Section of Pulmonary Diseases, Department of Medicine, Tulane Eosinophilic Disorders Centre, Tulane University School of Medicine , New Orleans, Louisiana.
Am J Physiol Gastrointest Liver Physiol. 2018 Feb 1;314(2):G211-G222. doi: 10.1152/ajpgi.00210.2017. Epub 2017 Sep 21.
Eosinophilic pancreatitis (EP) is reported in humans; however, the etiology and role of eosinophils in EP pathogenesis are poorly understood and not well explored. Therefore, it is interesting to examine the role of eosinophils in the initiation and progression of pancreatitis pathogenesis. Accordingly, we performed anti-major basic protein immunostaining, chloroacetate esterase, and Masson's trichrome analyses to detect eosinophils, mast cells, and collagen in the tissue sections of mouse and human pancreas. Induced eosinophils accumulation and degranulation were observed in the tissue sections of human pancreatitis, compared with no eosinophils in the normal pancreatic tissue sections. Similarly, we observed induced tissue eosinophilia along with mast cells and acinar cells atrophy in cerulein-induced mouse model of chronic pancreatitis. Additionally, qPCR and ELISA analyses detected induced transcript and protein levels of proinflammatory and profibrotic cytokines, chemokines like IL 5, IL-18, eotaxin-1, eotaxin-2, TGF-β1, collagen-1, collagen-3, fibronectin, and α-SMA in experimental pancreatitis. Mechanistically, we show that eosinophil-deficient GATA1 and endogenous IL-5-deficient mice were protected from the induction of proinflammatory and profibrotic cytokines, chemokines, tissue eosinophilia, and mast cells in a cerulein-induced murine model of pancreatitis. These human and experimental data indicate that eosinophil accumulation and degranulation may have a critical role in promoting pancreatitis pathogenesis including fibrosis. Taken together, eosinophil tissue accumulation needs appropriate attention to understand and restrict the progression of pancreatitis pathogenesis in humans. NEW & NOTEWORTHY The present study for the first time shows that eosinophils accumulate in the pancreas and promote disease pathogenesis, including fibrosis in earlier reported cerulein-induced experimental models of pancreatitis. Importantly, we show that GATA-1 and IL-5 deficiency protects mice form the induction of eosinophil active chemokines, and profibrotic cytokines, including accumulation of tissue collagen in an experimental model of pancreatitis. Additionally, we state that cerulein-induced chronic pancreatitis is independent of blood eosinophilia.
嗜酸性粒细胞性胰腺炎 (EP) 在人类中已有报道；然而，嗜酸性粒细胞在 EP 发病机制中的病因和作用仍知之甚少，也未得到充分探索。因此，研究嗜酸性粒细胞在胰腺炎发病机制中的起始和进展中的作用很有意思。因此，我们对小鼠和人胰腺组织切片进行了抗主要碱性蛋白免疫染色、氯乙酸酯酶和 Masson 三色分析，以检测嗜酸性粒细胞、肥大细胞和胶原。与正常胰腺组织切片相比，在人类胰腺炎组织切片中观察到嗜酸性粒细胞的诱导积聚和脱颗粒。同样，我们在胆酸钠诱导的慢性胰腺炎小鼠模型中观察到诱导的组织嗜酸性粒细胞增多以及肥大细胞和腺泡细胞萎缩。此外，qPCR 和 ELISA 分析检测到实验性胰腺炎中促炎和促纤维化细胞因子、趋化因子（如 IL-5、IL-18、嗜酸粒细胞趋化因子-1、嗜酸粒细胞趋化因子-2、TGF-β1、胶原-1、胶原-3、纤维连接蛋白和α-SMA）的诱导转录和蛋白水平。从机制上讲，我们表明 GATA1 缺陷型和内源性 IL-5 缺陷型小鼠在胆酸钠诱导的小鼠胰腺炎模型中免受促炎和促纤维化细胞因子、趋化因子、组织嗜酸性粒细胞和肥大细胞的诱导。这些人类和实验数据表明，嗜酸性粒细胞积聚和脱颗粒可能在促进胰腺炎发病机制（包括纤维化）中具有关键作用。总之，嗜酸性粒细胞组织积聚需要适当关注，以了解和限制人类胰腺炎发病机制的进展。新的和值得注意的是：本研究首次表明，嗜酸性粒细胞在胰腺中积聚并促进疾病发病机制，包括在之前报道的胆酸钠诱导的实验性胰腺炎模型中纤维化。重要的是，我们表明 GATA-1 和 IL-5 缺陷可防止小鼠在实验性胰腺炎模型中诱导嗜酸性粒细胞活性趋化因子和促纤维化细胞因子，包括组织胶原的积累。此外，我们指出胆酸钠诱导的慢性胰腺炎与血液嗜酸性粒细胞增多无关。
