Data for Fig 2 from Novel elucidation and treatment of pancreatic chronic graft-versus-host disease in mice

Chronic graft-versus-host disease (cGVHD) is a severe complication of allogeneic haematopoietic stem cell transplantation. There is a growing understanding of cGVHD, and several effective therapies for cGVHD have been reported. However, pancreatic cGVHD is a potentially untapped study field. Our thought-provoking study using a mouse model of cGVHD suggested that the pancreas could be impaired by cGVHD-induced inflammation and fibrosis and that endoplasmic reticulum (ER) stress was augmented in the pancreas affected by cGVHD. These findings urged us to treat pancreatic cGVHD through reduction of ER stress, and we used 4-phenylbutyric acid (PBA) as an ER stress reducer. A series of experiments have indicated that PBA can suppress cGVHD-elicited ER stress in the pancreas and accordingly alleviate pancreatic cGVHD. Furthermore, we focused on a correlation between epithelial to mesenchymal transition (EMT) and fibrosis in the cGVHD-affected pancreas, because EMT was conceivably implicated in various fibrosis-associated diseases. Our investigation has suggested that the expression of EMT markers was increased in the cGVHD-disordered pancreas and that it could be reduced by PBA. Taken together, we have provided a clue to elucidate the pathogenic process of pancreatic cGVHD and created a potentially effective treatment of this disease using the ER stress alleviator PBA.

慢性移植物抗宿主病（Chronic graft-versus-host disease，cGVHD）是异基因造血干细胞移植（allogeneic haematopoietic stem cell transplantation）后的严重并发症。目前学界对cGVHD的认知正逐步深化，已有多项针对该病的有效治疗方案被报道。然而，胰腺型慢性移植物抗宿主病仍是一个尚未得到充分探索的研究领域。本研究依托cGVHD小鼠模型开展实验，结果提示cGVHD诱导的炎症与纤维化可损伤胰腺组织，且受累胰腺内的内质网应激（endoplasmic reticulum stress，ER stress）水平显著上调。上述发现促使我们尝试通过缓解内质网应激干预胰腺cGVHD，并选用4-苯基丁酸（4-phenylbutyric acid，PBA）作为内质网应激调节剂。一系列实验结果证实，PBA可抑制cGVHD诱导的胰腺内质网应激，进而减轻胰腺cGVHD病变。此外，鉴于上皮间质转化（epithelial to mesenchymal transition，EMT）在多种纤维化相关疾病中被证实具有关键作用，我们重点探究了cGVHD受累胰腺中上皮间质转化与纤维化的相关性。研究发现，cGVHD损伤的胰腺组织中上皮间质转化标志物的表达水平显著升高，且该升高效应可被PBA有效抑制。综上，本研究为阐明胰腺型慢性移植物抗宿主病的致病进程提供了新的线索，并为使用内质网应激缓解剂PBA治疗该病提供了潜在的有效策略。