02749448). Findings: Spirometry test results were slightly improved after each injection. A gradual improvement was observed in the mean of 6MWT scores. CASA-Q and VAS scores were increased, while means of CAT and Borg-Score were decreased. A significant improvement was found for the mean of KL-6 (p=0.022) and CC16 (p=0.005) levels. Sputum levels of TAC and GSH had a tendency to be higher after each injection, while MDA content was decreased. An improvement was observed for antioxidants genes, especially for GSR, MT3 and LPO, compared to the baseline. A gradual upregulation was found for VEGF and TGF-β expression after MSCs therapy. MSCs caused a balance between MMP9/TIMP1 and MMP2/TIMP2 ratio. The MMP2/TIMP2 ratio was decreased from 4.9 on baseline to 0.71 on day 180 (p<0.001), while the MMP9/TIMP1 ratio was declined from 16.35 on baseline to 0.64 on day 180 (p<0.001). Interpretation: The findings suggest that MSCs therapy can be safely used for improvement of lung injury and regeneration in these patients without any adverse effects. Trial Registration Number: This study is registered with ClinicalTrials.gov (NCT02749448). Funding: Iran National Science Foundation and Veterans Foundation. Declaration of Interest: The authors confirm that there are no conflicts of interest. Ethical Approval: The ethics review board of the Baqiyatallah University of Medical Sciences (Cod: IR.BMSU.REC.1393.32) approved this survey and all patients signed an informed consent letter before the study.

Continuous exercise induces airway epithelium damage while a matched-intensity and volume intermittent exercise does not

BackgroundWhile continuous exercise (CE) induces greater ventilation ( dot{V} E) when compared to intermittent exercise (IE), little is known of the consequences on airway damage. Our aim was to investigate markers of epithelial cell damage – i.e. serum levels of CC16 and of the CC16/SP-D ratio - during and following a bout of CE and IE of matched work.MethodsSixteen healthy young adults performed a 30-min continuous (CE) and a 60-min intermittent exercise (IE; 1-min work: 1-min rest) on separate occasions in a random order. Intensity was set at 70% of their maximum work rate (WRmax). Heart rate (HR) and dot{V} E were measured throughout both tests. Blood samples were taken at rest, after the 10th min of the warm-up, at the end of both exercises, half way through IE (matched time but 50% work done for IE) as well as 30- and 60-min post-exercise. Lactate and CC16 and SP-D were determined.ResultsMean dot{V} E was higher for CE compared to IE (85 ± 17 l.min− 1 vs 50 ± 8 l.min− 1, respectively; P < 0.001). Serum-based markers of epithelial cell damage remained unchanged during IE. Interaction of test × time was observed for SP-D (P = 0.02), CC16 (μg.l− 1) (P = 0.006) and CC16/SP-D ratio (P = 0.03). Maximum delta CC16/SP-D was significantly correlated with mean dot{V} E sustained (r = 0.83, P < 0.001) during CE but not during IE.ConclusionThe 30-min CE performed at 70% WRmax induced mild airway damage, while a time- or work-matched IE did not. The extent of the damage during CE was associated with the higher ventilation rate.

Decreased serum club cell secretory protein in asthma and chronic obstructive pulmonary disease overlap: a pilot study.

PurposeImprovement in the diagnosis of asthma and chronic obstructive pulmonary disease (COPD) overlap (ACO), and identification of biomarkers for phenotype recognition will encourage good patient care by providing optimal therapy. We investigated club cell secretory protein (CC-16), a protective and anti-inflammatory mediator, as a new candidate biomarker for diagnosing ACO.Patients and methodsWe performed a multicenter cohort study. A total of 107 patients were divided into three groups – asthma, COPD, and ACO – according to the Spanish guidelines algorithm, and enrolled into the study. Serum CC-16 levels were measured using commercial ELISA kits.ResultsSerum CC-16 levels were the lowest in patients with ACO. Low serum CC-16 levels were a significant marker for the ACO even after adjustment for age, sex, and smoking intensity. Serum CC-16 levels were positively correlated with forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), forced expiratory flow at 25%–75% of FVC, FEV1/FVC, vital capacity, and diffusing capacity of the lung for carbon monoxide, and were negatively correlated with smoking amount (pack-years), bronchodilator response, fractional residual capacity, residual volume, and number of exacerbations per year. FEV1 and serum CC-16 levels were significantly lower in patients with frequent exacerbations.ConclusionSerum CC-16 has the potential to be a biomarker for ACO diagnosis and also treat frequent exacerbations in patients with chronic inflammatory airway diseases.

