Dataset Information

Club Cell Secretory Protein Deficiency Leads to Altered Lung Function.

ABSTRACT:

Rationale

CC16 (club cell secretory protein-16), a member of the secretoglobin family, is one of the most abundant proteins in normal airway secretions and has been described as a serum biomarker for obstructive lung diseases.

Objectives

To determine whether low CC16 is a marker for airway pathology or is implicated in the pathophysiology of progressive airway damage in these conditions.

Methods

Using human data from the birth cohort of the Tucson Children's Respiratory Study, we examined the relation of circulating CC16 levels with pulmonary function and responses to bronchial methacholine challenge from childhood up to age 32 years. In wild-type and CC16^-/- mice, we set out to comprehensively examine pulmonary physiology, inflammation, and remodeling in the naive airway.

Measurements and main results

We observed that Tucson Children's Respiratory Study participants in the lowest tertile of serum CC16 had significant deficits in their lung function and enhanced airway hyperresponsiveness to methacholine challenge from 11 years throughout young adult life. Similarly, CC16^-/- mice had significant deficits in lung function and enhanced airway hyperresponsiveness to methacholine as compared with wild-type mice, which were independent of inflammation and mucin production. As compared with wild-type mice, CC16^-/- mice had significantly elevated gene expression of procollagen type I, procollagen type III, and α-smooth muscle actin, areas of pronounced collagen deposition and significantly enhanced smooth muscle thickness.

Conclusions

Our findings support clinical observations by providing evidence that lack of CC16 in the lung results in dramatically altered pulmonary function and structural alterations consistent with enhanced remodeling.

SUBMITTER: Zhai J

PROVIDER: S-EPMC6363971 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Club cell secretory protein (Clara) (CC16) is produced mainly by bronchiolar club cells and has been shown to have protective effects against airway inflammation and oxidative stress from cigarette smoking and related carcinogens. The goal of this study was to establish whether serum CC16 concentrations predict all-cause and cancer-specific mortality in adults.We used data from the population-based Tucson Epidemiological Study of Airway Obstructive Diseases (TESAOD), a prospective cohort study of respiratory health initiated in Tucson, AZ, USA, in 1972, that recruited a multistage stratified cluster sample of non-Hispanic white households. We measured serum CC16 concentrations in cryopreserved serum samples and reviewed vital status up to Jan 1, 2011, through contact with next of kin, collection of death certificates, and searches of the National Death Index. Our primary analysis was the relation of baseline serum CC16 to all-cause mortality or cause-specific mortality risk, analysed by adjusted Cox proportional hazards models.1086 TESAOD participants aged 21-70 years at enrolment were eligible for inclusion. Of these, 653 (60%) had died by 2011, and cause of death was ascertained for 649 (99%). When adjusted for sex, age, education, body-mass index, smoking and pack-years, and baseline levels of lung function, serum CC16 concentrations at baseline were inversely associated with mortality risk over the study follow-up. Mortality risk increased for each 1-SD decrease in CC16 (adjusted hazard ratio [HR] 1·16 [95% CI 1·06-1·26]; p=0·0007). For cause-specific mortality, each 1-SD decrease in serum CC16 was associated with an increased risk of dying of cancer (adjusted HR 1·41 [1·19-1·67]; p<0·0001). In the subset of smokers, the corresponding adjusted HR for mortality by lung cancer was 1·52 (1·14-2·03; p=0·004).Serum CC16 concentrations can predict mortality risk in the general adult population. The excess risk associated with lower CC16 concentrations is predominantly driven by cancer, particularly lung cancer.National Heart, Lung, and Blood Institute.