Becker Felix, Potepalov Sergey, Shehzahdi Romana, Bernas Michael, Witte Marlys, Abreo Fleurette, Traylor James, Orr Wayne A, Tsunoda Ikuo, Alexander Jonathan Steven
*Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center Shreveport, Shreveport, Louisiana; †Department for General and Visceral Surgery, University of Münster, Münster, Germany; ‡Department of Medicine, Louisiana State University Health Sciences Center Shreveport, Shreveport, Louisiana; §Department of Surgery, University of Arizona, Tucson, Arizona; Departments of ‖Pathology, ¶Cellular Biology and Anatomy, and **Microbiology and Immunology, Louisiana State University Health Sciences Center Shreveport, Shreveport, Louisiana.
Inflamm Bowel Dis. 2015 Jun;21(6):1282-96. doi: 10.1097/MIB.0000000000000371.
Although inflammation-induced expansion of the intestinal lymphatic vasculature (lymphangiogenesis) is known to be a crucial event in limiting inflammatory processes, through clearance of interstitial fluid and immune cells, considerably less is known about the impact of an impaired lymphatic clearance function (as seen in inflammatory bowel diseases) on this cascade. We aimed to investigate whether the impaired intestinal lymphatic drainage function observed in FoxC2 mice would influence the course of disease in a model of experimental colitis.
Acute dextran sodium sulfate colitis was induced in wild-type and haploinsufficient FoxC2 mice, and survival, disease activity, colonic histopathological injury, neutrophil, T-cell, and macrophage infiltration were evaluated. Functional and structural changes in the intestinal lymphatic vessel network were analyzed, including submucosal edema, vessel morphology, and lymphatic vessel density.
We found that FoxC2 downregulation in FoxC2 mice significantly increased the severity and susceptibility to experimental colitis, as displayed by lower survival rates, increased disease activity, greater histopathological injury, and elevated colonic neutrophil, T-cell, and macrophage infiltration. These findings were accompanied by structural (dilated torturous lymphatic vessels) and functional (greater submucosal edema, higher immune cell burden) changes in the intestinal lymphatic vasculature.
These results indicate that sufficient lymphatic clearance plays a crucial role in limiting the initiation and perpetuation of experimental colitis and those disturbances in the integrity of the intestinal lymphatic vessel network could intensify intestinal inflammation. Future therapies might be able to exploit these processes to restore and maintain adequate lymphatic clearance function in inflammatory bowel disease.
尽管已知炎症诱导的肠道淋巴管系统扩张（淋巴管生成）是限制炎症过程的关键事件，可通过清除组织间液和免疫细胞来实现，但对于淋巴清除功能受损（如在炎症性肠病中所见）对这一过程的影响却知之甚少。我们旨在研究在FoxC2小鼠中观察到的肠道淋巴引流功能受损是否会影响实验性结肠炎模型中的疾病进程。
在野生型和单倍体不足的FoxC2小鼠中诱导急性葡聚糖硫酸钠结肠炎，并评估生存率、疾病活动度、结肠组织病理学损伤、中性粒细胞、T细胞和巨噬细胞浸润情况。分析肠道淋巴管网络的功能和结构变化，包括黏膜下水肿、血管形态和淋巴管密度。
我们发现，FoxC2小鼠中FoxC2的下调显著增加了实验性结肠炎的严重程度和易感性，表现为生存率降低、疾病活动度增加、组织病理学损伤加重以及结肠中性粒细胞、T细胞和巨噬细胞浸润增加。这些发现伴随着肠道淋巴管系统的结构（扩张迂曲的淋巴管）和功能（更大的黏膜下水肿、更高的免疫细胞负荷）变化。
这些结果表明，充足的淋巴清除在限制实验性结肠炎的起始和持续方面起着关键作用，肠道淋巴管网络完整性的紊乱可能会加剧肠道炎症。未来的治疗方法或许能够利用这些过程来恢复和维持炎症性肠病中足够的淋巴清除功能。