N-Acetylcysteine inhalation improves pulmonary function in patients received liver transplantation.

Postoperative pulmonary complications (PPCs) following orthotopic liver transplantation (OLT) are associated with high morbidity and mortality rates. The effect of N-acetylcysteine (NAC) inhalation on the incidence of PPCs and the outcomes of patients undergoing OLT is unknown. This prospective randomized controlled clinical trial was conducted to investigate the effect of NAC inhalation during OLT on PPCs. Sixty patients were randomly assigned to the NAC group (n = 30) or the control group (n = 30) to receive inhaled NAC or sterilized water, respectively, for 30 min before surgery and 3 h after reperfusion. The incidence of early PPCs and outcomes including survival rate were assessed. Biomarkers including tumor necrosis factor (TNF)-α, interleukin (IL)-8, Clara cell secretory protein (CC16), intercellular adhesion molecule (ICAM)-1, and superoxide dismutase (SOD) were measured in exhaled breath condensate (EBC) at T1 (before surgery) and T2 (at the end of operation) as well as in serum at T1, T2, T3 (12 h after operation), and T4 (24 h after operation). A total of 42 patients (20 in the NAC group and 22 in the control group) were enrolled in the final analysis. Atomization inhaled NAC significantly reduced the incidence of PPCs after OLT. The levels of TNF-α, IL-8, CC16, and ICAM-1 in EBC were significantly lower, and SOD activity was higher, at T2 in the NAC group; similar data were found in serum at T2, T3, and T4. In summary, perioperative NAC inhalation may reduce the incidence of PPCs and improve patient outcomes after OLT.

CC16 Levels into Adult Life Are Associated with Nitrogen Dioxide Exposure at Birth

Children&amp;#8217;s lung function and growth is adversely associated with exposure to nitrogen dioxide (NO2). Lower levels of circulating club cell secretory protein (CC16) in childhood are also associated with subsequent decreased lung function in adolescence and adulthood. Evidence from in vitro and in vivo studies suggests that NO2 exposure may induce epithelial damage in the lungs and altered club cell proliferation and morphology. Our objective was to determine if increased ambient NO2 levels at participants&amp;#8217; home addresses at birth or age 6 were associated with decreased levels of CC16 from age 6-32 years.Participants were enrolled at birth in the Tucson Children&amp;#8217;s Respiratory Study and had circulating CC16 measured at least once between age 6-32 years. Annual average estimates of NO2 were obtained for the address and year corresponding to each participant&amp;#8217;s home address at birth and at age 6. Linear mixed models were used to determine the association between exposure to NO2 at birth or age 6 with CC16 levels from age 6-32 years.NO2 exposures at birth or age 6 were available for 777 children with at least one CC16 measurement from ages 6-32. An interquartile range increase in NO2 at the children&amp;#8217;s birth address was associated with a 4.89% (95% CI -9.04, -0.75) decrease in CC16 levels from age 6-32 years. An interquartile range increase in NO2 at the children&amp;#8217;s age 6 address was not associated with a decrease in CC16 levels from age 6-32 years (-2.54%, 95% CI -7.03, 1.94). Similar results were obtained after adjusting for potential confounders including maternal smoking (NO2 at birth -4.83% [95% CI -9.00, -0.66]; NO2 at age 6 [-1.95%, 95% CI -6.47, 2.56]).Higher exposure to NO2 at birth is associated with persistently low levels of CC16 from 6-32 years. We speculate that persistently low levels of CC16 may reflect airway injury induced by exposure to NO2 during critical periods of lung growth, thus predisposing for diminished lung function later in life.

Clara cell protein 16 release from the nasal mucosa in allergic rhinitis, chronic rhinosinusitis, and exposure to air pollutants.

Clara cell protein 16 (CC16) is a small protein mainly produced by non-ciliated Clara cells in the respiratory epithelium. It has an anti-inflammatory role in chronic upper and lower airway eosinophilic inflammations. Decreased levels of CC16 are found in the nasal secretions and plasma of patients with chronic eosinophilic inflammatory disorders, such as asthma, allergic rhinitis, and chronic rhinosinusitis with or without nasal polyps, as well as in people exposed to high levels of air pollutants. Intranasal corticosteroid administration suppresses chronic inflammation of the nasal mucosa driven by eosinophils and stimulates local CC16 production. CC16 can be a reliable biomarker of the beneficial effects of perennial allergic rhinitis and chronic rhinosinusitis therapy and of the functional recovery of the nasal mucosa after treatment with topical glucocorticoids.

