Circulating CC16 and Asthma: A Population-based, Multicohort Study from Early Childhood through Adult Life.

Rationale: Club cell secretory protein (CC16) is an antiinflammatory protein highly expressed in the airways. CC16 deficiency has been associated with lung function deficits, but its role in asthma has not been established conclusively. Objectives: To determine 1) the longitudinal association of circulating CC16 with the presence of active asthma from early childhood through adult life and 2) whether CC16 in early childhood predicts the clinical course of childhood asthma into adult life. Methods: We assessed the association of circulating CC16 and asthma in three population-based birth cohorts: the Tucson Children's Respiratory Study (years 6-36; total participants, 814; total observations, 3,042), the Swedish Barn/Children, Allergy, Milieu, Stockholm, Epidemiological survey (years 8-24; total participants, 2,547; total observations, 3,438), and the UK Manchester Asthma and Allergy Study (years 5-18; total participants, 745; total observations, 1,626). Among 233 children who had asthma at the first survey in any of the cohorts, baseline CC16 was also tested for association with persistence of symptoms. Measurements and Main Results: After adjusting for covariates, CC16 deficits were associated with increased risk for the presence of asthma in all cohorts (meta-analyzed adjusted odds ratio per 1-SD CC16 decrease, 1.20; 95% confidence interval [CI], 1.12-1.28; P < 0.0001). The association was particularly strong for asthma with frequent symptoms (meta-analyzed adjusted relative risk ratio, 1.40; 95% CI, 1.24-1.57; P < 0.0001), was confirmed for both atopic and nonatopic asthma, and was independent of lung function impairment. After adjustment for known predictors of persistent asthma, children with asthma in the lowest CC16 tertile had a nearly fourfold increased risk for having frequent symptoms persisting into adult life compared with children with asthma in the other two CC16 tertiles (meta-analyzed adjusted odds ratio, 3.72; 95% CI, 1.78-7.76; P < 0.0001). Conclusions: Circulating CC16 deficits are associated with the presence of asthma with frequent symptoms from childhood through midadult life and predict the persistence of asthma symptoms into adulthood. These findings support a possible protective role of CC16 in asthma and its potential use for risk stratification.

Pneumoprotein CC16 in the Umbilical Cord Blood of Preterm Neonates.

OBJECTIVE: We examined the impact of perinatal factors on cord serum club cell protein (CC16) and the association of CC16 with mechanical ventilation and bronchopulmonary dysplasia (BPD) in preterm neonates. STUDY DESIGN: A retrospective cohort study including 60 neonates born with gestational age (GA) < 34 weeks. The impact of categorical perinatal factors on cord blood levels of CC16 was examined with univariate and multivariate regression analyses. RESULTS: In neonates with GA < 32 weeks, cord blood CC16 concentrations were significantly lower compared to neonates with GA between 320/7 and 336/7 weeks (5.4 ± 2.5 compared to 7.6 ± 2.9 ng/mL, p = 0.039). Neonates with prolonged rupture of membranes had significantly lower CC16 compared to those without prolonged rupture of membranes (4.0 ± 1.9 compared to 7.2 ± 2.2, p < 0.001). Finally, neonates with BPD had significantly lower CC16, compared to neonates without BPD (4.2 ± 2.1 compared to 7.0 ± 2.2 ng/mL, p = 0.004).Prolonged rupture of membranes was significantly negatively associated with CC16 (b = -2.67, 95% confidence interval [CI] -0.49 to -4.85, p = 0.017), after adjusting for GA (b = 0.23, 95% CI 0.03-0.42, p = 0.022), mode of conception, and mode of delivery. Finally, higher CC16 levels were significantly inversely associated with BPD (odds ratio = 0.33, 95% CI 0.12-0.88, p = 0.028), after adjusting for GA (b = 0.27, 95% CI 0.09-0.78, p = 0.015), and birth weight. CONCLUSION: Prolonged rupture of membranes was significantly negatively associated with cord serum CC16, after adjusting for GA, conception, and delivery mode, and CC16 was significantly inversely associated with BPD, after adjusting for GA and birth weight. KEY POINTS: · Neonates with prolonged rupture of membranes had lower CC16 levels.. · CC16 was significantly negatively associated with BPD.. · CC16 could be a biomarker of lung injury and BPD..

