Chronic obstructive pulmonary disease (COPD) is currently the third most common cause of global mortality. Acute exacerbations of COPD frequently necessitate hospital admission to enable more intensive therapy, incurring significant healthcare costs. COPD exacerbations are also associated with accelerated lung function decline and increased risk of mortality. Until recently, bacterial pathogens were believed to be responsible for the majority of disease exacerbations. However, with the advent of culture-independent molecular diagnostic techniques it is now estimated that viruses are detected during half of all COPD exacerbations and are associated with poorer clinical outcomes. Human rhinovirus, respiratory syncytial virus and influenza are the most commonly detected viruses during exacerbation. The role of persistent viral infection (adenovirus) has also been postulated as a potential pathogenic mechanism in COPD. Viral pathogens may play an important role in driving COPD progression by acting as triggers for exacerbation and subsequent lung function decline whilst the role of chronic viral infection remains a plausible hypothesis that requires further evaluation. There are currently no effective antiviral strategies for patients with COPD. Herein, we focus on the current understanding of the cellular and molecular mechanisms of respiratory viral infection in COPD.

The arrival of cystic fibrosis transmembrane conductance regulator (CFTR) modulators as a new class of treatment for cystic fibrosis (CF) in 2012 represented a pivotal advance in disease management, as these small molecules directly target the upstream underlying protein defect. Further advancements in the development and scope of these genotype-specific therapies have been transformative for an increasing number of people with CF (PWCF). Despite clear improvements in CFTR function and clinical endpoints such as lung function, body mass index (BMI), and frequency of pulmonary exacerbations, current evidence suggests that CFTR modulators do not prevent continued decline in lung function, halt disease progression, or ameliorate pathogenic organisms in those with established lung disease. Furthermore, it remains unknown whether their restorative effects extend to dysfunctional CFTR expressed in phagocytes and other immune cells, which could modulate airway inflammation. In this review, we explore the effects of CFTR modulators on airway inflammation, infection, and their influence on the impaired pulmonary host defences associated with CF lung disease. We also consider the role of inflammation-directed therapies in light of the widespread clinical use of CFTR modulators and identify key areas for future research.

Cellular senescence is a state of permanent cell cycle arrest triggered by various intrinsic and extrinsic stressors. Cellular senescence results in impaired tissue repair and remodeling, loss of physiological integrity, organ dysfunction, and changes in the secretome. The systemic accumulation of senescence cells has been observed in many age-related diseases. Likewise, cellular senescence has been implicated as a risk factor and driving mechanism in chronic obstructive pulmonary disease (COPD) pathogenesis. Airway epithelium exhibits hallmark features of senescence in COPD including activation of the p53/p21WAF1/CIP1 and p16INK4A/RB pathways, leading to cell cycle arrest. Airway epithelial senescent cells secrete an array of inflammatory mediators, the so-called senescence-associated secretory phenotype (SASP), leading to a persistent low-grade chronic inflammation in COPD. SASP further promotes senescence in an autocrine and paracrine manner, potentially contributing to the onset and progression of COPD. In addition, cellular senescence in COPD airway epithelium is associated with telomere dysfunction, DNA damage, and oxidative stress. This review discusses the potential mechanisms of airway epithelial cell senescence in COPD, the impact of cellular senescence on the development and severity of the disease, and highlights potential targets for modulating cellular senescence in airway epithelium as a potential therapeutic approach in COPD.

Cellular senescence has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). The mechanisms of senescence in the bronchial epithelium, however, remain largely unknown. In this study, we aimed to elucidate whether cellular senescence in COPD epithelial cells contributes to the pathogenesis of the disease and investigated the potential molecular mechanisms involved. Single-cell RNA sequencing was performed on well-differentiated primary bronchial epithelial cells from patients with COPD and healthy subjects. We evaluated the abundance and distribution of senescence markers in key epithelial differentiated subtypes and senescence-associated secretory phenotype involved in airway epithelial dysfunction. The effects of IFN-pathway inhibitors on cellular senescence were also investigated. There was increased expression of cellular senescence genes in the COPD cohort, which was predominantly in basal and club cells. Enhanced expression of cellular senescence markers, p16 and p21, was observed in COPD cultures, which was histologically confirmed in the lung tissue of patients with COPD. There was also a notable increase in IFN-β and IFN-γ. Senescence-associated secretory phenotype productions were increased in COPD and were attenuated by JAK-STAT or cGAS-STING pathway inhibitors (baricitinib or C-176). These inhibitors also effectively suppressed expression of senescence markers. COPD bronchial epithelium displays a senescence-driven phenotype which is mediated by Type I/II IFNs. Inhibition of JAK-STAT or STING-cGAS IFN pathways may represent targets to alleviate cellular senescence and chronic inflammation in COPD.

