Altered Colonic Mucosal Polyunsaturated Fatty Acid (PUFA) Derived Lipid Mediators in Ulcerative Colitis: New Insight into Relationship with Disease Activity and Pathophysiology
Altered Colonic Mucosal Polyunsaturated Fatty Acid (PUFA) Derived Lipid Mediators in Ulcerative Colitis: New Insight into Relationship with Disease Activity and Pathophysiology
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DOI：
10.1371/journal.pone.0076532
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发表时间：
2013-10-18
期刊：
影响因子：
3.7
通讯作者：
Trebble, Timothy M.
中科院分区：
文献类型：
--
作者：
Masoodi, Mojgan;Pearl, Daniel S.;Trebble, Timothy M.
目的：溃疡性结肠炎（UC）是一种复发性炎症性疾病，病因尚未确认，严重程度和临床病程各不相同，其特征是进行性组织学炎症和类二十烷酸升高，类二十烷酸在炎症中具有已知的病理生理作用。靶向类二十烷酸（5-氨基水杨酸（阿萨））的治疗干预是轻中度UC的有效一线和连续治疗，可实现和维持临床缓解。然而，对5-阿萨的可变临床反应和对环氧合酶（考克斯）抑制剂的反应频繁恶化，促使对UC炎症环境中的多种脂质介质（包括类花生酸）进行深入的同时评价。我们假设，炎症的严重程度与脂质介质的改变，在复发性UC。设计：研究是病例对照设计。通过LC-MS/MS脂质组学分析从复发性UC门诊患者中采集的粘膜活检组织中确定粘液脂质介质。单变量和多变量统计分析用于研究粘膜脂质介质与疾病状态和严重程度分级的相关性。结果：PGE（2）、PGD（2）、TXB 2、5-HETE、11-HETE、12-HETE和15-HETE的水平在炎症粘膜中显著升高，并与炎症的严重程度相关，使用有效的组织学评分系统确定。我们通过结合全面的脂质组学分析和计算建模来捕获UC不同阶段的炎症介质特征的方法可用于分类和预测轻度-中度炎症;然而，预测指数在重度炎症中减少。这种新的技术方法可以根据粘膜脂质介质的特点，为活动性UC患者量身定制药物治疗。
Objectives: Ulcerative colitis (UC) is a relapsing inflammatory disorder of unconfirmed aetiology, variable severity and clinical course, characterised by progressive histological inflammation and with elevation of eicosanoids which have a known pathophysiological role in inflammation. Therapeutic interventions targetting eicosanoids (5-aminosalicylates (ASA)) are effective first line and adjunctive treatments in mild-moderate UC for achieving and sustaining clinical remission. However, the variable clinical response to 5-ASA and frequent deterioration in response to cyclo-oxygenase (COX) inhibitors, has prompted an in depth simultaneous evaluation of multiple lipid mediators (including eicosanoids) within the inflammatory milieu in UC. We hypothesised that severity of inflammation is associated with alteration of lipid mediators, in relapsing UC.Design: Study was case-control design. Mucosal lipid mediators were determined by LC-MS/MS lipidomics analysis on mucosal biopsies taken from patients attending outpatients with relapsing UC. Univariate and multivariate statistical analyses were used to investigate the association of mucosal lipid mediators, with the disease state and severity graded histologically.Results: Levels of PGE(2), PGD(2), TXB2, 5-HETE, 11-HETE, 12-HETE and 15-HETE are significantly elevated in inflamed mucosa and correlate with severity of inflammation, determined using validated histological scoring systems.Conclusions: Our approach of capturing inflammatory mediator signature at different stages of UC by combining comprehensive lipidomics analysis and computational modelling could be used to classify and predict mild-moderate inflammation; however, predictive index is diminished in severe inflammation. This new technical approach could be developed to tailor drug treatments to patients with active UC, based on the mucosal lipid mediator profile.