Plasmin improves blood-gas barrier function in oedematous lungs by cleaving epithelial sodium channels.

British Journal of Pharmacology
Runzhen ZhaoHong-Long Ji

Abstract

Lung oedema in association with suppressed fibrinolysis is a hallmark of lung injury. Here, we have tested whether plasmin cleaves epithelial sodium channels (ENaC) to resolve lung oedema fluid. Human lungs and airway acid-instilled mice were used for analysing fluid resolution. In silico prediction, mutagenesis, Xenopus oocytes, immunoblotting, voltage clamp, mass spectrometry, and protein docking were combined for identifying plasmin cleavage sites. Plasmin improved lung fluid resolution in both human lungs ex vivo and injured mice. Plasmin activated αβγENaC channels in oocytes in a time-dependent manner. Deletion of four consensus proteolysis tracts (αΔ432-444, γΔ131-138, γΔ178-193, and γΔ410-422) eliminated plasmin-induced activation significantly. Further, immunoblotting assays identified 7 cleavage sites (K126, R135, K136, R153, K168, R178, K179) for plasmin to trim both furin-cleaved C-terminal fragments and full-length human γENaC proteins. In addition, 9 new sites (R122, R137, R138, K150, K170, R172, R180, K181, K189) in synthesized peptides were found to be cleaved by plasmin. These cleavage sites were located in the finger and the thumb, particularly the GRIP domain of human ENaC 3D model composed of two proteolytic ...Continue Reading

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Citations

Mar 29, 2020·Physiological Reviews·Hong-Long JiMichael A Matthay
Jan 5, 2021·Frontiers in Physiology·Giris JacobBenjamin Brenner
Jul 17, 2021·Pulmonary Pharmacology & Therapeutics·Hong-Long JiRunzhen Zhao

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