Increased Expression of CC16 in Patients with Idiopathic Pulmonary Fibrosis.

Ivette Buendía-Roldán,Víctor Ruiz,Moisés Selman,Anita Vega,Alfonso Salgado,Remedios Ramírez,Patricia Sierra,Annie Pardo,Mario H Vargas,Eduardo Montes,Mayra Mejía,Rory Edward Morty

doi:10.1371/journal.pone.0168552

Abstract

Idiopathic pulmonary fibrosis (IPF) is a devastating disease of unknown etiology. The pathogenic mechanisms are unclear, but evidence indicates that aberrantly activated alveolar epithelial cells secrete a variety of mediators which induce the migration, proliferation and activation of fibroblasts and finally the excessive accumulation of extracellular matrix with the consequent destruction of the lung parenchyma. CC16 (approved symbol SCGB1A1), a putative anti-inflammatory protein produced by “club” cells in the distal airways, has not been evaluated in IPF lungs. In this study, we determined the serum and bronchoalveolar lavage (BAL) levels as well as the lung cell localization of this protein. Also, we explored the usefulness of serum levels of CC16 for the differential diagnosis of IPF (n = 85), compared with non-IPF interstitial lung diseases [chronic hypersensitivity pneumonitis (cHP; n = 85) and connective tissue diseases (CTD-ILD; n = 85)]. CC16 was significantly increased in serum and BAL fluids of IPF patients and was found not only in club cells but also in alveolar epithelial cells. When compared with non-IPF patients and controls, serum levels were significantly increased (p<0.0001). Sensitivity and specificity for CC16 (cut-off 41ng/mL) were 24% and 90%, positive predictive value 56% and negative predictive value 69%. These findings demonstrate that CC16 is upregulated in IPF patients suggesting that may participate in its pathogenesis. Although higher than the serum levels of non-IPF patients it shows modest sensitivity to be useful as a potential biomarker for the differential diagnosis.

Highlights

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually lethal fibrosing interstitial pneumonia of unknown etiology and a median survival of 2–3 years after diagnosis [1]
We revealed by the first time that Club cell protein 16 (CC16) is expressed by these epithelial cells in IPF lungs and that is markedly increased in serum and bronchoalveolar lavage fluids obtained from these patients
Serum concentration of CC16 was significantly increased in IPF patients compared with the levels observed in non-IPF disorders, chronic hypersensitivity pneumonitis (cHP) and CTD-interstitial lung diseases (ILD), two diseases where immunopathological and inflammatory processes play a critical role

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually lethal fibrosing interstitial pneumonia of unknown etiology and a median survival of 2–3 years after diagnosis [1]. These epithelial cells are highly active and secrete a variety of growth factors, cytokines, chemokines, matrix metalloproteinases and coagulation factors that participate in the formation of the fibroblastic/myofibroblastic foci and the subsequent abnormal tissue remodeling [2]. In this context, we aimed to evaluate Club cell protein 16 (CC16) a mediator produced by non-ciliated airway epithelium, primarily bronchiolar club cells, with putative antiinflammatory properties. There is evidence that club cells may induce apoptosis of alveolar and bronchiolar epithelial cells, a process that play a critical role in the pathogenesis of IPF [4]

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