Silicon, an important exposure marker in vivo in silicosis research.

PURPOSE: The degree of silicosis exposure is closely related to the progress of silicosis. At present, we use animal and human studies to explore whether silicon can be an important exposure marker in the development of silicosis. METHODS: Rats were randomly divided into 2 groups: (1) controls; and (2) silicosis. Rats in the silicosis group were killed at 4, 8, 12, 16, 24 h, 3, 7, 14, 21, and 28 days. Hematoxylin-eosin (HE) and immunohistochemistry (IHC) were performed to observe the histomorphology of lung tissue. The expression levels of CC16 and SP-D were detected using ELISA kits. In addition, we conducted a population study. Workers who have been selected to work in an iron mine for more than 1 year as research objects. The population was divided into four groups: silicosis exposure group (workers exposed to silica dust for more than 1 year in an iron mine were selected); patients group (silicosis patients); observation group (evidence of disease not meeting formal diagnostic criteria) and control group. Both the levels of trace silicon in the urine and blood of rats and human subjects were measured with ICP-MS. RESULTS: Serum levels of silicon were immediately increased in rats exposed to silicon dust. Similarly, our population study revealed that the silicon level in the silica exposure group and the observing group (exposed but no obvious symptoms) were significantly increased over that of the control group (P < 0.05). In subjects with extended exposure to silica, the serum and urine silicon level in exposed workers appeared to rapidly increase, reaching its peak in 1-5 years, followed by a gradual decline thereafter. Workers exposed to dust for less than 10 years were divided into subgroups by 2-year limit. The levels of serum silicon, urine silicon, TGF-ß1, and TNF-α were significantly higher than that of control group. CONCLUSION: Changes of the serum levels of silicon occurred earlier than the expression of cytokines such as TNF-α, TGF-ß1, CC16, and SP-D. The level of silicon in workers rapidly increased after exposure to silica, and the change occurred before the expression of TGF-ß1 and TNF-α. As a whole, the findings suggest that determining the level of silicon in vivo might be an effective exposure marker in the diagnosis and pathogenesis of silicosis.

Protective effect of club cell secretory protein (CC-16) on COPD risk and progression: a Mendelian randomisation study.

BACKGROUND: The anti-inflammatory pneumoprotein club cell secretory protein-16 (CC-16) is associated with the clinical expression of chronic obstructive pulmonary disease (COPD). We aimed to determine if there is a causal effect of serum CC-16 level on the risk of having COPD and/or its progression using Mendelian randomisation (MR) analysis. METHODS: We performed a genome-wide association meta-analysis for serum CC-16 in two COPD cohorts (Lung Health Study (LHS), n=3850 and ECLIPSE, n=1702). We then used the CC-16-associated single-nucleotide polymorphisms (SNPs) as instrumental variables in MR analysis to identify a causal effect of serum CC-16 on 'COPD risk' (ie, case status in the International COPD Genetics Consortium/UK-Biobank dataset; n=35 735 COPD cases, n=222 076 controls) and 'COPD progression' (ie, annual change in forced expiratory volume in 1 s in LHS and ECLIPSE). We also determined the associations between SNPs associated with CC-16 and gene expression using n=1111 lung tissue samples from the Lung Expression Quantitative Trait Locus Study. RESULTS: We identified seven SNPs independently associated (p<5×10-8) with serum CC-16 levels; six of these were novel. MR analysis suggested a protective causal effect of increased serum CC-16 on COPD risk (MR estimate (SE) -0.11 (0.04), p=0.008) and progression (LHS only, MR estimate (SE) 7.40 (3.28), p=0.02). Five of the SNPs were also associated with gene expression in lung tissue (at false discovery rate <0.1) of several genes, including the CC-16-encoding gene SCGB1A1. CONCLUSION: We have identified several novel genetic variants associated with serum CC-16 level in COPD cohorts. These genetic associations suggest a potential causal effect of serum CC-16 on the risk of having COPD and its progression, the biological basis of which warrants further investigation.

Cross-sectional and longitudinal associations between urinary zinc and lung function among urban adults in China.

