Clusterin as a serum biomarker candidate contributes to the lung fibroblasts activation in chronic obstructive pulmonary disease

Abstract

Background: Fibrosis in the peripheral airways contributes to airflow limitation in patients with chronic obstructive pulmonary disease (COPD). However, the key proteins involved in its development are still poorly understood. Thus, we aimed to identify the differentially expressed proteins (DEPs) between smoker patients with and without COPD and elucidate the molecular mechanisms involved by investigating the effects of the identified biomarker candidate on lung fibroblasts. Methods: The potential DEPs were identified by isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomic analysis. The messenger RNA and protein levels of clusterin (CLU) in COPD patients and 12% cigarette smoke extract (CSE)treated human bronchial epithelial cells were determined at the indicated time points. Furthermore, an in vitro COPD model was established via the administration of 8% CSE to normal human lung fibroblasts (NHLFs) at indicated time points. The effects of CSE treatment and CLU silencing on proliferation and activation of lung fibroblasts were analyzed. Results: A total of 144 DEPs were identified between COPD patients and normal smokers. The iTRAQ-based proteomics and bioinformatics analyses identified CLU as a serum biomarker candidate. We also discovered that CLU levels were significantly increased (P < 0.0001) in Global Initiative for Obstructive Lung Disease II, III, and IV patients and correlated (P < 0.0001) with forced expiratory volume in 1 s (R = À0.7705), residual volume (RV) (R = 0.6281), RV/total lung capacity (R = 0.5454), and computerized tomography emphysema (R = 0.7878). Similarly, CLU levels were significantly increased in CSE-treated cells at indicated time points (P < 0.0001). The CSE treatment significantly inhibited the proliferation, promoted the inflammatory response, differentiation of NHLFs, and collagen matrix deposition, and induced the apoptosis of NHLFs; however, these effects were partially reversed by CLU silencing. Conclusion: Our findings suggest that CLU may play significant roles during airway fibrosis in COPD by regulating lung fibroblast activation.

Proteomics analysis of lung tissue reveals protein makers for the lung injury of adjuvant arthritis rats

“…Furthermore, Clu supplementation may alleviate hyperoxia-induced lung cell death ( 51 , 52 ). Zhang et al ( 53 ) reported that after Clu silencing, the protein expression levels of a-SMA, collagen I, III and MMP-9 in lung fibroblasts decreased, which inhibited the activation of lung fibroblasts. Besides, inflammatory factors such as IL-6, IL-8 and TNF-α were downregulated in lung fibroblasts to prevent an inflammatory response ( 53 ).…”

Role of Serum Clusterin in Bronchial Asthma

“…A positive correlation was found between Clusterin and FEV1/FVC ratio % in non atopic group. This may be attributed to the inhibiting action of Clusterin in the inflammatory response, differentiation, collagen matrix deposition, and apoptosis of normal human lung fibroblasts (NHLFs) that causes improvement in FEV1/FVC ratio % with Clusterin increase in non atopic group (26). Although Sobeih et al reported that no significant correlations with pulmonary function parameters (FEV1%, FVC% and FEV1/FVC ratio %) in asthmatic patients (18) , Lee et al reported that serum Clusterin levels were increased in severe asthma patients who show lower pulmonary functions tests as it increased with asthma severity (27) .…”

Clusterin Plasma Concentrations Are Decreased in Sepsis and Inversely Correlated with Established Markers of Inflammation

“…In consideration of its cellular, immunologic, and metabolic effects, clusterin has associations to various systemic inflammatory, metabolic, and neurological disorders; and their clinical outcome and phenotype, respectively [ 3 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ].…”