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Rehm, S.R.T. ; Smirnova, N.F. ; Morrone, C. ; Götzfried, J. ; Feuchtinger, A. ; Pedersen, J.* ; Korkmaz, B.* ; Yildirim, A.Ö. ; Jenne, D.

Premedication with a cathepsin C inhibitor alleviates early primary graft dysfunction in mouse recipients after lung transplantation.

Sci. Rep. 9:9925 (2019)

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Neutrophil serine proteases (NSPs), like proteinase 3 (PR3) and neutrophil elastase (NE) are implicated in ischemia-reperfusion responses after lung transplantation (LTx). Cathepsin C (CatC) acts as the key regulator of NSP maturation during biosynthesis. We hypothesized that CatC inhibitors would reduce vascular breakdown and inflammation during reperfusion in pretreated lung transplant recipients by blocking NSP maturation in the bone marrow. An orthotopic LTx model in mice was used to mimic the induction of an ischemia-reperfusion response after 18 h cold storage of the graft and LTx. Recipient mice were treated subcutaneously with a chemical CatC inhibitor (ICatC) for 10 days prior to LTx. We examined the effect of the ICatC treatment by measuring the gas exchange function of the left lung graft, protein content, neutrophil numbers and NSP activities in the bone marrow 4 h after reperfusion. Pre-operative ICatC treatment of the recipient mice improved early graft function and lead to the disappearance of active NSP protein in the transplanted lung. NSP activities were also substantially reduced in bone marrow neutrophils. Preemptive NSP reduction by CatC inhibition may prove to be a viable and effective approach to reduce immediate ischemia reperfusion responses after LTx.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Papillon-lefevre-syndrome; Dipeptidyl Peptidase-i; Neutrophil Elastase; Reperfusion Injury; Serine Proteases; Proteinase-3; Activation; Mutations; Survival; Gene

ISSN (print) / ISBN 2045-2322

e-ISSN 2045-2322

Journal Scientific Reports

Quellenangaben Volume: 9, Issue: 1, Article Number: 9925

Publisher Nature Publishing Group

Publishing Place London

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Lung Health and Immunity (LHI)
Institute of Lung Biology (LHI)
Research Unit Analytical Pathology (AAP)