BACKGROUND: Exposure to zinc was suggested to be associated with pulmonary damage, but whether zinc exposure affects lung function remains unclear. OBJECTIVES: To quantify the association between urinary zinc and lung function and explore the potential mechanisms. METHODS: Urinary zinc and lung function were measured in 3917 adults from the Wuhan-Zhuhai cohort and were repeated after 3 years of follow-up. Indicators of systemic inflammation (C reactive protein), lung epithelium integrity (club cell secretory protein-16) and oxidative damage (8-hydroxy-2'-deoxyguanosine and 8-isoprostane) were measured at baseline. Linear mixed models were used to estimate the exposure-response relationship between urinary zinc and lung function. Mediation analyses were conducted to assess mediating roles of inflammation and oxidative damage in above relationships. RESULTS: Each 1-unit increase in log-transformed urinary zinc values was associated with a 35.72 mL decrease in forced vital capacity (FVC) and a 24.89 mL decrease in forced expiratory volume in 1 s (FEV1) in the baseline analyses. In the follow-up analyses, there was a negative association between urinary zinc and FVC among participants with persistent high urinary zinc levels, with an estimated change of -93.31 mL (95% CI -178.47 to -8.14). Furthermore, urinary zinc was positively associated with restrictive ventilatory impairment. The mediation analyses suggested that C reactive protein mediated 8.62% and 8.71% of the associations of urinary zinc with FVC and FEV1, respectively. CONCLUSION: Urinary zinc was negatively associated with lung function, and the systemic inflammation may be one of the underlying mechanisms.

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

Rationale: Lung function and growth are adversely associated with nitrogen dioxide (NO2) exposure. Lower levels of circulating club cell secretory protein (CC16) in childhood are also associated with subsequent decreased lung function. NO2 exposure may induce epithelial damage in lungs and alter club cell proliferation and morphology.Objectives: To determine if increased ambient NO2 levels at participants' home addresses in early life were associated with decreased levels of CC16 from age 6 to 32 years.Methods: Participants were enrolled at birth in the Tucson Children's Respiratory Study and had circulating CC16 measured at least once between age 6 and 32. Linear mixed models were used to determine the association between estimated ambient NO2 exposure at participants' home address at birth or age 6 with CC16 levels from age 6 to 32.Measurements and Main Results: NO2 exposures at birth or age 6 were available for 777 children with one or more CC16 measurement. We found a negative association between NO2 exposure and CC16 levels, with a 4.7% (95% confidence interval, -8.6 to -0.7) decrease in CC16 levels from age 6 to 32 per interquartile range increase in NO2 exposure (6.0 ppb) at the participants' birth address. We observed modification by race (p interaction = 0.04), with stronger associations among participants with at least one black parent (-29.6% [95% confidence interval, -42.9% to -13.2%] per interquartile range). NO2 at participant's age 6 address was not significantly associated with CC16 levels (-1.9%; 95% confidence interval, -6.3 to 2.6).Conclusions: Higher exposure to NO2 at birth is associated with persistently low levels of CC16 from 6 to 32 years.

Serum Clara cell secretory protein (CC-16) in non-smoking patients with obstructive sleep apnea.

OBJECTIVE: This study aimed to determine the association between the severity of obstructive sleep apnea (OSA) and serum Clara cell protein (CC16) levels in non-smoking patients with OSA. METHODS: This prospective study included non-smoking patients who presented with sleep-related disturbances and underwent polysomnography (PSG). The serum CC16 level was measured and its relationship to PSG parameters was investigated. RESULTS: The study included 128 patients (83 men) with a mean age of 48.4 ± 11.9. OSA was detected in 66 men (70%) and 29 women (30%) (p = 0.051). The severity of OSA was mild in 32 (25%), moderate in 28 (22%), and severe in 35 (27%) of the patients. There was no significant difference in CC16 levels between the OSA group (1746 ± 1006) and the OSA negative group (1721 ± 1201, p = 0.91) levels. There was no significant difference between the CC16 levels of the each four groups. Mean serum CC16 levels were significantly lower in OSA negative men than OSA positive men (777 vs 1462, p = 0.005). No significant difference was observed in CC16 values according to OSA severity in women. CONCLUSION: The serum CC16 level does not differ between non-smoking OSA patients and OSA negative patients.