Relation between serum CC16 levels and asthma predictive index in pre-schoolers with recurrent wheezing

BackgroundLow levels of serum CC16 were reported in asthmatic adults, but the studies on children were scarce and conflicting. The aim of this study was to compare serum CC16 levels in pre-school children with recurrent wheezing assessed using an asthma predictive index (API). MethodsWe performed a case-control study based on API, with all enrolled pre-school children who had recurrent wheezing episodes (>3 episodes/last year confirmed by a physician) and had presented at one paediatric clinic in Santiago, Chile. The population was divided according to stringent API criteria into positive or negative. ResultsIn a one-year period, 60 pre-schoolers were enrolled. After excluding 12, 48 pre-schoolers remained (27 males, age range from 24 to 71 months) and completed the study; 34 were API positive and 14 were API negative. There were no significant differences in demographics between groups. The level of serum CC16 levels for pre-schoolers with a positive API and negative API were (median 9.2 [7.1–11.5] and 9.4 [5.5–10], p=0.26, respectively). The area under the curve for the serum CC16 levels to predict a positive API was 0.6, 95% CI [0.43–0.77], p=0.3. A correlation between serum CC16 levels and age was found (r=0.36 [0.07–0.59], p=0.01], but not between serum CC16 levels and peripheral eosinophils blood. ConclusionThere was no evidence that serum CC16 levels played a role in recurrent wheezing and a positive API in pre-school children. More studies are needed to confirm this finding.

Club cell protein 16 (Cc16) deficiency increases inflamm-aging in the lungs of mice.

Low serum CC16 levels are associated with accelerated lung function decline in human population studies, but it is not known whether low serum CC16 levels contribute to lung function decline, or are an epiphenomenon. We tested the hypothesis that unchallenged Cc16 −/− mice develop accelerated rates of pulmonary function test abnormalities and pulmonary pathologies over time compared with unchallenged WT mice. Respiratory mechanics, airspace enlargement, and small airway fibrosis were measured in unchallenged wild‐type (WT) versus Cc16 −/− mice over 6–18 months of age. Lung leukocyte counts and lung levels of metalloproteinases (Mmps), cytokines, oxidative stress, cellular senescence markers (p19 and p21), and lung cell apoptosis, and serum C‐reactive protein (CRP) levels were measured in age‐matched WT versus Cc16 −/− mice. Unchallenged Cc16 −/− mice developed greater increases in lung compliance, airspace enlargement, and small airway fibrosis than age‐matched WT mice over 6–18 months of age. Cc16 −/− mice had greater: (1) lung leukocyte counts; (2) lung levels of Ccl2, Ccl‐5, interleukin‐10, Mmp‐2, and Mmp‐9; (3) pulmonary oxidative stress levels, (4) alveolar septal cell apoptosis and staining for p16 and p21; and (5) serum CRP levels. Unchallenged Cc16 −/− mice had greater nuclear factor‐κB (NF‐κB) activation in their lungs than age‐matched WT mice, but similar lung levels of secretory phospholipase‐A2 activity. Cc16 deficiency in mice leads spontaneously to an accelerated lung aging phenotype with exaggerated pulmonary inflammation and COPD‐like lung pathologies associated with increased activation of NF‐ κB in the lung. CC16 augmentation strategies may reduce lung aging in CC16‐deficient individuals.

Club cell secretory protein (CC16) in gastric fluid at birth and subsequent lung disease in preterm infants.

Club cell secretory protein (CC16) probably has a role in protecting the lung from inflammation. To evaluate if low levels of CC16 in gastric fluid at birth, reflecting low levels of CC16 in the lung, would be associated with lung inflammation and respiratory morbidity. A study of 64 infants with mean gestational age 26.1 weeks. CC16 was analyzed in gastric fluid at birth. CC16, pro-inflammatory cytokines, and MMP-9 were analyzed in tracheal aspirate within 24 h from birth. CC16 in gastric fluid increased with gestational age (P = 0.033). Lower concentrations of CC16 in gastric fluid at birth were associated with higher concentrations of IL-1β (P = 0.028), TNF-α (P = 0.034), and MMP-9 (P = 0.015) in tracheal aspirate. Infants who needed mechanical ventilation at 24 and 72 h of age had lower CC16 in gastric fluid than those not ventilated at these ages (P = 0.011 and P = 0.024, respectively). Lower CC16 in gastric fluid was associated with higher FiO2 at 6 h (P = 0.009), higher PaCO2 at 24 h (P = 0.03), more ventilator days (P = 0.012) and more days with supplemental oxygen (P = 0.03). Infants who had either died or were still treated with supplemental oxygen at 36 weeks postmenstrual age had lower CC16 in gastric fluid than infants with none of these outcomes (P = 0.049). A low CC16 concentration in gastric fluid at birth was associated with increased inflammation in the trachea within the first 24 h of life and with more need for respiratory support in the neonatal period.

