神经周围的肥大细胞在胰腺癌和慢性胰腺炎的胰腺神经炎症和神经性疼痛中特异性富集。
Perineural mast cells are specifically enriched in pancreatic neuritis and neuropathic pain in pancreatic cancer and chronic pancreatitis.
机构信息
Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
出版信息
PLoS One. 2013;8(3):e60529. doi: 10.1371/journal.pone.0060529. Epub 2013 Mar 28.
BACKGROUND
Pancreatic neuritis is a histopathological hallmark of pancreatic neuropathy and correlates to abdominal neuropathic pain sensation in pancreatic adenocarcinoma (PCa) and chronic pancreatitis (CP). However, inflammatory cell subtypes that compose pancreatic neuritis and their correlation to the neuropathic pain syndrome in PCa and CP are yet unknown.
METHODS
Inflammatory cells within pancreatic neuritis lesions of patients with PCa (n = 20) and CP (n = 20) were immunolabeled and colorimetrically quantified with the pan-leukocyte marker CD45, with CD68 (macrophages), CD8 (cytotoxic T-lymphocytes), CD4 (T-helper cells), CD20 (B-lymphocytes), NCL-PC (plasma cells), neutrophil elastase, PRG2 (eosinophils), anti-mast cell (MC) tryptase and correlated to pain sensation. Perineural mast cell subtypes were analyzed by double immunolabeling with MC chymase. Expression and neural immunoreactivity of protease-activated receptor type 1 (PAR-1) and type 2 (PAR-2) were analyzed in PCa and CP and correlated to pain status of the patients.
RESULTS
In PCa and CP, nerves were predominantly infiltrated by cytotoxic T-lymphocytes (PCa: 35% of all perineural inflammatory cells, CP: 33%), macrophages (PCa: 39%, CP: 33%) and MC (PCa: 21%, CP: 27%). In both entities, neuropathic pain sensation was associated with a specific increase of perineural MC (PCa without pain: 14% vs. PCa with pain: 31%; CP without pain: 19% vs. CP with pain: 34%), not affecting the frequency of other inflammatory cell subtypes. The vast majority of these MC contained MC chymase. PAR-1 and PAR-2 expression did not correlate to the pain sensation of PCa and CP patients.
CONCLUSION
Pancreatic neuritis in PC and CP is composed of cytotoxic T-lymphocytes, macrophages and MC. The specific enrichment of MC around intrapancreatic nerves in neuropathic pain due to PCa and CP suggests the presence of MC-induced visceral hypersensitivity in the pancreas. Therefore, pancreatic and enteric neuropathies seem to share a similar type of neuro-immune interaction in the generation of visceral pain.
背景
胰腺神经炎症是胰腺神经病变的组织病理学标志，与胰腺腺癌（PCa）和慢性胰腺炎（CP）的腹部神经性疼痛感觉相关。然而，组成胰腺神经炎症的炎症细胞亚型及其与 PCa 和 CP 中的神经性疼痛综合征的相关性尚不清楚。
方法
用白细胞标志物 CD45 对 PCa（n=20）和 CP（n=20）患者胰腺神经炎症病变中的炎症细胞进行免疫标记，并进行比色定量，用 CD68（巨噬细胞）、CD8（细胞毒性 T 淋巴细胞）、CD4（辅助性 T 细胞）、CD20（B 淋巴细胞）、NCL-PC（浆细胞）、中性粒细胞弹性蛋白酶、PRG2（嗜酸性粒细胞）、抗肥大细胞（MC）类胰蛋白酶进行标记，并与疼痛感觉相关联。通过 MC 糜蛋白酶的双重免疫标记分析神经周围肥大细胞亚型。分析 PCa 和 CP 中蛋白酶激活受体 1（PAR-1）和 2（PAR-2）的表达和神经免疫反应性，并与患者的疼痛状况相关联。
结果
在 PCa 和 CP 中，神经主要被细胞毒性 T 淋巴细胞（PCa：所有神经周围炎症细胞的 35%，CP：33%）、巨噬细胞（PCa：39%，CP：33%）和 MC（PCa：21%，CP：27%）浸润。在这两种实体中，神经性疼痛感觉与神经周围 MC 的特定增加相关（PCa 无疼痛：14% vs. PCa 有疼痛：31%；CP 无疼痛：19% vs. CP 有疼痛：34%），但不影响其他炎症细胞亚型的频率。这些 MC 中的绝大多数含有 MC 糜蛋白酶。PAR-1 和 PAR-2 的表达与 PCa 和 CP 患者的疼痛感觉无关。
结论
PCa 和 CP 中的胰腺神经炎症由细胞毒性 T 淋巴细胞、巨噬细胞和 MC 组成。由于 PCa 和 CP 导致的胰腺神经性疼痛中 MC 特异性地围绕着胰腺内神经富集，提示存在 MC 诱导的胰腺内脏敏感性。因此，胰腺和肠神经病变似乎在产生内脏疼痛方面具有相似类型的神经免疫相互作用。
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