Renal dysfunction reduces the diagnostic and prognostic value of serum CC16 for acute respiratory distress syndrome in intensive care patients.

BACKGROUND: Contradictory results regarding changes in serum club cell protein 16 (CC16) levels in patients with acute respiratory distress syndrome (ARDS) have been reported, challenging the value of CC16 as a diagnostic and prognostic marker for ARDS. We have also observed increased serum CC16 levels in patients with renal dysfunction (RD). Therefore, the present study aimed to determine whether RD affects the diagnostic performance of CC16 for ARDS in intensive care unit (ICU) patients. METHODS: We measured serum CC16 concentrations in 479 ICU patients, who were categorized into six groups according to their diagnoses: control, acute kidney injury (AKI), chronic kidney disease (CKD), ARDS, ARDS+AKI, and ARDS+CKD. The sensitivity, specificity, and cutoff values for serum CC16 were assessed by receiver operating characteristic curve analysis. RESULTS: Serum CC16 concentrations were higher in the ARDS group than in the control group, and in ARDS patients with normal renal function, serum CC16 could identify ARDS and predict survival outcomes at 7 and 28 days. However, serum CC16 levels were similar among the ARDS+AKI, ARDS+CKD, AIK, and CKD groups. Consequently, in patients with AKI and/or CKD, the specificity of CC16 for diagnosing ARDS or ARDS+RD decreased from 86.62 to 2.82% or 81.70 to 2.12%, respectively. Consistently, the CC16 cutoff value of 11.57 ng/ml in patients with RD differed from the established values of 32.77-33.72 ng/ml with normal renal function. Moreover, the predictive value of CC16 for mortality in ARDS+RD patients was lost before 7 days but regained by 28 days. CONCLUSION: RD reduces the diagnostic specificity, diagnostic cutoff value, and predictive value for 7-day mortality of serum CC16 for ARDS among ICU patients.

Human arsenic exposure and lung function impairment in coal-burning areas in Guizhou, China.

To evaluate the effect of coal-burning arsenic (As) exposure on lung function and the potential underlying mechanisms, a total of 217 As-exposed subjects and 75 reference subjects were recruited into this study. Hair arsenic (H-As), pulmonary function tests, and serum inflammatory markers CC16, SP-A, MMP-9, and TIMP-1 were evaluated. Residents from As-exposed areas showed higher H-As concentrations (median 0.25 µg/g) than subjects from the reference area (median 0.14 µg/g). Large reductions in lung function parameters were noted in the As-exposed group. A significant negative correlation was observed between H-As concentrations and lung function. Specifically, monotonic negative dose-response relationships were observed between H-As and FEV1(%), FEV1/FVC (%) and FEF75 (%) (all P < 0.05), while the associations between H-As and FVC (%), FEF25 (%), and FEF50 (%) were nonlinear (P for nonlinearity = 0.03, 0.001, 0.01, respectively). In addition, there was a direct positive relationship between H-As and the inflammatory response. Alterations in inflammatory biomarkers (CC16, SP-A, MMP-9, and MMP-9/TIMP-1) were significantly associated with As-induced lung function impairment. Thus, this population-based study revealed that As exposure has significant toxic effects on lung function and increased inflammation may occur during this toxic process. We provide scientific evidence for an As-induced alteration in inflammatory biomarkers and pulmonary damage in an As-exposed population. The results of this study can inform risk assessment and risk control processes in relation to human As exposure in coal-burning arsenicosis areas.

A suitable biomarker of effect, club cell protein 16, from crystalline silica exposure among Thai stone-carving workers.

Exposure to respirable crystalline silica (RCS) reportedly induces chronic lung injury. We investigated the association between RCS exposure and two biomarkers of the effect, plasma club cell protein 16 (CC16) and heme oxygenase-1 (HO-1) levels, in stone-carving workers. Fifty-seven exposed workers (EWs) and 20 unexposed workers (UWs) were enrolled onto the study. Cumulative exposure to RCS was individually estimated using a filter-based gravimetric method. The plasma CC16 and HO-1 levels were determined using commercial kits. The 8-h time-weighted average for RCS concentration in the EW was significantly greater than this concentration in the UW (p < 0.001). The health risk characterization for RCS exposure expressed as a hazard quotient (HQ) indicated that crystalline silica might be a risk factor where there is chronic exposure (HQ = 4.48). The EW group presented a significant decrease in CC16 and an increase in HO-1 levels in comparison to the UW group (p < 0.001). In addition, we found a significant association between RCS concentration and plasma CC16 only. Therefore, our findings representing a significant decrease in CC16 in the plasma of stone-carving workers and this biological marker were significantly associated with RCS concentration. Our data indicated that CC16 might be a suitable biomarker to use to predict the health risk to stone-carving workers of exposure to RCS.

