Unraveling the Pathogenesis of Asthma and Chronic Obstructive Pulmonary Disease Overlap: Focusing on Epigenetic Mechanisms

Abstract

Asthma and COPD overlap (ACO) is characterized by patients presenting with persistent airflow limitation and features of both asthma and COPD. It is associated with a higher frequency and severity of exacerbations, a faster lung function decline, and a higher healthcare cost. Systemic inflammation in COPD and asthma is driven by type 1 T helper (Th1) and Th2 immune responses, respectively, both of which may contribute to airway remodeling in ACO. ACO-related biomarkers can be classified into four categories: neutrophil-mediated inflammation, Th2 cell responses, arachidonic acid-eicosanoids pathway, and metabolites. Gene–environment interactions are key contributors to the complexity of ACO and are regulated by epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNAs. Thus, this review focuses on the link between epigenetics and ACO, and outlines the following: (I) inheriting epigenotypes without change with environmental stimuli, or epigenetic changes in response to long-term exposure to inhaled particles plus intermittent exposure to specific allergens; (II) epigenetic markers distinguishing ACO from COPD and asthma; (III) potential epigenetic drugs that can reverse oxidative stress, glucocorticoid insensitivity, and cell injury. Improved understanding of the epigenetic regulations holds great value to give deeper insight into the mechanisms, and clarify their implications for biomedical research in ACO.

RNA modifications in pulmonary diseases

“…158 Regulatory functions of epigenetic modifications in COPD's onset, progression, and clinical prognosis have also been demonstrated. 159,160 Abnormal changes in miRNA activity have been proven to accelerate the onset of COPD. 161 Pulmonary inflammatory responses in COPD patients are attributed to dysregulated miRNA, impacting disease advancement.…”

“…Epigenetic changes are among the multiple pathogenic factors implicated in COPD 158 . Regulatory functions of epigenetic modifications in COPD's onset, progression, and clinical prognosis have also been demonstrated 159,160 . Abnormal changes in miRNA activity have been proven to accelerate the onset of COPD 161 .…”

Multifaced roles of desmoplastic reaction and fibrosis in pancreatic cancer progression: Current understanding and future directions

“…DNA methylation in the lung is associated with processes, such as alveolar epithelial cell differentiation, fibrosis promotion, and inflammatory response development 48 . It has been shown to play a role in the regulation of inflammatory responses to airway injury and may be important in pulmonary disease development and progression such as asthma and chronic obstructive pulmonary disease 49 . Additionally, DNA methylation has been implicated in lung cancer development and other disease progression, such as idiopathic pulmonary fibrosis 50 …”

“… 48 It has been shown to play a role in the regulation of inflammatory responses to airway injury and may be important in pulmonary disease development and progression such as asthma and chronic obstructive pulmonary disease. 49 Additionally, DNA methylation has been implicated in lung cancer development and other disease progression, such as idiopathic pulmonary fibrosis. 50 …”

Recent Developments in the Role of Histone Acetylation in Asthma

“…Molecular regulation of the AEC function by so-called epigenetic modifications, such as histone acetylation, plays an important role in the development and pathobiology of asthma [8][9][10][11][12][13]. Likewise, the same mechanisms may be engaged in controlling the activity of cells of the immune system, especially CD4+ T cells, also in the context of asthma [1,9,10,12,[14][15][16][17][18]. CD4+ T cells include T helper 1, T helper 2 (Th2), T helper 17, regulatory T cells, and others.…”