Hematopoietic protease nexin-1 protects against lung injury by preventing thrombin signaling in mice.

Autor:	François D; U1148-Laboratory for Vascular and Translational Science, INSERM, University Paris Diderot, Sorbonne Paris Cité, Paris, France., Arocas V; U1148-Laboratory for Vascular and Translational Science, INSERM, University Paris Diderot, Sorbonne Paris Cité, Paris, France., Venisse L; U1148-Laboratory for Vascular and Translational Science, INSERM, University Paris Diderot, Sorbonne Paris Cité, Paris, France., Aymonnier K; U1148-Laboratory for Vascular and Translational Science, INSERM, University Paris Diderot, Sorbonne Paris Cité, Paris, France., Idir L; U1148-Laboratory for Vascular and Translational Science, INSERM, University Paris Diderot, Sorbonne Paris Cité, Paris, France., Martos R; U1148-Laboratory for Vascular and Translational Science, INSERM, University Paris Diderot, Sorbonne Paris Cité, Paris, France., Gazit S; U970-Paris Cardiovascular Research Centre, INSERM, University Paris-Descartes, Paris, France; and., Couty L; U970-Paris Cardiovascular Research Centre, INSERM, University Paris-Descartes, Paris, France; and., Jandrot-Perrus M; U1148-Laboratory for Vascular and Translational Science, INSERM, University Paris Diderot, Sorbonne Paris Cité, Paris, France., Camerer E; U970-Paris Cardiovascular Research Centre, INSERM, University Paris-Descartes, Paris, France; and., Boulaftali Y; U1148-Laboratory for Vascular and Translational Science, INSERM, University Paris Diderot, Sorbonne Paris Cité, Paris, France.; Fibrosis, Inflammation, Remodeling in Cardiovascular, Respiratory and Renal Disease, Départements Hospitalo-Universitaires, Paris, France., Bouton MC; U1148-Laboratory for Vascular and Translational Science, INSERM, University Paris Diderot, Sorbonne Paris Cité, Paris, France.
Jazyk:	angličtina
Zdroj:	Blood advances [Blood Adv] 2018 Sep 25; Vol. 2 (18), pp. 2389-2399.
DOI:	10.1182/bloodadvances.2018018283
Abstrakt:	Coagulation and fibrinolytic system deregulation has been implicated in the development of idiopathic pulmonary fibrosis, a devastating form of interstitial lung disease. We used intratracheal instillation of bleomycin to induce pulmonary fibrosis in mice and analyzed the role of serine protease inhibitor E2 (serpinE2)/protease nexin-1 (PN-1), a tissue serpin that exhibits anticoagulant and antifibrinolytic properties. PN-1 deficiency was associated, after bleomycin challenge, with a significant increase in mortality, as well as a marked increase in active thrombin in bronchoalveolar lavage fluids, an overexpression of extracellular matrix proteins, and an accumulation of inflammatory cells in the lungs. Bone marrow transplantation experiments showed that protective PN-1 was derived from hematopoietic cell compartment. A pharmacological strategy using the direct thrombin inhibitor argatroban reversed the deleterious effects of PN-1 deficiency. Concomitant deficiency of the thrombin receptor protease-activated receptor 4 (PAR4) abolished the deleterious effects of PN-1 deficiency in hematopoietic cells. These data demonstrate that prevention of thrombin signaling by PN-1 constitutes an important endogenous mechanism of protection against lung fibrosis and associated mortality. Our findings suggest that appropriate doses of thrombin inhibitors or PAR4 antagonists may provide benefit against progressive lung fibrosis with evidence of deregulated thrombin activity. (© 2018 by The American Society of Hematology.)
Databáze:	MEDLINE
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