Airway extracellular LTA4H concentrations are governed by release from liver hepatocytes and changes in lung vascular permeability
Kyle T. Mincham,
Samia Akthar,
Dhiren F. Patel,
Garance F. Meyer,
Clare M. Lloyd,
Amit Gaggar,
James E. Blalock,
Robert J. Snelgrove
Affiliations
Kyle T. Mincham
Inflammation Repair and Development, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK
Samia Akthar
Inflammation Repair and Development, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK
Dhiren F. Patel
Inflammation Repair and Development, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK; Department of Cellular Microbiology, Max Planck Institute for Infection Biology, Charitéplatz 1, 10117 Berlin, Germany
Garance F. Meyer
Inflammation Repair and Development, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK
Clare M. Lloyd
Inflammation Repair and Development, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK
Amit Gaggar
Division of Pulmonary, Allergy & Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; Program in Protease and Matrix Biology, University of Alabama at Birmingham, Birmingham, AL, USA; Lung Health Center and Gregory Fleming James CF Center, University of Alabama at Birmingham, Birmingham, AL, USA; Birmingham VA Medical Center, Birmingham, AL, USA
James E. Blalock
Division of Pulmonary, Allergy & Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; Program in Protease and Matrix Biology, University of Alabama at Birmingham, Birmingham, AL, USA; Lung Health Center and Gregory Fleming James CF Center, University of Alabama at Birmingham, Birmingham, AL, USA
Robert J. Snelgrove
Inflammation Repair and Development, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK; Corresponding author
Summary: 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.
