A novel role for lipocalin 2 in ozone driven susceptibility to bacterial pneumonia.

About This Grant

PROJECT SUMMARY/ABSTRACT Ground-level ozone (O3) exposure is a harmful air pollutant that exacerbates cardiopulmonary diseases resulting in increased morbidity and mortality. Epidemiological studies have reported that following elevations in ambient O3, hospitalizations due to community acquired pneumonia (CAP) are increased. As global O3 concentrations continue to rise, the importance of understanding how O3 exposure heightens susceptibility to respiratory infection is essential. One potential mechanism by which O3 promotes pulmonary inflammation and infection is through disruption of iron homeostasis. O3 exposure increases airspace concentrations of iron as well as transferrin and ferritin, two proteins involved in maintaining iron homeostasis. Preliminary data from our lab has recapitulated these findings, and identified that Lipocalin 2 (LCN2), a host-protein secreted to reduce bacterial iron uptake during infection, is also elevated in the airspace following acute O3 exposure. Although LCN2 is best characterized for its role following infection, recent studies have identified LCN2 as a modulator of inflammation throughout the body due to its involvement in anti-inflammatory signaling. Our preliminary data has discovered that O3-induced increases in lung injury and airspace inflammation are augmented in LCN2 deficient mice compared to wild type controls, identifying LCN2 as a potential modulator of O3-driven inflammation and injury. However, the role of LCN2 in the lungs following O3 exposure and subsequent infection has not been identified. Therefore, we hypothesize that LCN2 mitigates O3 induced susceptibility to bacterial pneumonia by sequestering excess airspace iron and maintaining lung epithelial cell barrier integrity. To test this hypothesis, we will: 1) Investigate how LCN2 mediated clearance of airspace iron following O3 inhalation decreases susceptibility to Klebsiella pneumoniae (Kp) infection, and 2) Identify how secretory epithelial cell production of LCN2 mitigates O3-induced lung injury and Kp disease severity. Completion of the proposed aims will provide valuable insight as to how O3 exposure increases susceptibility to respiratory infections. We will elucidate LCN2’s protective effect on the lung epithelium following O3 exposure and evaluate how this interaction mediates susceptibility to respiratory infection. As global temperatures continue to rise, it is imperative to understand the mechanisms by which O3 impacts susceptibility to infection and provide prospective therapeutic treatments to reduce the health and economic burdens associated with O3. Through completing the proposed training program, the applicant will gain the necessary tools to become an independent scientist researching environmental lung disease: 1) advanced laboratory techniques; 2) scientific writing skills; 3) leadership experience; 4) a strong scientific network; and 5) ethical and collaborative research expertise.