Neutrophil extracellular traps (NETs) and pulmonary fibrosis: Mechanisms and implications

Pulmonary fibrosis is a fatal interstitial lung disease characterized by excessive fibroblast proliferation and aberrant deposition of extracellular matrix (ECM), ultimately leading to structural lung destruction and respiratory failure. Neutrophils, as key effector cells of innate immunity, have been increasingly recognized for their role in chronic inflammation and fibrotic diseases through the formation of neutrophil extracellular traps (NETs)-a distinct form of cell death. Distinguishing itself from prior reviews, this review aims to compare the cytotoxic effects of three NETosis subtypes (lytic, non-lytic, and mitochondrial) and to elucidate the dual (antimicrobial and pathogenic) roles of NETs in the initiation and progression of pulmonary fibrosis, with an emphasis on the multiple mechanisms by which NETs amplify fibrotic progression-including activation of inflammatory responses, injury to alveolar epithelial cells, and direct or indirect activation of fibroblasts. Finally, we discuss potential therapeutic strategies targeting NETs, thereby offering a novel perspective for both mechanistic understanding and therapeutic development in NETs-amplified pulmonary fibrosis.