[Xinfeng Capsule improves cardiopulmonary function of knee osteoarthritis rats by BTLA-HVEM signaling pathway to induce Treg immune tolerance].

Aim: To observe the effects of Xinfeng Capsule (XFC) on cardiopulmonary function of knee osteoarthritis (KOA) rats and explore its molecular mechanism.

Methods: Forty rats were randomly divided into normal control (NC) group, model control (MC) group, glucosamine control (GS) group and XFC group, 10 in each group. All rats were induced to KOA by injected papain and L-Cys into the right knee joint except NC group. Fourteen days after modeling, NC and MC groups were given normal saline (0.01 g/kg), GS and XFC groups were given glucosamine (0.098 g/kg) and XFC suspension (0.375 g/kg), respectively. Cardiac and pulmonary function were detected by ultrasonography and animal spirometry, respectively. B and T lymphocyte attenuator (BTLA), herpesvirus entry mediator (HVEM), interleukin (IL)-17, IL-4, transforming growth factor-beta (TGF-β1) were detected by ELISA; CD4(+);CD25(+);Treg and CD4(+); CD25(+);Foxp3(+); Treg were detected by flow cytometry.

Results: Compared with NC group, body mass, levels of early diastolic peak flow velocity (E), early diastolic peak flow velocity/atrial peak flow velocity (E/A), forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), 25% forced expiratory flow (FEF25), 50% forced expiratory flow (FEF50), 75% forced expiratory flow (FEF75), maximal mid-expiratory flow (MMF), peak expiratory flow (PEF), expressions of BTLA, HVEM, IL-4, CD4(+);CD25(+);Treg and CD4(+);CD25(+);Foxp3(+); Treg significantly decreased, and TGF-β1, IL-17 significantly increased in MC group (P<0.01 or P<0.05). Compared with MC group, weight, levels of E, E/A, FEV1, FEF50, FEF75, PEF, BTLA, HVEM, IL-4, CD4(+);CD25(+);Treg and CD4(+);CD25(+);Foxp3(+); Treg significantly increased, and Mankin score, cardiacindex (CI), lung index (LI), TGF-β1, IL-17 significantly decreased in GS and XFC groups (P<0.01 or P<0.05); Compared with GS group, weight and Treg were significantly elevated in XFC group (P<0.01 or P<0.05).

Conclusion: XFC can decrease Mankin scores of cartilage and improve cardiopulmonary function of KOA rats. Its mechanism may be enhancing BTLA-HVEM negative co-stimulatory signals, inducing Treg immune tolerance, up-regulating IL-4, down-regulating IL-17, TGF-β1, then to inhibit abnormal inflammatory immune response.