COPD is a chronic lung disorder characterized by a progressive and irreversible airflow obstruction, and persistent pulmonary inflammation. It has become a global epidemic affecting 10% of the population, and is the third leading cause of death worldwide. Respiratory viruses are a primary cause of COPD exacerbations, often leading to secondary bacterial infections in the lower respiratory tract. COPD patients are more susceptible to viral infections and associated severe disease, leading to accelerated lung function deterioration, hospitalization, and an increased risk of mortality. The airway epithelium plays an essential role in maintaining immune homeostasis, and orchestrates the innate and adaptive responses of the lung against inhaled and pathogen insults. A healthy airway epithelium acts as the first line of host defense by maintaining barrier integrity and the mucociliary escalator, secreting an array of inflammatory mediators, and initiating an antiviral state through the interferon (IFN) response. The airway epithelium is a major site of viral infection, and the interaction between respiratory viruses and airway epithelial cells activates host defense mechanisms, resulting in rapid virus clearance. As such, the production of IFNs and the activation of IFN signaling cascades directly contributes to host defense against viral infections and subsequent innate and adaptive immunity. However, the COPD airway epithelium exhibits an altered antiviral response, leading to enhanced susceptibility to severe disease and impaired IFN signaling. Despite decades of research, there is no effective antiviral therapy for COPD patients. Herein, we review current insights into understanding the mechanisms of viral evasion and host IFN antiviral defense signaling impairment in COPD airway epithelium. Understanding how antiviral mechanisms operate in COPD exacerbations will facilitate the discovery of potential therapeutic interventions to reduce COPD hospitalization and disease severity.

Background: Respiratory viral infections are closely associated with COPD exacerbations, hospitalisations, and significant morbidity and mortality. The consequences of the persisting inflammation and differentiation status in virus associated severe disease is not fully understood. The aim of this study was to evaluate barrier function, cellular architecture, the inflammatory response in severe COPD bronchial epithelium to human rhinovirus (HRV) induced pathological changes and innate immune responses. Methods: Well-differentiated primary bronchial epithelial cells (WD-PBECs) derived from severe COPD patients and age-matched healthy controls were cultured in the air-liquid interface (ALI) model. The differentiation phenotype, epithelial barrier integrity, pathological response and cytokine secreting profile of these cultures before and after HRV infection were investigated. Results: WD-PBECs derived from severe COPD patients showed aberrant epithelium differentiation with a decreased proportion of ciliated cells but increased numbers of club cells and goblet cells compared with healthy controls. Tight junction integrity was compromised in both cultures following HRV infection, with heightened disruptions in COPD cultures. HRV induced increased epithelial cell sloughing, apoptosis and mucus hypersecretion in COPD cultures compared with healthy controls. A Th1/Th2 imbalance and a strong interferon and pro-inflammatory cytokine response was also observed in COPD cultures, characterized by increased levels of IFNγ, IFNβ, IP-10, IL-10 and decreased TSLP and IL-13 cytokine levels prior to HRV infection. Significantly enhanced basolateral secretion of eotaxin 3, IL-6, IL-8, GM-CSF were also observed in both mock and HRV infected COPD cultures compared with corresponding healthy controls. In response to HRV infection, all cultures displayed elevated levels of IFNλ1 (IL-29), IP-10 and TNFα compared with mock infected cultures. Interestingly, HRV infection dramatically reduced IFNλ levels in COPD cultures compared with healthy subjects. Conclusion: An altered differentiation phenotype and cytokine response as seen in severe COPD WD-PBECs may contribute to increased disease susceptibility and an enhanced inflammatory response to HRV infection.