Introduction
Chronic obstructive pulmonary disease (COPD) encompasses a spectrum of chronic inflammatory lung diseases characterized by persistent airflow limitation and progressive decline in lung function. Beyond traditional risk factors like tobacco exposure, accumulating evidence highlights the role of cellular stress responses—particularly endoplasmic reticulum (ER) stress—in COPD pathogenesis. ER stress activates the unfolded protein response (UPR), a signaling network aimed at restoring cellular homeostasis. When overwhelmed, however, UPR can contribute to inflammation, apoptosis, and tissue remodeling—key features of COPD. This article surveys ER stress-related biomarkers in COPD, their biological basis, and how they might inform prognosis and treatment.
ER stress and the unfolded protein response in COPD
The ER ensures proper protein folding. In COPD, oxidative stress, cigarette smoke constituents, and inflammatory mediators disrupt this balance, leading to accumulation of misfolded proteins. The UPR involves three major signaling branches—PERK, IRE1, and ATF6—that coordinate transcriptional and translational programs to reduce protein load and increase folding capacity. When ER stress persists, CHOP and other pro-apoptotic pathways may be triggered, contributing to epithelial damage and alveolar destruction. In COPD, ER stress is linked to mucus hypersecretion, airway remodeling, and reduced mucociliary clearance, creating a vicious cycle of inflammation and tissue injury.
Key ER stress–related biomarkers in COPD
Biomarkers of ER stress can be detected in blood, sputum, bronchoalveolar lavage fluid, and airway epithelium. Their interpretation requires context, as levels may reflect local lung stress, systemic inflammation, or both.
- BiP/GRP78 (glucose-regulated protein 78): A central chaperone upregulated during ER stress, BiP serves as a sentinel of UPR activation. Elevated BiP levels have been reported in COPD patients and correlate with disease severity and inflammatory markers, suggesting BiP as a noninvasive indicator of airway stress.
- CHOP (C/EBP homologous protein): A pro-apoptotic transcription factor induced by prolonged ER stress. Higher CHOP expression in airway cells may reflect epithelial injury and susceptibility to apoptosis in COPD, potentially linking ER stress to emphysematous changes.
- ATF4 (activated transcription factor 4) and ATF6: Downstream effectors of the UPR that govern amino acid metabolism, antioxidant responses, and chaperone production. Altered ATF4/ATF6 signaling has been associated with inflammatory responses and could serve as indicators of maladaptive ER stress in COPD.
- IRE1–XBP1 axis: Splicing of XBP1 mRNA by IRE1 yields a transcription factor that enhances chaperone production and protein folding capacity. Dysregulated XBP1 activity may contribute to goblet cell hyperplasia and mucus hypersecretion, linking ER stress to clinical phenotypes in COPD.
- PERK–eIF2α pathway: Activation reduces general protein synthesis while promoting selective translation of stress-related proteins. Persistent PERK signaling can influence cell survival and inflammation in the airways of people with COPD.
Clinical relevance and research directions
ER stress biomarkers hold promise for refining COPD phenotyping, tracking disease progression, and identifying patients who might benefit from targeted therapies. For example, higher BiP or CHOP levels could flag patients with greater epithelial injury and robust inflammatory activity, potentially guiding escalation of anti-inflammatory or antioxidant strategies. Moreover, ER stress markers may help monitor response to therapies aimed at restoring proteostasis, such as chemical chaperones or modulators of UPR signaling.
However, several challenges remain. Heterogeneity in COPD means ER stress signatures may vary across phenotypes (emphysematous vs. chronic bronchitis) and between tissue compartments. Standardized assay platforms, longitudinal studies, and integration with imaging and pulmonary function data are needed to establish clinical utility.
From bench to bedside: practical considerations
Noninvasive or minimally invasive sampling—such as blood and induced sputum—could enable routine monitoring of ER stress biomarkers in outpatient settings. Combining ER stress indicators with established red flags (exacerbation frequency, spirometric decline) may enhance risk stratification and enable personalized management plans. In addition, understanding how lifestyle factors (smoking cessation, nutrition, physical activity) modulate ER stress could inform comprehensive COPD care.
Therapeutic implications
Targeting ER stress pathways offers a novel avenue for COPD intervention. Pharmacologic agents that reduce ER stress or selectively modulate UPR branches could dampen airway inflammation, protect epithelial integrity, and slow disease progression. Any such approach would require careful balancing of protective and deleterious consequences of UPR signaling, plus validation in well-designed clinical trials.
Conclusion
ER stress–related biomarkers provide a mechanistic bridge between cellular stress responses and COPD pathophysiology. While promising as tools for refining phenotypes and guiding therapy, these biomarkers demand rigorous validation and standardization. As research advances, integrating ER stress biology into COPD care could lead to more precise prognosis and personalized treatments that improve patient outcomes.