Fourth generation e-cigarette vaping induces transient lung inflammation and gas exchange disturbances: results from two randomized clinical trials.

When heated by an electronic cigarette, propylene glycol and glycerol produce a nicotine-carrying-aerosol. This hygroscopic/hyperosmolar aerosol can deposit deep within the lung. Whether these deposits trigger local inflammation and disturb pulmonary gas exchanges is not known. The aim of this study was to assess the acute effects of high-wattage electronic cigarette vaping with or without nicotine on lung inflammation biomarkers, transcutaneous gas tensions, and pulmonary function tests in young and healthy tobacco smokers. Acute effects of vaping without nicotine on arterial blood gas tensions were also assessed in heavy smokers suspected of coronary artery disease. Using a single-blind within-subjects study design, 25 young tobacco smokers underwent three experimental sessions in random order: sham-vaping and vaping with and without nicotine at 60 W. Twenty heavy smokers were also exposed to sham-vaping (n = 10) or vaping without nicotine (n = 10) in an open-label, randomized parallel study. In the young tobacco smokers, compared with sham-vaping: 1) serum club cell protein-16 increased after vaping without nicotine (mean ± SE, -0.5 ± 0.2 vs. +1.1 ± 0.3 µg/l, P = 0.013) and vaping with nicotine (+1.2 ± 0.3 µg/l, P = 0.009); 2) transcutaneous oxygen tension decreased for 60 min after vaping without nicotine (nadir, -0.3 ± 1 vs. -15.3 ± 2.3 mmHg, P < 0.001) and for 80-min after vaping with nicotine (nadir, -19.6 ± 2.8 mmHg, P < 0.001). Compared with sham vaping, vaping without nicotine decreased arterial oxygen tension for 5 min in heavy-smoking patients (+5.4 ± 3.3 vs. -5.4 ± 1.9 mmHg, P = 0.012). Acute vaping of propylene glycol/glycerol aerosol at high wattage with or without nicotine induces airway epithelial injury and sustained decrement in transcutaneous oxygen tension in young tobacco smokers. Intense vaping conditions also transiently impair arterial oxygen tension in heavy smokers.

Club cell protein 16 in sera from trauma patients modulates neutrophil migration and functionality via CXCR1 and CXCR2.

BACKGROUND: Club Cell protein (CC)16 correlates with lung injury and respiratory complications, which are in part triggered by polymorphonuclear leukocytes (PMNL) in severely traumatized patients (TP). CC16 exerts anti-inflammatory and immunosuppressive effects, however, its influence on PMNL functions after trauma is unknown. Here, we evaluated whether CC16 present in sera from TP could modify the biological functions of PMNL. METHODS: Sera from 16 severely injured TP without pneumonia (no P, n = 8) or with pneumonia (P, n = 8) were collected at admission to emergency department (ED) and 1 day prior pneumonia and pre-incubated with or without anti-CC16 antibody for CC16 neutralization. Samples from the equal post-injury days in the corresponding no P group were used. Neutrophils were isolated from healthy volunteers (HV, n = 5) and incubated with 20% of the serum medium from TP, respectively. In PMNL, CD62L, CD11b/CD18 and CD31 expression, migratory capacity, phagocytosis rate, oxidative burst and apoptosis were investigated. In isolated PMNL, CXCR1 and CXCR2 were neutralized before stimulation with CC16, and oxidative burst, phagocytosis and apoptosis were analyzed in neutrophils and their subsets. RESULTS: Serum from the P group enhanced significantly PMNL migration compared to no P group, while CC16-neutralization further increased the migratory rate of PMNL in both groups. CC16-neutralization increased significantly the expression of CD62L in the P group at ED. Oxidative burst was significantly increased in the P group vs. no P during the study period. CC16 seemed to have no influence on oxidative burst and phagocytosis in TP. However, in a more controlled study design, CC16 induced a significant increase of oxidative burst and a decrease of apoptosis of CD16+ granulocytes. These effects were markedly observed in mature CD16brightCD62Lbright and immune suppressive CD16brightCD62Ldim neutrophils. In mature subset, CXCR1 and CXCR2 neutralization diminished CC16-induced effects. CONCLUSIONS: CC16 in sera from multiply traumatized patients, notably of those with pneumonia, has significant effects on PMNL. The results suggest an association of CC16 with CXCR1 and CXCR2. Our data suggest that CC16 reduces the migratory capacity of PMNL and thus modulates their function in patients with respiratory complications after trauma.

