title: Local inhibition of elastase reduces EMILIN1 cleavage reactivating lymphatic vessel function in a mouse lymphoedema model.
abstract: Lymphatic vasculature critically depends on the connections of lymphatic endothelial cells with the extracellular matrix (ECM), which are mediated by anchoring filaments (AFs). The ECM protein EMILIN1 is a component of AFs and is involved in the regulation of lymphatic vessel functions: accordingly, Emilin1(-/-) mice display lymphatic vascular morphological alterations, leading to functional defects such as mild lymphoedema, lymph leakage and compromised lymph drainage. In the present study, using a mouse post-surgical tail lymphoedema model, we show that the acute phase of acquired lymphoedema correlates with EMILIN1 degradation due to neutrophil elastase (NE) released by infiltrating neutrophils. As a consequence, the intercellular junctions of lymphatic endothelial cells are weakened and drainage to regional lymph nodes is severely affected. The local administration of sivelestat, a specific NE inhibitor, prevents EMILIN1 degradation and reduces lymphoedema, restoring a normal lymphatic functionality. The finding that, in human secondary lymphoedema samples, we also detected cleaved EMILIN1 with the typical bands of an NE-dependent pattern of fragmentation establishes a rationale for a powerful strategy that targets NE inhibition. In conclusion, the attempts to block EMILIN1 degradation locally represent the basis for a novel 'ECM' pharmacological approach to assessing new lymphoedema treatments.
authors.affiliation: Experimental Oncology 2, Department of Translational Research, CRO-IRCCS, National Cancer Institute, 33081, Aviano, Italy.
authors.forename: Eliana
authors.initials: E
authors.lastname: Pivetta
authors.affiliation: Experimental Oncology 2, Department of Translational Research, CRO-IRCCS, National Cancer Institute, 33081, Aviano, Italy.
authors.forename: Bruna
authors.initials: B
authors.lastname: Wassermann
authors.affiliation: Experimental Oncology 2, Department of Translational Research, CRO-IRCCS, National Cancer Institute, 33081, Aviano, Italy Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors.forename: Lisa
authors.initials: L
authors.lastname: Del Bel Belluz
authors.affiliation: Experimental Oncology 2, Department of Translational Research, CRO-IRCCS, National Cancer Institute, 33081, Aviano, Italy Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, U.S.A.
authors.forename: Carla
authors.initials: C
authors.lastname: Danussi
authors.affiliation: Experimental Oncology 2, Department of Translational Research, CRO-IRCCS, National Cancer Institute, 33081, Aviano, Italy.
authors.forename: Teresa Maria Elisa
authors.initials: TM
authors.lastname: Modica
authors.affiliation: Experimental Oncology 2, Department of Translational Research, CRO-IRCCS, National Cancer Institute, 33081, Aviano, Italy.
authors.forename: Orlando
authors.initials: O
authors.lastname: Maiorani
authors.affiliation: Experimental Oncology 2, Department of Translational Research, CRO-IRCCS, National Cancer Institute, 33081, Aviano, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Bosisio
authors.affiliation: Department of Surgery-Unit of Lymphatic Surgery, IRCCS S. Martino University Hospital-IST, National Institute for Cancer Research, University of Genoa, 16132 Genoa, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Boccardo
authors.affiliation: Division of Pathology, Department of Translational Research, CRO-IRCCS, National Cancer Institute, 33081, Aviano, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Canzonieri
authors.affiliation: Experimental Oncology 2, Department of Translational Research, CRO-IRCCS, National Cancer Institute, 33081, Aviano, Italy.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Colombatti
authors.affiliation: Experimental Oncology 2, Department of Translational Research, CRO-IRCCS, National Cancer Institute, 33081, Aviano, Italy pspessotto@cro.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Spessotto
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000502:physiology; D005260:Female; D006801:Humans; D042601:Lymphatic Vessels / Q000187:drug effects / Q000502:physiology*; D008209:Lymphedema / Q000188:drug therapy* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration; D053491:Proteinase Inhibitory Proteins, Secretory / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D008562:Membrane Glycoproteins; D053491:Proteinase Inhibitory Proteins, Secretory; C030340:elastin microfibril interface located protein
keywords: EMILIN1; extracellular matrix; human lymphoedematous tissue; neutrophil elastase; secondary lymphoedema; sivelestat