Iron Chelation in Murine Models of Systemic Inflammation Induced by Gram-Positive and Gram-Negative Toxins

Abstract

Iron is an essential element for various physiological processes, but its levels must remain tightly regulated to avoid cellular damage. Similarly, iron plays a dual role in systemic inflammation, such as with sepsis. Leukocytes utilize iron to produce reactive oxygen species (ROS) to kill bacteria, but pathologically increased iron-catalyzed ROS production in sepsis can lead to damage of host cells, multi-organ failure and death. Temporary reduction in bioavailable iron represents a potential therapeutic target in sepsis. This study investigates the effect of the novel iron chelator, DIBI, in murine models of systemic (hyper-)inflammation: C57BL/6 mice were challenged with toxins from Gram-positive (Staphylococcus aureus: lipoteichoic acid, peptidoglycan) and Gram-negative bacteria (Escherichia coli and Klebsiella pneumoniae: lipopolysaccharide). Intravital microscopy (IVM) was performed to assess immune cell activation and its impact on microvascular blood flow in vivo in the microcirculation of the gut. Plasma inflammatory mediators were measured via multiplex assay, and morphologic change in intestinal tissue was evaluated. DIBI treatment decreased leukocyte (hyper-)activation induced by Gram-positive and Gram-negative toxins. In some cases, it preserved capillary perfusion, reduced plasma inflammatory markers and attenuated tissue damage. These findings support the utility of DIBI as a novel treatment for systemic inflammation, e.g., sepsis.

Comparison of Treatment Effects of Different Iron Chelators in Experimental Models of Sepsis

“…Consistent with previous reports, LPS increased leukocyte adherence in intestinal submucosal venules [ 16 , 17 , 18 ]. LPS activates Toll-like receptor 4 (TLR4) and downstream inflammatory cascades that result in upregulation of adhesion molecule expression [ 19 ].…”

Recent Advances in Iron Chelation and Gallium-Based Therapies for Antibiotic Resistant Bacterial Infections

“…In addition to its antimicrobial activity, data from preclinical experimental models have indicated that DIBI has anti-inflammatory activity during sepsis [ 56 , 57 ]. Treatment with DIBI was able to reduce inflammation-associated markers (leukocyte activation, loss of capillary perfusion and tissue damage) after administration of lipotechoic acid from S. aureus and lipopolysaccharide from E. coli and K. pneumoniae [ 56 ].…”

“…In addition to its antimicrobial activity, data from preclinical experimental models have indicated that DIBI has anti-inflammatory activity during sepsis [ 56 , 57 ]. Treatment with DIBI was able to reduce inflammation-associated markers (leukocyte activation, loss of capillary perfusion and tissue damage) after administration of lipotechoic acid from S. aureus and lipopolysaccharide from E. coli and K. pneumoniae [ 56 ]. Although the molecular mechanisms underlying the anti-inflammatory activity observed with DIBI are not fully understood, it has been hypothesized that is may be due to reduced iron-catalyzed reactive oxygen species production by leukocytes during sepsis [ 56 , 57 ].…”

“…Treatment with DIBI was able to reduce inflammation-associated markers (leukocyte activation, loss of capillary perfusion and tissue damage) after administration of lipotechoic acid from S. aureus and lipopolysaccharide from E. coli and K. pneumoniae [ 56 ]. Although the molecular mechanisms underlying the anti-inflammatory activity observed with DIBI are not fully understood, it has been hypothesized that is may be due to reduced iron-catalyzed reactive oxygen species production by leukocytes during sepsis [ 56 , 57 ]. Taken together, these studies indicate that DIBI may be a promising antimicrobial compound.…”

Gram-Negative Bloodstream Infection: Implications of Antimicrobial Resistance on Clinical Outcomes and Therapy

“…Moreover, the authors describe two new multi-locus sequence typing (MLST)-based sequence types of K. pneumoniae [ 27 ]. In the second basic science article of this Special Issue, Fokam and colleagues examine iron chelation in murine models of systemic inflammation induced by Gram-positive and Gram-negative bacterial toxins [ 28 ]. This is a timely topic, given the recent development of cefiderocol, a novel antimicrobial agent for the treatment of Gram-negative bacteria with DTR that utilizes the iron transport system.…”