The role of leukotriene A4 hydrolase in dictating inflammation and remodelling in chronic lung diseases (360G-Wellcome-209458_A_17_Z)

Whilst inflammation and ensuing repair are critical to the body’s response to infection/injury, aberrant inflammatory and reparative processes and subsequent pathological remodelling are cardinal features of chronic lung diseases (CLDs). I believe the enzyme leukotriene A4 hydrolase (LTA4H) critically regulates inflammation/repair processes through dual activities that generate lipid mediator leukotriene B4 (LTB4) but degrade matrikine Pro-Gly-Pro (PGP). PGP is a neutrophil chemoattractant whilst LTB4 drives the recruitment/activation of numerous immune cells. Additionally, I now demonstrate that PGP regulates epithelial and fibroblast functions critical to repair/remodelling. I hypothesise that intrinsic and extrinsic perturbation of the LTA4H axis drives distinct pathological inflammatory and remodelling phenotypes in CLDs. The key goals of this proposal are: Dissect how the dual functions of LTA4H regulate pathological inflammatory and remodelling features of CLDs, and infer if novel LTA4H modulators show therapeutic potential. Understand how LTA4H is perturbed by genetic influences and environmental insults resulting persistent inflammation and pathological remodelling. Evaluate the LTA4H axis in CLD patients to ascertain why it is aberrant and how it correlates with pathological and clinical endpoints. These studies examine biological pathways that define the balance between health and disease, and will facilitate the endotyping of patients for therapeutic intervention.