Anti-Inflammatory Effects of the Iron Chelator, DIBI, in Experimental Acute Lung Injury

Abstract

Iron plays a critical role in the immune response to inflammation and infection due to its role in the catalysis of reactive oxygen species (ROS) through the Haber-Weiss and Fenton reactions. However, ROS overproduction can be harmful and damage healthy cells. Therefore, iron chelation represents an innovative pharmacological approach to limit excess ROS formation and the related pro-inflammatory mediator cascades. The present study was designed to investigate the impact of the iron chelator, DIBI, in an experimental model of LPS-induced acute lung injury (ALI). DIBI was administered intraperitoneally in the early and later stages of lung inflammation as determined by histopathological evaluation. We found that lung tissues showed significant injury, as well as increased NF-κB p65 activation and significantly elevated levels of various inflammatory mediators (LIX, CXCL2, CCL5, CXCL10, IL-1𝛽, IL-6) 4 h post ALI induction by LPS. Mice treated with DIBI (80 mg/kg) in the early stages (0 to 2 h) after LPS administration demonstrated a significant reduction of the histopathological damage score, reduced levels of NF-κB p65 activation, and reduced levels of inflammatory mediators. Intravital microscopy of the pulmonary microcirculation also showed a reduced number of adhering leukocytes and improved capillary perfusion with DIBI administration. Our findings support the conclusion that the iron chelator, DIBI, has beneficial anti-inflammatory effects in experimental ALI.

Selective CB2 Receptor Agonist, HU-308, Reduces Systemic Inflammation in Endotoxin Model of Pneumonia-Induced Acute Lung Injury

“…We observed a significant increase in lung histopathology injury scores following intranasal administration of LPS from P. aeruginosa at 4 and 6 h post-induction. Similar timepoints have been demonstrated in previous studies employing LPS from common respiratory pathogens, P. aeruginosa and E. coli [ 30 , 31 ]. Notably, intranasal saline administration was associated with a minor increase in lung histopathology vs. naïve ( Figure S1 ).…”

Sea Cucumber and Blueberry Extracts Suppress Inflammation and Reduce Acute Lung Injury through the Regulation of NF-κB/MAPK/JNK Signaling Pathway in Lipopolysaccharide-Treated C57BL/6 Mice

“…Life-threatening systemic inflammation (cytokine storm) can be triggered by various pathological conditions [39,40]. We used LPS to induce ALI in C57BL/6 mice.…”

“…C57BL/6 mice were challenged with 5 mg/kg lipopolysaccharide (LPS) via intranasal instillation to induce experimental ALI [40]. Briefly, the mice were anesthetized using 5% isoflurane in the presence of oxygen.…”

“…The duration for the extract administration was based on the modification of previous studies [75,76]. Six hours after LPS instillation [40], behavioral assessment was conducted, including the mobility score and body weight. The combination of C. frondosa extract and V. angustifolium extract was based on the Chou-Talalay isobologram combination method [77] where synergism was achieved at SC + WB; 25: 100 µg/mL ratio.…”

Iron Chelation as a Potential Therapeutic Approach in Acute Lung Injury

“…In addition, compared to conventional iron chelators, DIBI has a low toxicity profile and has been extensively studied for a wide variety of iron chelation applications [ 90 , 91 , 92 , 93 , 94 ]. Our group has recently reported that through binding to extracellular iron and reducing overall iron bioavailability, DIBI administration significantly attenuated LPS-induced tissue damage, inhibited inflammatory mediator release, and improved microcirculation in ALI [ 95 ]. Experimental studies utilizing iron chelators in ALI are shown in Table 1 .…”