Airway extracellular LTA4H concentrations are governed by release from liver hepatocytes and changes in lung vascular permeability

Leukotriene A₄ hydrolase (LTA₄H) is a bifunctional enzyme, with dual activities critical in defining the scale of tissue inflammation and pathology. LTA₄H classically operates intracellularly, primarily within myeloid cells, to generate pro-inflammatory leukotriene B₄. However, LTA₄H also operates extracellularly to degrade the bioactive collagen fragment proline-glycine-proline to limit neutrophilic inflammation and pathological tissue remodeling. While the dichotomous functions of LTA₄H are dictated by location, the cellular source of extracellular enzyme remains unknown. We demonstrate that airway extracellular LTA₄H concentrations are governed by the level of pulmonary vascular permeability and influx of an abundant repository of blood-borne enzyme. In turn, blood LTA₄H originates from liver hepatocytes, being released constitutively but further upregulated during an acute phase response. These findings have implications for our understanding of how inflammation and repair are regulated and how perturbations to the LTA₄H axis may manifest in pathologies of chronic diseases.