CC16 levels correlate with cigarette smoke exposure in bronchial epithelial cells and with lung function decline in smokers

BackgroundClub cell protein-16 (CC16) expression has been associated with smoking-related lung function decline. The study hypothesis was that CC16 expression in both serum and bronchial epithelium is associated with lung function decline in smokers, and exposure to cigarette smoke will lead to reduction in CC16 expression in bronchial epithelial cells.MethodsIn a cohort of community-based male Chinese subjects recruited for lung function test in 2000, we reassessed their lung function ten years later and measured serum levels of CC16. CC16 expression was further assayed in bronchial epithelium from endobronchial biopsies taken from an independent cohort of subjects undergoing autofluorescence bronchoscopy, and tested for correlation between CC16 immunostaining intensity and lung function. In an in-vitro model, bronchial epithelial cells were exposed to cigarette smoke extract (CSE), and the expression levels of CC16 were measured in bronchial epithelial cells before and after exposure to CSE.ResultsThere was a significant association between FEV1 decline and serum CC16 levels in smokers. Expression of CC16 in bronchial epithelium showed significant correlation with FEV1/FVC. Bronchial epithelial cells showed significant decrease in CC16 expression after exposure to CSE, followed by a subsequent rise in CC16 expression upon removal of CSE.ConclusionsResults of these clinical and laboratory investigations suggested that low serum CC16 was associated with smoking-related decline in lung function, demonstrated the first time in a Chinese cohort. The data also lend support to the putative role of CC16 in protection against smoking-related bronchial epithelial damage.( word count: 243)US clinical trial registryNCT01185652, first posted 20 August, 2010.

Grading Severity of Productive Cough Based on Symptoms and Airflow Obstruction

ABSTRACTThe binary approach to the diagnosis of Chronic Bronchitis (CB) is a major barrier to the study of the disease. We investigated whether severity of productive cough can be graded using symptoms and presence of fixed airflow obstruction (FAO), and whether the severity correlates with health status, exposures injurious to the lung, biomarkers of inflammation, and measures of airway wall thickening. Findings from a cross-sectional sample of 1,422 participants from the Lovelace Smokers Cohort (LSC) were validated in 4,488 participants from the COPDGene cohort (COPDGene). Health status was based on the St. George's Respiratory Questionnaire, and Medical Outcomes Study 36-Item Short Form Health Survey. Circulating CC16 levels were quantified by ELISA (LSC), and airway wall thickening was measured using computed tomography (COPDGene). FAO was defined as postbronchodilator FEV1/FVC <0.7. The presence and duration of productive cough and presence of FAO or wheeze were graded into Healthy Smokers, Productive Cough (PC), Chronic PC, PC with Signs of Airflow Obstruction, and Chronic PC with Signs of Airflow Obstruction. In both cohorts, higher grade of severity correlated with lower health status, greater frequency of injurious exposures, greater airway wall thickening, and lower circulating CC16 levels. Further, longitudinal follow-up suggested that disease resolution can occur at every grade of severity but is more common in groups of lower severity and least common once airway remodeling develops. Therefore, severity of productive cough can be graded based on symptoms and FAO and early intervention may benefit patients by changing the natural history of disease.

Markers and metabolites related to inflammation in bronchiectasis with airflow limitation vs. chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a systemic progressive inflammatory disease resulting from an abnormal inflammatory response to noxious stimuli. Bronchiectasis is also a chronic inflammatory condition, usually caused by repetitive infections. However, it is not clear whether the inflammatory signaling pathways involved are the same in both diseases. Therefore, we here compared the markers and metabolites related to inflammation in COPD and in bronchiectasis to elucidate the pathological mechanisms. We compared markers and metabolites in patients with COPD and in those with bronchiectasis with airflow limitation. The levels of the following inflammatory biomarkers were assessed: erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), interleukin (IL)-6, and club cell secretory protein (CC)-16. Additionally, high-resolution metabolomic evaluation was conducted to evaluate the differentially expressed metabolic signature of the two diseases. The ESR and CRP levels were significantly higher, and the levels of CC-16 and IL-6 tended to be higher, among patients with bronchiectasis than among those with COPD. In the metabolomics analysis, serum metabolites of biliverdin IX alpha (m/z: 565.24 [M+H-H2O]+) and L-carnitine (m/z: 184.09 [M+Na]+) were significantly upregulated in sera of bronchiectasis patients. In sera of COPD patients, the levels of nicotine (m/z: 163.12 [M+H]+) and N-acetyl serotonin (m/z: 201.102 [M+H-H2O]+) were significantly higher. Patients with bronchiectasis with airflow limitation had higher levels of inflammatory biomarkers (ESR and CRP) and markers indicating compensation for inflammatory damage (biliverdin IX alpha and L-carnitine), than did patients with COPD. Further treatments modulating the inflammatory process may be useful in patients with bronchiectasis.

