Excessive fibrin deposition in nasal polyps caused by fibrinolytic impairment through reduction of tissue plasminogen activator expression

Tetsuji Takabayashi, Atsushi Kato, Anju T. Peters, Kathryn E. Hulse, Lydia A. Suh, Roderick Carter, James Norton, Leslie C. Grammer, Seong H. Cho, Bruce K. Tan, Rakesh K. Chandra, David B. Conley, Robert C. Kern, Shigeharu Fujieda, Robert P. Schleimer*

*Corresponding author for this work

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)49-57
Number of pages9
JournalAmerican journal of respiratory and critical care medicine
Volume187
Issue number1
DOIs
StatePublished - Jan 1 2013

Fingerprint

Nasal Polyps
Tissue Plasminogen Activator
Fibrin
Blood Proteins
Fluorescent Antibody Technique
Epithelial Cells
Immunohistochemistry
Proteins
Plasminogen Activators
Fibrinolysis
Nose
Real-Time Polymerase Chain Reaction
Albumins
Edema
Down-Regulation
Epithelium
Enzyme-Linked Immunosorbent Assay
Cytokines
Gene Expression

Keywords

  • Chronic rhinosinusitis
  • Fibrin
  • Fibrinolysis
  • Nasal polyps
  • Tissue plasminogen activator

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

@article{136d5cecc9174c4b86ece14f70f1ba77,
title = "Excessive fibrin deposition in nasal polyps caused by fibrinolytic impairment through reduction of tissue plasminogen activator expression",
abstract = "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.",
keywords = "Chronic rhinosinusitis, Fibrin, Fibrinolysis, Nasal polyps, Tissue plasminogen activator",
author = "Tetsuji Takabayashi and Atsushi Kato and Peters, {Anju T.} and Hulse, {Kathryn E.} and Suh, {Lydia A.} and Roderick Carter and James Norton and Grammer, {Leslie C.} and Cho, {Seong H.} and Tan, {Bruce K.} and Chandra, {Rakesh K.} and Conley, {David B.} and Kern, {Robert C.} and Shigeharu Fujieda and Schleimer, {Robert P.}",
year = "2013",
month = "1",
day = "1",
doi = "10.1164/rccm.201207-1292OC",
language = "English (US)",
volume = "187",
pages = "49--57",
journal = "American Journal of Respiratory and Critical Care Medicine",
issn = "1073-449X",
publisher = "American Thoracic Society",
number = "1",

}

TY - JOUR

T1 - Excessive fibrin deposition in nasal polyps caused by fibrinolytic impairment through reduction of tissue plasminogen activator expression

AU - Takabayashi, Tetsuji

AU - Kato, Atsushi

AU - Peters, Anju T.

AU - Hulse, Kathryn E.

AU - Suh, Lydia A.

AU - Carter, Roderick

AU - Norton, James

AU - Grammer, Leslie C.

AU - Cho, Seong H.

AU - Tan, Bruce K.

AU - Chandra, Rakesh K.

AU - Conley, David B.

AU - Kern, Robert C.

AU - Fujieda, Shigeharu

AU - Schleimer, Robert P.

PY - 2013/1/1

Y1 - 2013/1/1

N2 - 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.

AB - 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.

KW - Chronic rhinosinusitis

KW - Fibrin

KW - Fibrinolysis

KW - Nasal polyps

KW - Tissue plasminogen activator

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U2 - 10.1164/rccm.201207-1292OC

DO - 10.1164/rccm.201207-1292OC

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JF - American Journal of Respiratory and Critical Care Medicine

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