Exogenous mesenchymal stem cells affect the function of endogenous lung stem cells (club cells) in phosgene-induced lung injury.

Exogenous mesenchymal stem cells (MSCs) affect lung cells via cytokines as well as vesicles and activate the Notch signaling pathway thus affecting the proliferation of endogenous stem cells to repair damaged tissue. Club cells are endogenous lung stem cells whose proliferation is also closely related to the Notch signaling pathway. The club cell secretory protein (CCSP) has anti-inflammatory and anti-oxidative properties. This study aimed to investigate whether exogenous MSCs affect the function of club cells in an injured lung and whether these effects are related to the Notch signaling pathway. CCSP levels in bronchoalveolar lavage fluid (BALF) and serum were evaluated using enzyme-linked immunosorbent assay (ELISA) and the average fluorescence intensity (AFI) of CCSP in club cells was determined using flow cytometry. Immunohistochemistry and immunofluorescence were used to visualize club cells and proliferative club cells. The expression of important Notch signaling pathway components including Notch1∼4, c-myc, Hey1 and Hes1 were also assessed. LY3039478 (LY), a specific inhibitor of the Notch signaling pathway, was applied. After MSCs intervention, CCSP levels decreased, and club cell AFI increased, indicating that the secretion of club cells had weakened. The expression of Notch1, Notch2, c-myc, Hey1, Hes1 increased, accompanied by an increase in the number of proliferative club cells. Furthermore, MSCs enhanced the proliferation of club cells, while LY suppressed this phenomenon. In summary, MSCs reduced the secretion of club cells. And MSCs enhanced the proliferation of club cells partly via activating the Notch signaling pathway, which promoted lung injury repair.

[The effects of long-term exposure to silica dust on serum CC16 and KL-6 levels].

Objective: To investigate the effects of long-term exposure to silica dust on serum CC16 and KL-6 levels. Methods: The patients with stage I silicosis who were hospitalized in our hospital from April 2016 to April 2017 were treated as silicosis group. The silica dust exposed workers without silicosis who were taken the physical examination in our hospital were taken as a dust-exposed group. The healthy control group comes from in the same period of community physical examination did not touch the dust. The levels of CC16 and KL-6 in serum of all subjects were determined by enzyme-linked immunosorbent assay (ELISA) , and the levels of CC16 and KL-6 in serum were compared in three groups. Results: Compared with the control group, the serum levels of CC16 in the silicosis group (P<0.01) and the dust-exposed group (P<0.01) were significantly lower. Compared with the control group, the level of serum KL-6 in the silicosis group was significantly decreased (P<0.01) compared with the control group, while the level of KL-6 in the serum of the dust-exposed group was significantly increased (P<0.01) . The ROC area of CC16 for diagnosis of silicosis was 0.92 (P<0.01) , with a sensitivity of 81.37%, specificity of 92.63% and Kappa value of 0.74. Conclusion: Long-term exposure to silica dust may lead to a decrease in serum CC16 levels. Reduced serum CC16 levels may be useful in identifying the diagnosis of silicosis.

Lung function trajectories and chronic obstructive pulmonary disease: current understanding and knowledge gaps.

