Journal Article

Assessment of the Therapeutic Potential of Enhancer of Zeste Homolog 2 Inhibition in a Murine Model of Bronchiolitis Obliterans Syndrome

Matsudo, Kyoto, Yoshizumi, Tomoharu, Kohno, Mikihiro, Hashinokuchi, Asato, Takamori, Shinkichi, Toyokawa, Gouji, Shimokawa, Mototsugu, Nagano, Taichi, Akamine, Takaki, Kinoshita, Fumihiko, Takenaka, Tomoyoshi

2024

Overview

Bronchiolitis obliterans syndrome (BOS) is a chronic complication following lung transplantation that limits the long-term survival. Although the enhancer of zeste homolog 2 (EZH2) is involved in post-transplantation rejection, its involvement in BOS pathogenesis remains unclear. We aimed to investigate the therapeutic potential of EZH2 inhibition in BOS. 3-deazaneplanocin A (DZNep) was administered intraperitoneally to heterotopic tracheal transplant recipient model mice. Tracheal allografts were obtained on days 7, 14, 21, and 28 after transplantation. The obstruction ratios of the DZNep and control groups on days 7, 14, 21, and 28 were 15.1% ± 0.8% vs. 20.4% ± 3.6% ( p = 0.996), 16.9% ± 2.1% vs. 67.7% ± 11.5% ( p < 0.001), 47.8% ± 7.8% vs. 92.2% ± 5.4% ( p < 0.001), and 60.0% ± 9.6% vs. 95.0% ± 2.3% ( p < 0.001), respectively. The levels of interleukin (IL)-6 and interferon-γ on day 7 and those of IL-2, tumor necrosis factor, and IL-17A on days 14, 21, and 28 were significantly reduced following DZNep treatment. DZNep significantly decreased the number of infiltrating T-cells on day 14. In conclusion, DZNep-mediated EZH2 inhibition suppressed the inflammatory reactions driven by pro-inflammatory cytokines and T cell infiltration, thereby alleviating BOS symptoms.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: 3-deazaneplanocin A / Adenosine - analogs & derivatives / Animal models / Animals / Bronchiolitis obliterans / Bronchiolitis Obliterans - drug therapy / Bronchiolitis Obliterans Syndrome / Bronchopneumonia / chronic lung allograft dysfunction / Cytokines / Cytokines - metabolism / Disease Models, Animal / enhancer of zeste homolog 2 / Enhancer of Zeste Homolog 2 Protein - antagonists & inhibitors / Graft rejection / Inflammation / Interleukin-17 - metabolism / Laboratory animals / lung transplantation / Lung Transplantation - adverse effects / Lymphocytes / Lymphocytes T / Male / Metastases / Mice / Mice, Inbred BALB C / Mice, Inbred C57BL / Pathogenesis / Proteins / Transplantation / Transplants & implants / Tumor necrosis factor-TNF / γ-Interferon