Thorburn Taylor, Aali Maral, Kostek Lisanne, LeTourneau-Paci Chloe, Colp Patricia, Zhou Juan, Holbein Bruce, Hoskin David, Lehmann Christian
Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada.
Department of Anesthesia, Pain Management and Perioperative Medicine, Dalhousie University, Halifax, NS, Canada.
Clin Hemorheol Microcirc. 2017;67(3-4):241-250. doi: 10.3233/CH-179205.
Iron catalyzes the generation of reactive oxygen species (ROS) as part of the innate antimicrobial defense. During sepsis, the dysregulated systemic inflammatory response to infection, iron homeostasis becomes disrupted, generating an excess of ROS causing damage to tissues. This can be potentially suppressed using iron chelators that selectively bind iron to prevent its participation in ROS-related inflammatory reactions.
We hypothesize that administration of DIBI, a novel iron-chelator, attenuates the dysregulated systemic immune response and reduces tissue damage in experimental endotoxemia.
Five groups of animals (n = 5-10) were included in this study: control, untreated endotoxemia, and endotoxemia animals treated with either DIBI-A, MAHMP, or DIBI-B. Intravital microscopy was performed on the intestine of anesthesized mice to observe leukocyte endothelial interactions and evaluate the intestinal microcirculation.
Treatment of endotoxemic mice with DIBI-B reduced the number of adhering leukocytes in submucosal collecting (V1) venules by 68%. DIBI-B, MAHMP, and DIBI-A were able to restore functional capillary density (FCD) in the intestinal muscle layer by 74%, 44%, and 11%, respectively.
DIBI-B reduces leukocyte recruitment and improves FCD in experimental endotoxemia, outperforming other chelators tested. These findings suggest a potential role for DIBI-B as a candidate drug for sepsis treatment.
铁催化活性氧（ROS）的生成，这是固有抗菌防御的一部分。在脓毒症期间，对感染的全身炎症反应失调，铁稳态被破坏，产生过量的ROS，导致组织损伤。使用选择性结合铁以防止其参与ROS相关炎症反应的铁螯合剂可能会抑制这种情况。
我们假设新型铁螯合剂DIBI的给药可减轻实验性内毒素血症中失调的全身免疫反应并减少组织损伤。
本研究纳入五组动物（n = 5 - 10）：对照组、未治疗的内毒素血症组以及用DIBI - A、MAHMP或DIBI - B治疗的内毒素血症动物组。对麻醉小鼠的肠道进行活体显微镜检查，以观察白细胞与内皮细胞的相互作用并评估肠道微循环。
用DIBI - B治疗内毒素血症小鼠可使黏膜下集合（V1）小静脉中黏附白细胞的数量减少68%。DIBI - B、MAHMP和DIBI - A分别能够使肠肌层的功能性毛细血管密度（FCD）恢复74%、4%和11%。
在实验性内毒素血症中，DIBI - B可减少白细胞募集并改善FCD，其效果优于其他测试的螯合剂。这些发现表明DIBI - B作为脓毒症治疗候选药物具有潜在作用。
