The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom.
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston MA 02115.
Proc Natl Acad Sci U S A. 2017 Apr 11;114(15):3963-3968. doi: 10.1073/pnas.1617290114. Epub 2017 Mar 29.
The resolution of inflammation is an active process orchestrated by specialized proresolving lipid mediators (SPM) that limit the host response within the affected tissue; failure of effective resolution may lead to tissue injury. Because persistence of inflammatory signals is a main feature of chronic inflammatory conditions, including inflammatory bowel diseases (IBDs), herein we investigate expression and functions of SPM in intestinal inflammation. Targeted liquid chromatography-tandem mass spectrometry-based metabololipidomics was used to identify SPMs from n-3 polyunsaturated fatty acids in human IBD colon biopsies, quantifying a significant up-regulation of the resolvin and protectin pathway compared with normal gut tissue. Systemic treatment with protectin (PD)1 or resolvin (Rv)D5 protected against colitis and intestinal ischemia/reperfusion-induced inflammation in mice. Inhibition of 15-lipoxygenase activity reduced PD1 and augmented intestinal inflammation in experimental colitis. Intravital microscopy of mouse mesenteric venules demonstrated that PD1 and RvD5 decreased the extent of leukocyte adhesion and emigration following ischemia-reperfusion. These data were translated by assessing human neutrophil-endothelial interactions under flow: PD1 and RvD5 reduced cell adhesion onto TNF-α-activated human endothelial monolayers. In conclusion, we propose that innovative therapies based on n-3 DPA-derived mediators could be developed to enable antiinflammatory and tissue protective effects in inflammatory pathologies of the gut.
炎症消退是由专门的促解决脂质介质（SPM）协调的主动过程，可限制受影响组织中的宿主反应；解决无效可能导致组织损伤。由于炎症信号的持续存在是包括炎症性肠病（IBD）在内的慢性炎症性疾病的主要特征，因此我们在此研究了 SPM 在肠道炎症中的表达和功能。基于靶向液相色谱-串联质谱的代谢脂质组学用于鉴定来自人 IBD 结肠活检组织中 n-3 多不饱和脂肪酸的 SPM，与正常肠道组织相比，发现 resolvin 和 protectin 途径的表达显著上调。系统给予保护素（PD）1 或 resolvin（Rv）D5 可预防小鼠结肠炎和肠缺血/再灌注引起的炎症。抑制 15-脂氧合酶活性可降低 PD1 并增强实验性结肠炎中的肠道炎症。对小鼠肠系膜静脉的活体显微镜检查表明，PD1 和 RvD5 可减少缺血再灌注后白细胞黏附和迁移的程度。通过在流动条件下评估人中性粒细胞-内皮细胞相互作用对这些数据进行了转化：PD1 和 RvD5 可减少细胞黏附到 TNF-α 激活的人内皮单层上。总之，我们提出可以开发基于 n-3 DPA 衍生介质的创新疗法，以在肠道炎症性疾病中发挥抗炎和组织保护作用。
