Chronic Obstructive Pulmonary Disease (COPD) is characterised by upregulation of inflammatory mechanisms in the lungs, influenced by a variety of environmental and genetic factors. Tobacco smoke (TS) is the most prominent risk factor and one of the most potent sources of oxidative stress. It is accompanied by two conditions, chronic bronchitis and emphysema, which lead to airflow obstruction. The hallmarks of COPD are breathlessness (dyspnea), a persistent cough, and sputum production. Toxins in TS trigger the release of damage-associated molecular patterns (DAMPs), inducing oxidative stress in cells. Various studies show that mtROS elevation following TS exposure is mainly due to dysregulation of mitochondrial antioxidant systems. A significant increase in intracellular ROS further activates redox-sensitive inflammatory pathways and induces the production of pro-inflammatory cytokines. So, mitochondrial damage induced by TS in immune cells intensifies oxidative stress, causing inflammation, structural remodelling, and cellular senescence in COPD. Significantly increased levels of freely circulating mitochondrial DNA (mtDNA) in the plasma and bronchoalveolar lavage fluid of COPD patients have been observed, indicating mitochondrial damage. The released mtDNA is sensed by Cyclic GMP-AMP synthase (cGAS), activating the cGAS-STING signalling pathway, with functional effects on tissue repair and inflammatory responses, as well as cytokine induction. The involvement of cGAS in human COPD samples emphasises its pathogenic relevance in persistent airway inflammation. The NLRP3 inflammasome pathway also serves as a key regulator of innate immune-mediated inflammation by activating caspase-1 and further maturing pro-inflammatory cytokines, interleukin-1β (IL-1β) and interleukin-18 (IL-18). Various studies have implicated cGAS-STING in regulating NLRP3 inflammasome activation, suggesting that crosstalk occurs between the pathways, which play central roles in sterile inflammation and airway injury in COPD. This review aims to understand the mechanisms by which mtDNA-mediated stimulation of the cGAS-STING pathway contributes to COPD pathogenesis and its interaction with the NLRP3 inflammasome, which amplifies inflammation and tissue injury.
