Osteopontin contributes to late-onset asthma phenotypes in adult asthma patients

Hoang Kim Tu Trinh,Seo-Hee Kim,Hae-Sim Park,Thuy Van Thao Nguyen,Quoc Quang Luu,Thi Bich Tra Cao,Seung-Hyun Kim

doi:10.1038/s12276-020-0376-2

Hoang Kim Tu Trinh, Seo-Hee Kim + Show 5 more

Open Access

https://doi.org/10.1038/s12276-020-0376-2

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Abstract

Patients with late-onset asthma (LOA) have poor clinical outcomes. Osteopontin (OPN) is associated with airway inflammation and remodeling. To investigate the role of OPN in LOA compared to early-onset asthma (EOA), serum OPN levels were compared between 131 adult asthma patients (48 LOA and 83 EOA patients) and 226 healthy controls (HCs). BALB/c mice were sensitized with ovalbumin with/without polyinosinic-polycytidylic acid (poly(I:C)) from week 6 (A6 mice) or week 12 (A12 mice) after birth. Airway hyperresponsiveness (AHR), bronchoalveolar lavage fluid (BALF), cell counts, histology, and Spp1 expression were assessed. The levels of OPN, transforming growth factor β1 (TGF-β1), chitinase 3-like 1 (CH3L1), and interleukin (IL) 5 were measured by ELISA. The expression of Smad3 phosphorylation and tissue transglutaminase 2 (TGM2) was evaluated by Western blot. The serum OPN levels were significantly higher in asthma patients than in HCs and in LOA patients than in those with EOA (P < 0.05) and were positively correlated with serum TGF-β1 and CH3L1 (r = 0.174, r = 0.264; P < 0.05). A12 mice showed elevated AHR with increased levels of OPN/TGF-β1/IL-5 in BALF and Spp1 compared to A6 mice. Poly(I:C) induced remarkable TGF-β1, CH3L1, Th2 cytokine, and OPN levels in BALF and the expression of phosphorylated Smad3, TGM2, and Spp1 in the lungs. OPN triggered TGF-β1/Smad3 signaling in the lungs, which was suppressed by dexamethasone and anti-IL5 antibody. In conclusion, aging and exposure to viral infections may induce OPN release and consequently modulate inflammation and TGF-β1/Smad3-related remodeling, contributing to the development of LOA.

Highlights

The prevalence of asthma in the aged populations is increasing, causing an economic burden in Korea and worldwide
This study demonstrated the role of OPN as a central mediator in the pathogenesis of late-onset asthma (LOA) rather than early-onset asthma (EOA)
The upregulation of OPN may be attributed to the aging process and viral infections in older subjects with asthma, which can accelerate airway remodeling by enhancing transforming growth factor β1 (TGF-β1)/Smad3-related pathways in the pathogenesis of LOA

Summary

Introduction

The prevalence of asthma in the aged populations is increasing, causing an economic burden in Korea and worldwide. Asthma is characterized by chronic inflammation of the respiratory tract and consists of various phenotypes[1]. Late-onset asthma (LOA) is a phenotype that results in the development of asthma symptoms after 40 years of age and is characterized as being less eosinophilic, with a female predominance and more severe clinical features associated with a progressive decline in lung function[2,3]. Airway remodeling consists of changes in the components and organization of the airway wall, which occurs in the epithelium, subepithelial layer, extracellular matrix (ECM) proteins, smooth muscle, and blood vessels[6]. In subjects with LOA, airway remodeling can be either pathological or physiological due to aging-related structural changes in the airway[2,8]. Viral respiratory infections can worsen airway remodeling in adult asthma[9].

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