PURPOSE OR REVIEW: Population-based studies have shown a significant heterogeneity in patients with chronic obstructive pulmonary disease (COPD), regarding both the attainment of maximal lung function and the subsequent decline over time. This review will highlight recent advances in the understanding of lung function trajectory in COPD, focusing on factors that influence peak adult lung function, markers of accelerated lung function decline and pharmacologic interventions in early phases of the disease. RECENT FINDINGS: Recent data have shown that individuals with lower lung function early in life will go on to develop lower forced expiratory volume in 1 s (FEV1) in adulthood. Smoking can amplify the effect of specific childhood exposures on maximal adult lung function. Clinical symptoms such as chronic mucous hypersecretion and the biomarker club cell secretory protein have been associated with lung function decline over time. New computed tomography imaging markers also show promise as a way to detect early small airway disease, but need to be examined more longitudinally. In addition to these advances, a slower decline in FEV1 has been demonstrated in two randomized clinical trials studying tiotropium and inhaled fluticasone. SUMMARY: A better understanding of lung function development and eventual decline in those at risk for progression to COPD will aide in a precision medicine approach, in which markers for those at risk of low maximal lung function and accelerated decline are identified. Targeted therapy can then be used early to modify disease activity and outcomes.

Pneumoproteins and markers of inflammation and platelet activation in the blood of grain dust exposed workers.

PURPOSE: To investigate if blood biomarkers could indicate early signs of lung damage or cardiovascular risk due to exposure to grain dust. MATERIALS AND METHODS: Pneumoproteins and markers of inflammation and platelet activation were analysed in blood samples of 102 grain elevator and compound feed mill workers. Differences between exposed (n = 67) and controls (n = 35), and associations with exposure measurements and respiratory health were investigated by multiple linear regression analyses. RESULTS: Concentrations of CC-16 and IL-6 were higher in exposed workers compared with controls (p < 0.001 for both), whereas fibrinogen was lower (p = 0.005). Concentrations of CRP, TNF-α, sCD40L and sP-selectin were similar in both groups. Serum CC-16 was significantly higher in workers with farm childhood, regardless of exposure. The impact of farm childhood on CC-16 interacted with smoking. None of the biomarkers were associated with exposure measurements or any of the tested respiratory health parameters. CONCLUSION: Dust exposure induced inflammatory and anti-inflammatory reactions, but did not induce systemic inflammation and had no effect on platelet activation. No cause-effect relationship could be established in spite of relatively high exposure levels, particularly to endotoxin. Whether increased serum CC-16 is an early sign of lung damage or a reversible defense reaction remains unclear.

Club cell protein (CC16) in plasma, bronchial brushes, BAL and urine following an inhaled allergen challenge in allergic asthmatics.

BACKGROUND: Club cell protein (CC16) is a pneumoprotein secreted by epithelial club cells. CC16 possesses anti-inflammatory properties and is a potential biomarker for airway epithelial damage. We studied the effect of inhaled allergen on pulmonary and systemic CC16 levels. METHODS: Thirty-four subjects with allergic asthma underwent an inhaled allergen challenge. Bronchoscopy with bronchoalveolar lavage (BAL) and brushings was performed before and 24 h after the challenge. CC16 was quantified in BAL and CC16 positive cells and CC16 mRNA in bronchial brushings. CC16 was measured in plasma and urine before and repeatedly after the challenge. Thirty subjects performed a mannitol inhalation challenge prior to the allergen challenge. RESULTS: Compared to baseline, CC16 in plasma was significantly increased in all subjects 0-1 h after the allergen challenge, while CC16 in BAL was only increased in subjects without a late allergic response. Levels of CC16 in plasma and in the alveolar fraction of BAL correlated significantly after the challenge. There was no increase in urinary levels of CC16 post-challenge. Mannitol responsiveness was greater in subjects with lower baseline levels of CC16 in plasma. CONCLUSIONS: The increase in plasma CC16 following inhaled allergen supports the notion of CC16 as a biomarker of epithelial dysfunction.

Plasma level of club-cell (CC-16) predicts outcome in amyotrophic lateral sclerosis.

