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

Growing evidence indicates that dysregulated iron metabolism with altered and excess iron availability in some body compartments plays a significant role in the course of infection and sepsis in humans. Given that all bacterial pathogens require iron for growth, that iron withdrawal is a normal component of innate host defenses and that bacterial pathogens have acquired increasing levels of antibiotic resistance, targeting infection and sepsis through use of appropriate iron chelators has potential to provide new therapeutics. We have directly compared the effects of three Food and Drug Administration (FDA)-approved chelators (deferoxamine-DFO; deferiprone-DFP; and deferasirox-DFX), as were developed for treating hematological iron overload conditions, to DIBI, a novel purpose-designed, anti-infective and anti-inflammatory water-soluble hydroxypyridinone containing iron-selective copolymers. Two murine sepsis models, endotoxemia and polymicrobial abdominal sepsis, were utilized to help differentiate anti-inflammatory versus anti-infective activities of the chelators. Leukocyte adhesion, as measured by intravital microscopy, was observed in both models, with DIBI providing the most effective reduction and DFX the poorest. Inflammation in the abdominal sepsis model, assessed by cytokine measurements, indicated exacerbation by DFX and DFO for plasma Interleukin (IL)-6 and reductions to near-control levels for DIBI and DFP. Peritoneal infection burden was reduced 10-fold by DIBI while DFX and DFP provided no reductions. Overall, the results, together with those from other studies, revealed serious limitations for each of the three hematological chelators, i.e., as potentially repurposed for treating infection/sepsis. In contrast, DIBI provided therapeutic benefits, consistent with various in vitro and in vivo results from other studies, supporting the potential for its use in treating sepsis.

The novel iron chelator, DIBI, attenuates inflammation and improves outcome in colon ascendens stent peritonitis-induced experimental sepsis.

BACKGROUND: Sepsis is the result of a dysregulated host immune response to an infection. An ideal therapy would target both the underlying infection and the dysregulated immune response. DIBI, a novel iron-binding polymer, was specifically developed as an antimicrobial agent and has also demonstrated in vivo anti-inflammatory properties. OBJECTIVE: This study aimed to further investigate the effects of DIBI with and without the antibiotic imipenem (IMI) in colon ascendens stent peritonitis (CASP)-induced experimental sepsis. METHODS: Vehicle, DIBI and/or IMI were administered in C57BL/6 mice after CASP surgery. Intestinal leukocyte activation and capillary perfusion was evaluated by intravital microscopy. Moreover, bacterial load in peritoneal lavage fluid and blood, and plasma cytokine levels were assessed. In a second series of experiments, surgery to repair the colon was performed at 5 hr and these mice were followed for long-term survival over 7 days. RESULTS: DIBI reduced leukocyte adhesion, improved capillary blood flow, and decreased key plasma cytokines levels. DIBI also improved survival of infected mice and greatly improved IMI efficacy. Survivors treated with IMI and DIBI were found to be free of systemic infection. CONCLUSIONS: DIBI has promising potential for sepsis treatment including its use as a sole or an adjunct therapeutic with antibiotics.

Immune response to systemic inflammation in the intestinal microcirculation.

Systemic inflammation is characterized by acute or chronic dysregulation of the host immune response. The intestine plays an important role in systemic inflammation. Disturbances in the intestinal microcirculation due to infiltration of immune cells during systemic inflammation can increase bacterial translocation from the gut to the circulation and aggravate the pathological condition. Therefore, the intestinal microcirculation is relevant with respect to two aspects - as pathophysiological trigger and therapeutic target in systemic inflammation. Experimental intravital microscopy represents a unique method to study the immune response in organs and tissues in vivo. Novel non-invasive imaging technologies facilitate the examination of the human microcirculation. Future developments are needed to miniaturize the imaging technologies and automate the time-consuming analyses of the in vivo data in order to make the intestinal microcirculation accessible for routine diagnostics and therapeutic monitoring.

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

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.

Iron chelation as novel treatment for lung inflammation in cystic fibrosis.

Cystic fibrosis (CF) is an autosomal recessive genetic disorder that results in defective cystic fibrosis transmembrane conductance regulator (CFTR) protein expression and function in various tissues. The leading cause of CF mortality and morbidity is the progressive destruction of the lungs due to recurrent infections and chronic inflammation. CFTR defect also affects immune cells, including neutrophils, resulting in ineffective, severe and persistent inflammatory response. Since unopposed recruitment of neutrophils significantly contributes to lung tissue damage through the generation of reactive oxygen species (ROS), we hypothesize that the administration of iron chelators could serve as a novel treatment to attenuate chronic inflammation in CF lungs since iron is significantly involved in ROS production by neutrophils. Ideally, the iron chelator should sequester host iron effectively, prevent bacterial access to chelator-bound iron and penetrates lung tissues efficiently, e.g. by inhalational route of administration.