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Rationale: CC16 is a protein mainly produced by nonciliated bronchial epithelial cells (BECs) that participates in host defense. Reduced CC16 protein concentrations in BAL and serum are associated with asthma susceptibility. Objectives: Few studies have investigated the relationship between CC16 and asthma progression, and none has focused on BECs. In this study, we sought to determine if CC16 mRNA expression levels in BECs are associated with asthma severity. Methods: Association analyses between CC16 mRNA expression levels in BECs (242 asthmatics and 69 control subjects) and asthma-related phenotypes in Severe Asthma Research Program were performed using a generalized linear model. Measurements and Main Results: Low CC16 mRNA expression levels in BECs were significantly associated with asthma susceptibility and asthma severity, high systemic corticosteroids use, high retrospective and prospective asthma exacerbations, and low pulmonary function. Low CC16 mRNA expression levels were significantly associated with high T2 inflammation biomarkers (fractional exhaled nitric oxide and sputum eosinophils). CC16 mRNA expression levels were negatively correlated with expression levels of Th2 genes (IL1RL1, POSTN, SERPINB2, CLCA1, NOS2, and MUC5AC) and positively correlated with expression levels of Th1 and inflammation genes (IL12A and MUC5B). A combination of two nontraditional T2 biomarkers (CC16 and IL-6) revealed four asthma endotypes with different characteristics of T2 inflammation, obesity, and asthma severity. Conclusions: Our findings indicate that low CC16 mRNA expression levels in BECs are associated with asthma susceptibility, severity, and exacerbations, partially through immunomodulation of T2 inflammation. CC16 is a potential nontraditional T2 biomarker for asthma development and progression.

Rationale: CC16 (Club Cell Secretory Protein) is a protein produced by club cells and other non-ciliated epithelial cells within the lungs. CC16 has been shown to protect against the development of obstructive lung diseases and attenuate pulmonary pathogen burden. Despite recent advances in understanding CC16 effects in circulation, the biological mechanisms of CC16 in pulmonary epithelial responses have not been elucidated. Objectives: We sought to determine if CC16 deficiency impairs epithelial-driven host responses and identify novel receptors expressed within the pulmonary epithelium through which CC16 imparts activity. Methods: We utilized mass spectrometry and quantitative proteomics to investigate how CC16 deficiency impacts apically secreted pulmonary epithelial proteins. Mouse tracheal epithelial cells (MTECS), human nasal epithelial cells (HNECs) and mice were studied in naïve conditions and after Mp challenge. Measurements and main results: We identified 8 antimicrobial proteins significantly decreased by CC16-/- MTECS, 6 of which were validated by mRNA expression in Severe Asthma Research Program (SARP) cohorts. Short Palate Lung and Nasal Epithelial Clone 1 (SPLUNC1) was the most differentially expressed protein (66-fold) and was the focus of this study. Using a combination of MTECs and HNECs, we found that CC16 enhances pulmonary epithelial-driven SPLUNC1 expression via signaling through the receptor complex Very Late Antigen-2 (VLA-2) and that rCC16 given to mice enhances pulmonary SPLUNC1 production and decreases Mycoplasma pneumoniae (Mp) burden. Likewise, rSPLUNC1 results in decreased Mp burden in mice lacking CC16 mice. The VLA-2 integrin binding site within rCC16 is necessary for induction of SPLUNC1 and the reduction in Mp burden. Conclusion: Our findings demonstrate a novel role for CC16 in epithelial-driven host defense by up-regulating antimicrobials and define a novel epithelial receptor for CC16, VLA-2, through which signaling is necessary for enhanced SPLUNC1 production. [ABSTRACT FROM AUTHOR]

Rationale: People with better early-life respiratory health may be more likely to work in occupations with high workplace exposures in adult life compared with people with poor respiratory health. This may manifest as a healthy worker effect bias, potentially confounding the analysis of environmental exposure studies. Objectives: To evaluate associations between lung function in adolescence and occupational exposures at initial adult employment. Methods: The TCRS (Tucson Children's Respiratory Study) is a long-term prospective study of respiratory health beginning at birth. Associations between respiratory function at age 11 years and occupational exposures at first job at age 26 years were evaluated with logistic regression. We calculated percentage predicted values for forced expiratory volume in one second (FEV1), forced vital capacity (FVC), FEV1:FVC ratio, and forced expiratory flow from 25% to 75% of vital capacity at age 11. At the 26-year visit, participants self-reported occupational exposures to dust, smoke, and fumes/gas at first job in a standardized interview. Results: Forced expiratory flow from 25% to 75% of vital capacity and FEV1:FVC ratio at age 11 were positively associated with dust workplace exposures at the first job. Each 10% increase in percentage predicted prebronchodilator FEV1:FVC ratio was associated with 30% higher odds of workplace dust exposure (odds ratio for a 1% increase, 1.03 [95% confidence interval, 1.00-1.06; P = 0.045]). Similar associations were observed for FEV1 and FVC with workplace smoke exposures. We also observed modification by time at job: associations were stronger for those who remained in their jobs longer than 12 months. In addition, those with better function at age 11 were more likely to stay in their jobs longer than 12 months if their first jobs involved exposure to dust. Conclusions: Childhood lung function affects initial career choice. This study supports the premise of the healthy worker effect. [ABSTRACT FROM AUTHOR]

The article offers several studies that have assessed various protein panels in asthma with most using airway-derived samples, recruiting clinic-based cohorts and focuses on cytokines and chemokines. Topics include examines there is a lack of large-scale population-based studies that examine multiple circulating proteins for association with asthma in children.

