Patients with chronic obstructive pulmonary disease (COPD) suffer from a persistent and progressive airflow limitation, leading to severe breathing difficulties. Smoking is the most important risk factor and causes an abnormal inflammatory response in the airways and lungs, resulting in airway remodeling and emphysema. It's the third leading cause of death globally and poses a significant economic burden on healthcare systems. There is still no available treatment to cure or stop the progression of COPD. Understanding the disease pathogenesis and identifying key immune mediators are crucial for developing effective diagnostic and therapeutic targets. Our previous research has provided strong evidence that Toll-like receptor 7 (TLR7) plays a crucial role in the development of both human and experimental COPD, highlighting its potential as a therapeutic target. To further investigate this, we will utilize a comprehensive approach that includes in vivo experimental COPD models, ex vivo studies using primary human tissues and cells, and in silico transcriptomic analyses. Our study aims to: (1) characterize the expression and activation of TLR7 in human and experimental COPD, (2) identify transfer RNA (tRNA) halves as endogenous activators of TLR7, and (3) elucidate the mechanisms by which TLR7 contributes to emphysema and COPD progression. These findings have the potential to support the development of new therapeutic strategies for COPD.