Mechanism of SLC15A3 Regulating Macrophage Oxidative Stress in the Pathogenesis of Traumatic Tracheal Stenosis.

BACKGROUND: Studies have shown that upregulation of Solute carrier family 15 member 3 (SLC15A3, PHT2) on the surface of macrophages can suppress the activation of the Sequestosome 1 (p62)-Nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant stress pathway, thereby facilitating the progression of pulmonary fibrosis. However, the association between SLC15A3 and traumatic tracheal stenosis (TS)-hereafter referred to as TS-remains unclear. METHODS: This study detected and analyzed relevant indicators via three approaches: clinical specimens were used to assess target indicators; for in vitro experiments, human THP-1 cells were induced to differentiate into M2 macrophages using phorbol 12-myristate 13-acetate (PMA) combined with interleukin-4 (IL-4) and interleukin-13 (IL-13), and after inducing oxidative stress with hydrogen peroxide (H2O2), the M2 macrophages were co-cultured with tracheal fibroblasts; for in vivo experiments, Sprague-Dawley (SD) rats were randomly divided into four groups (Control, TS, Sh-NC+TS, and Sh-SLC15A3+TS), and the TS model was established by scraping the tracheal mucosa with a nylon brush to induce traumatic injury. RESULTS: Experimental analyses detected M2 macrophage accumulation in TS patients. We observed elevated expression of SLC15A3, collagen type I alpha 1 (COL1A1) and α-smooth muscle actin (α-SMA), alongside reduced levels of the antioxidant molecules p62, Nrf2 and superoxide dismutase 2 (SOD2). In vitro and in vivo data indicate a possible association between SLC15A3 knockdown, altered p62-Nrf2 pathway activity, attenuated inflammation and relieved tissue fibrosis, which might be relevant to alleviated airway stenosis severity. CONCLUSION: This study clarifies the regulatory role of SLC15A3 in the pathogenesis of TS, providing a novel potential therapeutic target for inhibiting tracheal fibrosis in clinical practice.