OBJECTIVES: The club cell protein (CC-16) is a biomarker associated with respiratory distress and pulmonary inflammation. We evaluated CC-16 as a candidate biomarker for respiratory failure in amyotrophic lateral sclerosis (ALS). MATERIALS AND METHODS: We studied 81 ALS patients and 30 matched controls. We used an ALS-related measure of functional capacity, and tested forced vital capacity (FVC) and the amplitude of the diaphragmatic response by phrenic nerve stimulation (PhrenAmpl). Plasma CC-16 levels were measured in venous blood. Kaplan-Meier survival curves were plotted to evaluate risk to non-invasive ventilation and death in patients with abnormal CC-16 levels. RESULTS: CC-16 levels were significantly raised in ALS patients (10.56 ng/mL ± 6.84 vs 8.34 ng/mL ± 3.10, P = .02), and in 17% of them, CC-16 level was above the upper cutoff value (mean + 2.5SD). CC-16 levels did not correlate with age, onset region, disease duration, functional status, FVC, and PhrenAmpl. In patients with increased CC-16 level, the risk of non-invasive was greater in the following 6 months (P = .01) and tended to have higher mortality in the following 30 months (P = .07). CONCLUSIONS: We propose that increased CC-16 levels is a marker of lung inflammatory response that associated with ventilatory insufficiency are related to impending respiratory failure, not fully predicted by conventional respiratory tests. The latter are limited by the moment of testing.

Burnt sugarcane harvesting work: effects on pulmonary and systemic inflammatory markers.

Objective: To evaluate the effects of burnt sugarcane harvesting on the plasmatic and urinary concentrations of the club cell secretory protein (CC16) and inflammatory systemic biomarkers in a group of sugarcane cutters. Methods: Seventy-eight sugar cane workers were evaluated. The plasmatic and urinary concentrations of CC16, a pulmonary damage marker and inflammatory systemic biomarkers were collected at three time points: before, three months after and six months after the onset of the burnt sugarcane harvesting period. All evaluations were performed at ∼7 am, before the daily work shift. In the three-month evaluation, a post-work shift assessment (acute effect) was also performed. Results: The age of the workers was 37.9 ± 11.0 years. The PM2.5 concentrations were 27.0 (23.0-33.0) and 101.0 (31.0-139.5) µg/m3 in the pre harvest and harvest periods, respectively (p < .001). Burnt sugarcane harvesting was associated with a reduction, throughout the work during burnt sugarcane harvesting (subchronic effect), in plasmatic and urinary CC16 concentrations. Acutely, there was a decrease in plasmatic concentrations. There were acute and subchronic increases in inflammatory markers (neutrophils, monocytes) and muscle damage markers (CK and LDH) and a decrease in red blood cells. Conclusions: Harvesting of burnt sugarcane was associated with acute and subchronic reductions in the plasmatic and urinary concentrations of CC16 protein and changes in systemic inflammatory markers.

Diagnostic and prognostic values of Club cell protein 16 (CC16) in critical care patients with acute respiratory distress syndrome.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a critical condition characterized by bilateral pulmonary infiltrates and severe hypoxemia. This study aimed to evaluate the diagnostic and prognostic values of Club cell protein 16 (CC16) in critical care patients with ARDS. METHODS: In this retrospective observational study, 83 patients with ARDS and 129 non-ARDS patients on ICU admission were enrolled. The differences in serum CC16 and other laboratory indicators between two groups were analyzed. The sensitivity, specificity, positive and negative predictive values, and accuracy of CC16 as a diagnostic marker on ICU admission were determined by receiver operating characteristic (ROC) curve analysis. The correlation between serum CC16 levels and the severity of ARDS as quantified by PaO2 /FiO2 ratio were further assessed. CC16 levels were compared between survivors and non-survivors. The relationships between CC16 levels and duration of ICU and hospitalization were evaluated. RESULTS: The serum CC16 levels in ARDS patients were significantly higher than that in non-ARDS patients (54.44±19.62 vs 24.13±12.32 ng/mL, P=.001). ROC analysis showed that the sensitivity, specificity, positive predictive value, and negative predictive value were 90.4%, 79.8%, 74.2%, and 92.8%, respectively, when the cut-off value was set at 33.3 ng/mL. CC16 levels were correlated with the severity of ARDS. The serum CC16 levels were significantly greater in non-survivors than in survivors from the ARDS group. CC16 levels were associated with ICU stay but not hospital stay. CONCLUSIONS: CC16 may serve as a diagnostic and stratification marker for ARDS. However, it provided limited prognostic information for ARDS.