Thrombin and activated coagulation factor X stimulate the release of cytokines and fibronectin from nasal polyp fibroblasts via protease-activated receptors.

Abstract

Nasal epithelial cells and infiltrating eosinophils express tissue factor, and high thrombin activity and excess fibrin deposition are found in nasal secretion and in nasal polyp from patients with chronic rhinosinusitis with nasal polyp (CRSwNP). Activated coagulation factors play important roles not only in thrombosis but also in inflammation through interaction with protease-activated receptors (PAR). However, little is known about the effects of activated coagulation factors on the release of cytokines and extracellular matrix from nasal polyp fibroblasts (NPF). The purpose of this study was to analyze the expression of PARs, which are receptors for activated coagulation factors, on NPFs and to determine the roles of thrombin and activated coagulation factor X (FXa) in the release of cytokines and fibronectin from NPFs. NPFs were obtained from patients with CRSwNP, and the messenger RNA (mRNA) and protein expression of PARs in these NPFs were examined. We then investigated whether thrombin or FXa stimulates the release of transforming growth factor (TGF) beta 1, fibronectin, eotaxin-1, interleukin (IL) 6, or IL-8 from cultured NPFs. The effects of PAR agonists on the release of cytokines and fibronectin were also examined. NPFs expressed the mRNA and proteins of all four PARs: PAR-1, PAR-2, PAR-3, and PAR-4. Both thrombin and FXa significantly stimulated the release of TGF beta 1, fibronectin, eotaxin-1, IL-6, and IL-8 from cultured NPFs. PAR-1 and PAR-2 agonists stimulated the secretion of TGF beta 1, fibronectin, eotaxin-1, IL-6, and IL-8. PAR-3 agonist stimulated the release of TGF beta 1, fibronectin, and eotaxin-1. PAR-4 agonist did not induce the release of these molecules. NPFs play important roles in the pathophysiology of CRSwNP such as in nasal polyp formation and inflammatory cell infiltration by releasing cytokines and extracellular matrix proteins. Activated coagulation factors, thrombin and FXa, stimulate the release of these cytokines and fibronectin from NPFs via PARs.