Inhibition of 5-hydroxyindoleacetic acid to reduce neutrophil extracellular trap production improves lung condition in chronic obstructive pulmonary disease mice

Neutrophil extracellular trap (NET) correlate with chronic obstructive pulmonary disease (COPD) severity. Platelets can promote NET generation. However, serotonin alone or serotonin-deficient platelets do not adequately promote NET production. The metabolism of serotonin to 5-hydroxyindoleacetic acid (5-HIAA) in platelets may be the key to this difference. The study aimed to determine whether 5-HIAA can influence NET production and thus play a role in COPD. After a 4-hour co-incubation with lipopolysaccharide (LPS) and 5-HIAA, NET and ROS levels in the culture medium were measured by ELISA, and NET production with aryl hydrocarbon receptor (AHR) expression in adherent cells were analyzed by immunofluorescence.A COPD model was established in C57BL/6 mice through smoke exposure combined with LPS tracheal administration, followed by selegiline or 5-HIAA treatment. Post-intervention, lung function tests and sample collection were performed. The levels of 5-HIAA, ROS‌, NET‌, IL-6‌, and AHR ‌in the samples were quantified by ELISA, pathological changes were assessed by HE staining, and NET/AHR expression was detected by immunofluorescence. 5-HIAA promoted NET production <i>in vitro</i>, and the nuclei of neutrophils secreting NET-like structures express AHR. In animal experiments, 5-HIAA levels were higher in both the plasma and lung tissues of COPD mice compared with normal mice. Inhibition of 5-HIAA in COPD mice down-regulated AHR expression, reduced reactive oxygen species and NET generation, elevated lung function indices (FEV0.1, FVC, PEF, and FEV0.1/FVC), decreased interleukin-6 levels, and improved lung tissue condition. Inhibiting 5-HIAA reduces NET generation, thereby improving lung conditions in COPD mice, which is associated with the 5-HIAA/AHR pathway.