Rationale: CC16 is a protein mainly produced by nonciliated bronchial epithelial cells (BECs) that participates in host defense. Reduced CC16 protein concentrations in BAL and serum are associated with asthma susceptibility. Objectives: Few studies have investigated the relationship between CC16 and asthma progression, and none has focused on BECs. In this study, we sought to determine if CC16 mRNA expression levels in BECs are associated with asthma severity. Methods: Association analyses between CC16 mRNA expression levels in BECs (242 asthmatics and 69 control subjects) and asthma-related phenotypes in Severe Asthma Research Program were performed using a generalized linear model. Measurements and Main Results: Low CC16 mRNA expression levels in BECs were significantly associated with asthma susceptibility and asthma severity, high systemic corticosteroids use, high retrospective and prospective asthma exacerbations, and low pulmonary function. Low CC16 mRNA expression levels were significantly associated with high T2 inflammation biomarkers (fractional exhaled nitric oxide and sputum eosinophils). CC16 mRNA expression levels were negatively correlated with expression levels of Th2 genes (IL1RL1, POSTN, SERPINB2, CLCA1, NOS2, and MUC5AC) and positively correlated with expression levels of Th1 and inflammation genes (IL12A and MUC5B). A combination of two nontraditional T2 biomarkers (CC16 and IL-6) revealed four asthma endotypes with different characteristics of T2 inflammation, obesity, and asthma severity. Conclusions: Our findings indicate that low CC16 mRNA expression levels in BECs are associated with asthma susceptibility, severity, and exacerbations, partially through immunomodulation of T2 inflammation. CC16 is a potential nontraditional T2 biomarker for asthma development and progression. [ABSTRACT FROM AUTHOR]

Rationale: Recent evidence highlights the importance of optimal lung development during childhood for health throughout life.Objectives: To explore the plasticity of individual lung function states during childhood.Methods: Pre-bronchodilator FEV1 z-scores determined at age 8, 16 and 24 years in the Swedish population-based birth cohort BAMSE (N=3,069) were used. An unbiased, data-driven dependent mixture model was applied to explore lung function states and individual state chains. Lung function catch-up was defined as participants moving from low/very low states to normal/high/very high states, and growth failure as moving from normal/high/very high states to low/very low states. At 24 years, we compared respiratory symptoms, small airway function (multiple-breath washout), and circulating inflammatory protein levels, by using proteomics, across states. Models were replicated in the independent Dutch population-based PIAMA cohort.Measurements and Main Results: Five lung function states were identified in BAMSE. Lung function catch-up and growth failure were observed in 74 (14.5%) BAMSE participants with low/very low states and 36 (2.4%) participants with normal/high/very high states, respectively. The occurrence of catch-up and growth failure was replicated in PIAMA. Early-life risk factors were cumulatively associated with the very low state, as well as with catch-up (inverse association) and growth failure. The very low state as well as growth failure were associated with respiratory symptoms, airflow limitation, and small airway dysfunction at adulthood. Proteomics identified Interleukin-6 and C-X-C motif chemokine 10 as potential biomarkers of impaired lung function development.Conclusions: Individual lung function states during childhood are plastic, including catch-up and growth failure. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/). [ABSTRACT FROM AUTHOR]

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Study Objectives: The goal of this study was to evaluate the association between a polygenic risk score (PRS) for QT prolongation (QTc-PRS), QTc intervals and sudden cardiac death (SCD) in participants enrolled in the UK Biobank with and without sleep-disordered breathing (SDB)., Methods: The QTc-PRS was calculated using allele copy number and previously reported effect estimates for each single nuclear polymorphism SNP. Competing-risk regression models adjusting for age, sex, BMI, QT prolonging medication, race, and comorbid cardiovascular conditions were used for SCD analyses., Results: 500,584 participants were evaluated (56.5 ±8 years, 54% women, 1.4% diagnosed with sleep apnea). A higher QTc-PRS was independently associated with the increased QTc interval duration (p<0.0001). The mean QTc for the top QTc-PRS quintile was 15 msec longer than the bottom quintile (p<0.001). SDB was found to be an effect modifier in the relationship between QTc-PRS and SCD. The adjusted HR per 5-unit change in QTc-PRS for SCD was 1.64 (95% CI 1.16 - 2.31, p=0.005) among those with SDB and 1.04 (95% CI 0.95 - 1.14, p=0.44) among those without SDB (p for interaction =0.01). Black participants with SDB had significantly elevated adjusted risk of SCD (HR=9.6, 95% CI 1.24 - 74, p=0.03)., Conclusions: In the UK Biobank population, the QTc-PRS was associated with SCD among participants with SDB but not among those without SDB, indicating that SDB is a significant modifier of the genetic risk. Black participants with SDB had a particularly high risk of SCD., (© 2024 American Academy of Sleep Medicine.)