BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by persistent tissue remodeling, but the mechanisms underlying impaired fibrinolysis were not fully understood. SERPIN family B member 2 (SERPINB2/plasminogen activator inhibitor type 2 PAI-2) is a known inhibitor of tissue plasminogen activator (tPA). However, its role in CRSwNP pathogenesis remains unclear. This study investigated whether SERPINB2 contributes to fibrinolytic dysfunction in CRSwNP. METHODS: tPA and SERPINB2 expression levels were assessed in nasal polyp and control turbinate tissues using qRT-PCR, Western blot, and immunofluorescence. Primary human nasal epithelial cells were stimulated with IFN-γ, IL-13, or IL-17A to evaluate cytokine-mediated regulation. The direct effects of SERPINB2 on tPA expression were examined using recombinant protein treatment and siRNA-mediated knockdown. tPA enzymatic activity and fibrinolytic function were measured using a fluorometric substrate assay and D-dimer ELISA, respectively. RESULTS: tPA expression was significantly reduced in nasal polyp tissues compared to control turbinate and inversely correlated with SERPINB2 levels. Immunofluorescence analysis revealed decreased tPA-positive and increased SERPINB2-positive cells in the nasal epithelium. Both the Th1 cytokine IFN-γ and the Th2 cytokine IL-13 downregulated tPA while upregulating SERPINB2 in primary nasal epithelial cells, whereas IL-17A showed no significant effect. Notably, recombinant SERPINB2 dose-dependently suppressed epithelial tPA expression, while SERPINB2 knockdown rescued cytokine-induced tPA downregulation. Functionally, SERPINB2 inhibited tPA enzymatic activity in a dose-dependent manner and significantly impaired fibrinolytic function. CONCLUSIONS: This study identifies a novel SERPINB2-tPA regulatory axis in nasal epithelial cells. The convergent regulation by both Th1 and Th2 cytokines suggests that fibrinolytic dysfunction occurs across different CRSwNP inflammatory endotypes. These findings provide mechanistic insights into fibrin accumulation in nasal polyps and identify SERPINB2 as a potential therapeutic target for the prevention of polyp formation and recurrence.
Zhu et al. (Thu,) studied this question.