THE ROLE OF IRON CHELATION IN PULMONARY INFLAMMATION

Abstract

Iron plays a critical role in the human body, e.g., in hemoglobin and DNA synthesis, but it is also important in the regulation of the immune response. Iron’s role in the immune system is closely related to the catalysis of reactive oxygen species (ROS). ROS are needed to fight pathogens, but overproduction of ROS can kill healthy cells. Therefore, therapeutic iron chelation is a potential pharmacological approach to limit ROS formation and pro-inflammatory mediator release. The present research has been designed to study the impact of iron chelation by a novel, highly specific, synthetic iron chelator DIBI in an experimental model of lung inflammation in C57Bl/6 mice. First, we established a rodent lung inflammation model using intranasal instillation of LPS from Pseudomonas aeruginosa at different observation time points. The lung immune response was evaluated by histological analysis of lung tissue, NF-kB activation, and measurement of inflammatory cytokines and chemokines levels in plasma and lung tissues. Second, to assess the anti-inflammatory properties of DIBI, we administered DIBI intraperitoneally in the early and later stages of lung inflammation. We found that lung tissues showed significant histological injury and increased NF-𝜅B P65 activation, 4 hours post LPS administration at a sublethal dosage (5 mg/kg). We also measured a significant elevation of LIX, CXCL2, CCL5, CXCL10, IL-1𝛽, IL-6, and CXCL1 in the lung and CXCL2, CCL5, CXCL10, IL-6 and CXCL1 in the plasma relative to their respective control groups. Mice treated with DIBI (80 mg/kg) intraperitoneally in early stages (0 and 2 hours) after LPS-induced lung inflammation demonstrated a significant reduction of histopathological signs, reduced NF-𝜅B P65 activation, and reduced levels of inflammatory mediators. Our data support the conclusion that LIX, CXCL2 (MIP-2), CCL5, CXCL10 (IP-10), IL-1𝛽, IL-6, and CXCL1 (KC) play essential roles in our LPSinduced lung inflammation model. Moreover, we can conclude that DIBI administration represents a potential alternative treatment for pulmonary inflammation.