Reduced serum club cell protein as a pulmonary damage marker for chronic fine particulate matter exposure in Chinese population

BackgroundExposure to fine particulate matter (PM2.5) pollution is associated with increased morbidity and mortality from respiratory diseases. However, few population-based studies have been conducted to assess the alterations in circulating pulmonary proteins due to long-term PM2.5 exposure. MethodsWe designed a two-stage study. In the first stage (training set), we assessed the associations between PM2.5 exposure and levels of pulmonary damage markers (CC16, SP-A and SP-D) and lung function in a coke oven emission (COE) cohort with 558 coke plant workers and 210 controls. In the second stage (validation set), significant initial findings were validated by an independent diesel engine exhaust (DEE) cohort with 50 DEE exposed workers and 50 controls. ResultsSerum CC16 levels decreased in a dose response manner in association with both external and internal PM2.5 exposures in the two cohorts. In the training set, serum CC16 levels decreased with increasing duration of occupational PM2.5 exposure history. An interquartile range (IQR) (122.0μg/m3) increase in PM2.5 was associated with a 5.76% decrease in serum CC16 levels, whereas an IQR (1.06μmol/mol creatinine) increase in urinary 1-hydroxypyrene (1-OHP) concentration was associated with a 5.36% decrease in serum CC16 levels in the COE cohort. In the validation set, the concentration of serum CC16 in the PM2.5 exposed group was 22.42% lower than that of the controls and an IQR (1.24μmol/mol creatinine) increase in urinary 1-OHP concentration was associated with a 12.24% decrease in serum CC16 levels in the DEE cohort. ConclusionsSerum CC16 levels may be a sensitive marker for pulmonary damage in populations with high PM2.5 exposure.

Urinary polycyclic aromatic hydrocarbon metabolites, Club cell secretory protein and lung function

BackgroundExposure to polycyclic aromatic hydrocarbons (PAHs) has been associated with lung function decline. However, the underlying mechanisms for the association remain unclear. ObjectivesTo explore potential role of a lung epithelial biomarker, Club cell secretory protein (CC16), in associations between PAH exposures and lung function decline. MethodsWe investigated 3384 adults from the Wuhan-Zhuhai cohort, and followed up at three years after first examination. Linear mixed models was used to quantify dose-response relationships between urinary monohydroxylated PAH metabolites (OH-PAHs) and lung function, as well as OH-PAHs and plasma CC16. Mediation analysis was conducted to investigate role of CC16 in the association between OH-PAHs and lung function. We also estimated the relationships between OH-PAHs and lung function change in three years among participants with different levels of CC16. ResultsEach 1-unit increase of log-transformed total urinary high and low molecular weight OH-PAHs (∑HMW OH-PAH and ∑LMW OH-PAHs) were associated with a 22.59 and 25.25ml reduction of FEV1 respectively, while∑HMW OH-PAH was associated with a 30.38ml reduction of FVC. Moreover, these negative associations between OH-PAHs and lung function levels were significant only among low CC16 group (<15.83ng/ml). CC16 concentration decreased monotonically with increased high molecular weight OH-PAHs (∑HMW OH-PAHs) when ∑HMW OH-PAH concentration was over 0.67μg/mmol Cr. CC16 mediated 22.13% of the association between ∑HMW OH-PAH and FVC among individuals with higher ∑HMW OH-PAH. After three years of follow-up, subjects with low level of plasma CC16 had a significant decline of FVC when exposed to high level of ∑HMW OH-PAH. ConclusionsCC16 play an important role in the association between high molecular weight PAHs and FVC. Individuals with low plasma CC16 level might suffer a decline in lung function when exposed to high level of high molecular weight PAHs.