Pneumonia is a leading cause of pediatric death world-wide. This mortality is not solely related to infection; unmitigated neutrophilic inflammatory responses destroy pulmonary parenchyma and contribute to respiratory decline. Neutrophilic destruction can occur quickly, as seen in acute respiratory distress syndrome (ARDS), or progressively, as seen in cystic fibrosis (CF). In ARDS, neutrophils flood the lung and drive subsequent edema and injury. In CF, thick, purulent airway secretions filled with neutrophils and bacteria, most commonly Pseudomonas aeruginosa, lead to progressive bronchiectasis. It has been shown that pathogen engagement with airway epithelium results in release of the arachidonic acid metabolite, hepoxilin A3, a neutrophil-specific chemoattractant, driving neutrophils to breach the airway mucosa. Migrated neutrophils then release LTB4, a second arachidonic acid metabolite and neutrophil chemoattractant, greatly augmenting neutrophil airway breach. Further elucidation of the mechanisms driving this process warrant exploration. I plan to specifically focus on the role of LTA4 hydrolase in bacterial-induced neutrophil transepithelial migration. Additionally, I have identified Pseudomonas genes that appear to play a role in neutrophil transepithelial migration. In this grant proposal, I will further define the role of bacterial factors in this inflammatory process, which may shed light on novel bacterial targets to promote tolerance of bacteria within the airway and minimize the excessive, destructive inflammatory process. Together, the aims outlined in this grant proposal will focus on unique aspects of airway inflammation, with the goal of identifying novel therapeutic targets, ultimately reducing the morbidity and mortality associated with pediatric pneumonia.
Excessive neutrophil inflammation is a major contributor to lung disease related to infection. Focusing on cellular and molecular mechanisms driving infection-mediated neutrophil transepithelial migration and host-pathogen interactions at the airway mucosal surface will significantly advance our understanding of inflammatory pathways in the airway and may offer novel therapeutic targets.
