Role of Thrombin in Chronic Rhinosinusitis–associated Tissue Remodeling

Shimizu, Shino; Gabazza, Esteban C.; Ogawa, Takao; Tojima, Ichiro; Hoshi, Eriko; Kouzaki, Hideaki; Shimizu, Takeshi

doi:10.2500/ajra.2011.25.3535

Cited by 56 publications

(67 citation statements)

References 41 publications

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“…If NP formation is due to excessive fibrin deposition caused by down-regulation of t-PA, it may be feasible to diminish NP formation by administration of t-PA or activators of t-PA or administration of inhibitors of fibrinogenesis. Although in this study we did not assess the coagulation status in NPs, a recent study demonstrated that thrombin, a central component of the coagulation cascade, was up-regulated in NPs (42). Thus, the coagulation cascade might be involved in excessive fibrin deposition in NPs, interacting with the reduced fibrinolytic properties of the tissue that we describe herein.…”

Section: Discussionmentioning

confidence: 82%

Excessive Fibrin Deposition in Nasal Polyps Caused by Fibrinolytic Impairment through Reduction of Tissue Plasminogen Activator Expression

Takabayashi

Kato²,

Peters³

et al. 2013

Am J Respir Crit Care Med

147

205

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Rationale: Nasal polyps (NPs) are characterized by intense edema or formation of pseudocysts filled with plasma proteins, mainly albumin. However, the mechanisms underlying NP retention of plasma proteins in their submucosa remain unclear. Objectives: We hypothesized that formation of a fibrin mesh retains plasma proteins in NPs. We assessed the fibrin deposition and expression of the components of the fibrinolytic system in patients with chronic rhinosinusitis (CRS). Methods:We assessed fibrin deposition in nasal tissue from patients with CRS and control subjects by means of immunofluorescence. Fibrinolytic components, d-dimer, and plasminogen activators were measured using ELISA, real-time PCR, and immunohistochemistry. We also performed gene expression and protein quantification analysis in cultured airway epithelial cells. Measurements and Main Results: Immunofluorescence data showed profound fibrin deposition in NP compared with uncinate tissue (UT) from patients with CRS and control subjects. Levels of the cross-linked fibrin cleavage product protein, d-dimer, were significantly decreased in NP compared with UT from patients with CRS and control subjects, suggesting reduced fibrinolysis (P , 0.05). Expression levels of tissue plasminogen activator (t-PA) mRNA and protein were significantly decreased in NP compared with UT from patients with CRS and control subjects (P , 0.01). Immunohistochemistry demonstrated clear reduction of t-PA in NP, primarily in the epithelium and glands. Th2 cytokine-stimulated cultured airway epithelial cells showed down-regulation of t-PA, suggesting a potential Th2 mechanism in NP. Conclusions: A Th2-mediated reduction of t-PA might lead to excessive fibrin deposition in the submucosa of NP, which might contribute to the tissue remodeling and pathogenesis of CRS with nasal polyps.

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Section: Discussionmentioning

confidence: 82%

Excessive Fibrin Deposition in Nasal Polyps Caused by Fibrinolytic Impairment through Reduction of Tissue Plasminogen Activator Expression

Takabayashi

Kato²,

Peters³

et al. 2013

Am J Respir Crit Care Med

147

205

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“…48 A role for PAI-1 is consistent, with recent observations regarding the expression of PAI-1 and thrombotic/fibrinolytic pathways in patients with CS. 49,50 The 4G allele of this gene has been linked to the regulation of fibrosis in asthmatic patients and in particular to airway remodeling leading to irreversible obstruction. 51 In our study the 4G allele was overrepresented in the NES group compared with the control group of subjects without sinus disease (0.53 vs 0.45).…”

Section: Noneosinophilic Sinusitismentioning

confidence: 99%

Genetics and phenotyping in chronic sinusitis

Payne

Borish

Steinke

2011

Journal of Allergy and Clinical Immunology

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“…The tissue concentrations of transforming growth factor beta 1 (TGF-β1) were found correlated with plasminogen activator inhibitor-1 (PAI-1) in CRSsNP, and ECP correlated with urokinase-type plasminogen activator receptor (uPAR) protein in CRSwNP [19]. Exposure to thrombin and protease activator receptor-1 (PAR-1) agonist peptide increases significantly vascular endothelial growth factor (VEGF) production from cultured human airway epithelial cells [20].…”

Section: Coagulation Factorsmentioning

confidence: 96%

“…Finally, thrombin and thrombin-antithrombin (TAT) complexes were found significantly increased in nasal secretions of patients with CRSwNP with asthma compared with the control group [20].…”

Section: Coagulation Factorsmentioning

confidence: 99%

Remodeling and Repair in Rhinosinusitis

Watelet

Dogné

Mullier

2015

Curr Allergy Asthma Rep

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Remodeling refers to the development of specific but potentially irreversible structural changes in tissue. Caucasian eosinophilic chronic rhinosinusitis (CRS) with polyps associated or not with cystic fibrosis was discriminated by edema from CRS without nasal polyps, characterized by extensive fibrotic fields. However, changes in epithelial and extracellular matrix structures are common findings in all types of chronic inflammatory diseases of upper airways, but rarely specific and highly variable in extend. Recent studies have shown that remodeling in CRS appears to occur in parallel, rather than purely subsequent to inflammation. Furthermore, some preferential remodeling associations can be recognized. Tremendous efforts have been put in research on coagulation factors, cytokines, growth factors, and proteases supporting all phases of upper airway remodeling. The current exploration of other CRS sub-groups and of the particular link with concomitant asthma aims to optimize the classification of CRS and its staging modes and to develop novel therapies.

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Role of Thrombin in Chronic Rhinosinusitis–associated Tissue Remodeling

Abstract: The results of this study showed that there is increased activation of the coagulation system in the nasal mucosa of CRS patients and that thrombin may play a role in nasal polyp formation by stimulating VEGF production from airway epithelial cells.

Cited by 56 publications

References 41 publications

Excessive Fibrin Deposition in Nasal Polyps Caused by Fibrinolytic Impairment through Reduction of Tissue Plasminogen Activator Expression

Excessive Fibrin Deposition in Nasal Polyps Caused by Fibrinolytic Impairment through Reduction of Tissue Plasminogen Activator Expression

Genetics and phenotyping in chronic sinusitis

Remodeling and Repair in Rhinosinusitis

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