Local inhibition of elastase reduces EMILIN1 cleavage reactivating lymphatic vessel function in a mouse lymphoedema model

Eliana Pivetta, Bruna Wassermann, Lisa Del Bel Belluz, Carla Danussi, Teresa Maria Elisa Modica, Orlando Maiorani, Giulia Bosisio, Francesco Boccardo, Vincenzo Canzonieri, Alfonso Colombatti, Paola Spessotto

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1221-1236
Number of pages16
JournalClinical Science
Volume130
Issue number14
DOIs
Publication statusPublished - 2016

Fingerprint

Lymphatic Vessels
Lymphedema
Pancreatic Elastase
Leukocyte Elastase
Lymph
Extracellular Matrix
Drainage
Endothelial Cells
Secretory Proteinase Inhibitory Proteins
Intercellular Junctions
Extracellular Matrix Proteins
Blood Vessels
Tail
Neutrophils
Lymph Nodes
Pharmacology

Keywords

  • EMILIN1
  • Extracellular matrix
  • Human lymphoedematous tissue
  • Neutrophil elastase
  • Secondary lymphoedema
  • Sivelestat

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Local inhibition of elastase reduces EMILIN1 cleavage reactivating lymphatic vessel function in a mouse lymphoedema model. / Pivetta, Eliana; Wassermann, Bruna; Del Bel Belluz, Lisa; Danussi, Carla; Modica, Teresa Maria Elisa; Maiorani, Orlando; Bosisio, Giulia; Boccardo, Francesco; Canzonieri, Vincenzo; Colombatti, Alfonso; Spessotto, Paola.

In: Clinical Science, Vol. 130, No. 14, 2016, p. 1221-1236.

Research output: Contribution to journalArticle

Pivetta, E, Wassermann, B, Del Bel Belluz, L, Danussi, C, Modica, TME, Maiorani, O, Bosisio, G, Boccardo, F, Canzonieri, V, Colombatti, A & Spessotto, P 2016, 'Local inhibition of elastase reduces EMILIN1 cleavage reactivating lymphatic vessel function in a mouse lymphoedema model', Clinical Science, vol. 130, no. 14, pp. 1221-1236. https://doi.org/10.1042/CS20160064
Pivetta, Eliana ; Wassermann, Bruna ; Del Bel Belluz, Lisa ; Danussi, Carla ; Modica, Teresa Maria Elisa ; Maiorani, Orlando ; Bosisio, Giulia ; Boccardo, Francesco ; Canzonieri, Vincenzo ; Colombatti, Alfonso ; Spessotto, Paola. / Local inhibition of elastase reduces EMILIN1 cleavage reactivating lymphatic vessel function in a mouse lymphoedema model. In: Clinical Science. 2016 ; Vol. 130, No. 14. pp. 1221-1236.
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