15 February 2020

A novel pulmonary epithelial prostacyclin pathway provides systemic anti-thrombotic protection

Prostacyclin is a powerful anti-thrombotic and vasodilator hormone synthesised by cyclo-oxygenase (COX)-1 enzymes. It is abundantly produced by the lung and isolated vessels where COX-1 and prostacyclin synthase are enriched in endothelial cells (EC). This has led to the universal assumption that the endothelium is the primary source of prostacyclin and been the basis of our understanding of prostacyclin’s role in systemic and pulmonary vascular disease. Here we have used novel conditional knockout mice where COX-1 is deleted from EC to definitively determine their contribution to pulmonary and vascular prostacyclin production.

EC-specific or global COX-1 deletion reduced prostacyclin release from aorta and pulmonary arteries by >80%. However, in lung parenchyma, total prostacyclin release was reduced by global but not EC-specific COX-1 deletion. Prostacyclin production by aortic EC isolated by fluorescence-activated cell sorting was ~10-fold greater than by EC isolated from lung parenchyma. Instead, in the lung, the major prostacyclin producing cells were type I epithelial cells with little contribution from platelets, leucocytes or other stromal cells. In agreement, type I epithelial cells expressed mRNA for both COX-1 and prostacyclin synthase. To identify a functional role of epithelial-derived prostacyclin a ferric chloride carotid thrombosis model was used. In EC-specific COX-1 knockout mice, thrombotic occlusion time was reduced by a global COX-1 inhibitor (SC-560) indicating that COX-1 outside of EC actively works to reduce systemic thrombotic tone.

These data demonstrate that whilst EC produce the majority of prostacyclin in large systemic and pulmonary blood vessels, within the lung parenchyma, a novel epithelial cell COX-1 pathway is the major the source of prostacyclin and functions to reduce systemic thrombotic tone. Further work is now required to the role of epithelium-derived prostacyclin in pulmonary vascular disease pathology and in cardiovascular consequences of pulmonary airway disease.

Key Contributors

Nicholas S. Kirkby, Fisnik Shala, Youssef Elghazouli, Harvey R. Herschman, Jane A. Mitchell National Heart & Lung Institute, Imperial College London, UK

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