Introduction
Asthma is a chronic and complex pulmonary inflammation disease which is
characterized by aberrant immune responses to allergen, reversible
airflow obstruction, and airway hyper-responsiveness (AHR). Although
bronchodilators and inhaled/systemic corticosteroids are highly
effective in most asthma patients, approximately 5-10% asthma patients
are still steroid-refractory which always have lower lung function and
higher mortality [1, 2]. Classical ”allergic constitution” or
”airway inflammation” cannot fully explain the occurrence and
development of asthma. Thus, accumulating studies are
attempted to further elucidate the inner pathogenesis of asthma and
identify novel therapeutic targets.
Intriguingly, asthma is common among older adults (age over 65 years)
which is usually more severe, with little opportunities of remission
[3]. Accumulative studies have demonstrated the involvement of aging
in the parthenogenesis of chronic pulmonary diseases, including
idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary
diseases (COPD). As is known that the pathological changes in asthma
resemble COPD, such as airway remodeling, chronic inflammation and
decreased lung function [4, 5]. It is feasible to speculate the
possible involvement of aging in the development of asthma. Indeed, some
valuable evidences have implicated that aging is a vital dangerous
factor for the development of asthma [6]. Aging-related changes have
also been found in structural cells and immune cells of asthma patients.
Of particular note is that the hallmarks of aging such as telomere
attrition, epigenetic alterations, loss of proteostasis, and altered
intercellular communication have also been detected in asthma patients
[7]. Besides, aging can affects the asthma severity along with its
diagnosis and management which is significant for the treatment of
asthma [6]. The aging of different targeted cells can also
contribute to the pathobiology of asthma, including airway inflammation,
airway remodeling and decreased lung function [8]. Furthermore, it
has been confirmed that anti-aging strategies can improve pathological
processes such as airway inflammation and airway remodeling in asthma
patients [9].
Although more and more undeniable studies have evidenced the association
between aging and asthma. It is still obscure about
the role of aging and the mechanism
behind differential expression of aging-related genes remains unknown. A
serious of recent researches have confirmed that epigenetic mechanisms
are involved in the regulation of the expression of aging-related gene
[10, 11]. Epigenetic mechanisms containing DNAm,
microRNAs
expression and
histone modifications
could regulate the transcription activities of target genes without
alteration of nucleotide sequence. In particularly, DNAm is the most
deeply studied epigenetic regulation, which have been proven to play a
crucial role in the regulation of aging-related genes [12].
Specifically, it has been verified that cytosine methylation at the CpG
site affected multiple regulatory mechanisms of aging-related genes
during transcription [13, 14] and further participated in
aging-related disease such as asthma and COPD [15-17]. However,
there is still no definitive literature on the DNAm variations of
aging-related genes in asthma patients.
Our previous study screened and evaluated the differentially mRNA
expression and altered methylation levels of 9 aging-related genes
(AREG, ATG3, E2F1, FOXO3, HDAC1, MMP2, NUF2, TGFB1and TP53) in COPD
patients [18]. It is found that DNAm was involved in regulating the
expression of 9 aging-related genes in peripheral venous blood of COPD
patients. Besides, the methylation level of certain special CpG sites
was associated with the incidence and severity of COPD [18].
In this study, we further aim to
probe the potential involvement of these previous screened 9
aging-related genes in the parthenogenesis of asthma. Firstly, we
inspected the changes in DNAm and mRNA expression of the 9 aging-related
genes in peripheral venous blood of HCs and asthmatic patients. Then, we
analyzed the correlation between DMSs and clinical indicators in
asthmatic patients. Finally, we assessed the feasibility of the
candidate CpG sites as biomarkers for asthma.