Endoplasmic Reticulum Stress, Redox Signaling, and Neutrophil Effector Functions in Chronic Lung Diseases: Evidence and Research Priorities.

Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) signaling intersect with inflammatory and redox pathways. Experiments in primary neutrophils link selected UPR pathways to mitochondrial reactive oxygen species, neutrophil extracellular trap (NET) formation, antimicrobial activity, and immune regulation under defined conditions. This review organizes these findings by cell type, experimental model, and the relationship tested, distinguishing them from cell-line experiments, other-cell mechanisms, clinical associations, and database connections. We examine calcium signaling, compartmentalized oxidant production, antioxidant defenses, and redox-dependent UPR sensor modifications. Several molecular mechanisms of sensor modification derive from non-neutrophil systems and require separate validation in neutrophils. Their relevance is assessed across chronic obstructive pulmonary disease, asthma, and pulmonary fibrosis, with cystic fibrosis (CF) blood-neutrophil transcript measurements distinguished from functional pathway evidence. To our knowledge, no study has established direct causality between neutrophil-intrinsic UPR signaling and NET formation in primary neutrophils obtained from human chronic lung disease tissue or pulmonary neutrophilic patient cohorts. We identify dose-, time-, and branch-resolved experiments needed to evaluate individual neutrophil functions without assigning their direction to acute or prolonged stress. Pharmacological UPR modulation is considered separately from delivery platforms evaluated with non-UPR cargoes. This evidence-based assessment defines the cellular boundaries of current knowledge and prioritizes experiments needed to establish disease relevance and preserve antimicrobial defense.