Anti-inflammatory effects of a novel iron chelator, DIBI, in experimental sepsis

Issue title: Selected papers of the 36th Conference of the German Society for Clinical Microcirculation and Hemorheology, 5–8. June, 2017, Greifswald, Germany

Guest editors: M. Jünger, A. Krüger-Genge and F. Jung

Article type: Research Article

Authors: Thorburn, Taylor^{a; c} | Aali, Maral^{b; c} | Kostek, Lisanne^c | LeTourneau-Paci, Chloe^a | Colp, Patricia^d | Zhou, Juan^{a; c} | Holbein, Bruce^{a; e} | Hoskin, David^a | Lehmann, Christian^{a; b; c; *}

Affiliations: [a] Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada | [b] Department of Physiology and Biophysics, Dalhousie University, Halifax, NS, Canada | [c] Department of Anesthesia, Pain Management and Perioperative Medicine, Dalhousie University, Halifax, NS, Canada | [d] Department of Pathology, Dalhousie University, Halifax, NS, Canada | [e] Chelation Partners Inc., Halifax, NS, Canada

Correspondence: [*] Corresponding author: Dr. Christian Lehmann, MD, PhD, FRCPC, Department of Anesthesia, Pain Management and Perioperative Medicine, 5850 College Street, B3H 1X5, Halifax, NS, Canada. Tel.: +1 902 473 2331; Fax: +1 902 423 9454; E-mail: [email protected].

Abstract: BACKGROUND: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. OBJECTIVE:We hypothesize that administration of DIBI, a novel iron-chelator, attenuates the dysregulated systemic immune response and reduces tissue damage in experimental endotoxemia. METHODS: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. RESULTS: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. CONCLUSIONS: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.

Keywords: Intravital microscopy, leukocyte adhesion, functional capillary density (FCD), microcirculation, inflammation, iron chelation, endotoxemia

DOI: 10.3233/CH-179205

Journal: Clinical Hemorheology and Microcirculation, vol. 67, no. 3-4, pp. 241-250, 2017