Abstract：
BACKGROUND: The natural history and pathophysiology of diverticular disease (DD) are still uncertain. An ex-vivo human complicated DD (cDD) model has recently shown a predominant transmural oxidative imbalance. The present study aims to evaluate whether the previously described alterations may precede the symptomatic form of the disease.
METHODS: Colonic surgical samples obtained from patients with asymptomatic diverticulosis (DIV), complicated DD, and controls were systematically and detailed morphologically and molecularly analyzed. Therefore, histologic, histomorphometric, immunohistochemical evaluation, and gene and protein expression analysis were performed to characterize colonic muscle changes and evaluate chronic inflammation, oxidative imbalance, and hypoxia. Functional muscle activity was tested on strips and isolated cells in response to contractile and relaxant agents.
RESULTS: Compared with controls, DD showed a marketed increase in muscle layer thickness, smooth muscle cell syncytium disarray, and increased interstitial fibrosis; moreover, the observed features were more evident in the cDD group. These changes mainly affected longitudinal muscle and were associated with altered contraction-relaxation dynamics and fibrogenic switch of smooth muscle cells. Chronic lymphoplasmacytic inflammation was primarily evident in the mucosa and spared the muscle. A transmural increase in carbonylated and nitrated proteins, with loss of antioxidant molecules, characterized both stages of DD, suggesting early oxidative stress probably triggered by recurrent ischemic events, more pronounced in cDD, where HIF-1 was detected in both muscle and mucosa.
CONCLUSIONS: The different DD clinical scenarios are part of a progressive process, with oxidative imbalance representing a new target in the management of DD.
METHODS: Colonic surgical samples obtained from patients with asymptomatic diverticulosis (DIV), complicated DD, and controls were systematically and detailed morphologically and molecularly analyzed. Therefore, histologic, histomorphometric, immunohistochemical evaluation, and gene and protein expression analysis were performed to characterize colonic muscle changes and evaluate chronic inflammation, oxidative imbalance, and hypoxia. Functional muscle activity was tested on strips and isolated cells in response to contractile and relaxant agents.
RESULTS: Compared with controls, DD showed a marketed increase in muscle layer thickness, smooth muscle cell syncytium disarray, and increased interstitial fibrosis; moreover, the observed features were more evident in the cDD group. These changes mainly affected longitudinal muscle and were associated with altered contraction-relaxation dynamics and fibrogenic switch of smooth muscle cells. Chronic lymphoplasmacytic inflammation was primarily evident in the mucosa and spared the muscle. A transmural increase in carbonylated and nitrated proteins, with loss of antioxidant molecules, characterized both stages of DD, suggesting early oxidative stress probably triggered by recurrent ischemic events, more pronounced in cDD, where HIF-1 was detected in both muscle and mucosa.
CONCLUSIONS: The different DD clinical scenarios are part of a progressive process, with oxidative imbalance representing a new target in the management of DD.
摘要：
背景：憩室病（DD）的自然史和病理生理学仍不确定。离体人类复杂DD（cDD）模型最近显示出主要的透壁氧化失衡。本研究旨在评估先前描述的改变是否可能先于疾病的症状形式。
方法：从无症状憩室病（DIV）患者获得的结肠手术样本，复杂的DD，和对照进行了系统详细的形态学和分子分析。因此,组织学，组织形态计量学,免疫组织化学评估，和基因和蛋白质表达分析进行表征结肠肌肉变化和评估慢性炎症，氧化失衡，和缺氧。在条状和分离的细胞上测试了对收缩剂和松弛剂的反应的功能性肌肉活性。
结果：与对照组相比，DD显示肌肉层厚度的增加，平滑肌细胞合胞体紊乱，间质纤维化增加；此外，观察到的特征在cDD组中更为明显.这些变化主要影响纵向肌肉，并与平滑肌细胞的收缩-松弛动力学和纤维化转换有关。慢性淋巴浆细胞性炎症主要在粘膜中明显，并使肌肉幸免。羰基化和硝化蛋白的跨壁增加，随着抗氧化剂分子的损失，以DD的两个阶段为特征，提示早期氧化应激可能由复发性缺血事件引发，在cDD中更明显，其中在肌肉和粘膜中均检测到HIF-1。
结论：不同的DD临床情景是渐进过程的一部分，氧化失衡代表了DD管理的新目标。
方法：从无症状憩室病（DIV）患者获得的结肠手术样本，复杂的DD，和对照进行了系统详细的形态学和分子分析。因此,组织学，组织形态计量学,免疫组织化学评估，和基因和蛋白质表达分析进行表征结肠肌肉变化和评估慢性炎症，氧化失衡，和缺氧。在条状和分离的细胞上测试了对收缩剂和松弛剂的反应的功能性肌肉活性。
结果：与对照组相比，DD显示肌肉层厚度的增加，平滑肌细胞合胞体紊乱，间质纤维化增加；此外，观察到的特征在cDD组中更为明显.这些变化主要影响纵向肌肉，并与平滑肌细胞的收缩-松弛动力学和纤维化转换有关。慢性淋巴浆细胞性炎症主要在粘膜中明显，并使肌肉幸免。羰基化和硝化蛋白的跨壁增加，随着抗氧化剂分子的损失，以DD的两个阶段为特征，提示早期氧化应激可能由复发性缺血事件引发，在cDD中更明显，其中在肌肉和粘膜中均检测到HIF-1。
结论：不同的DD临床情景是渐进过程的一部分，氧化失衡代表了DD管理的新目标。
