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
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DOI：
10.1164/rccm.201207-1292oc
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发表时间：
2013-01-01
影响因子：
24.7
通讯作者：
Schleimer, Robert P.
中科院分区：
文献类型：
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作者：
Takabayashi, Tetsuji;Kato, Atsushi;Schleimer, Robert P.
理由：鼻息肉（NPs）的特征是剧烈水肿或形成充满血浆蛋白（主要是白蛋白）的假性囊肿。然而，血浆蛋白在粘膜下层中NP滞留的机制尚不清楚。目的：我们假设纤维蛋白网的形成保留了NPs中的血浆蛋白。我们评估了慢性鼻窦炎（CRS）患者纤维蛋白沉积和纤维蛋白溶解系统组分的表达。方法：采用免疫荧光法检测CRS患者及对照组鼻组织纤维蛋白沉积情况。纤维蛋白溶解组分，d-二聚体；用ELISA、实时PCR和免疫组织化学检测纤溶酶原激活物。我们还对培养的气道上皮细胞进行了基因表达和蛋白定量分析。测量和主要结果：免疫荧光数据显示，与CRS患者和对照组的钩骨组织（UT）相比，NP中有较深的纤维蛋白沉积。与UT相比，CRS患者和对照组NP中交联纤维蛋白裂解产物蛋白d-二聚体水平显著降低，表明纤维蛋白溶解减少（P < 0.05）。CRS患者和对照组NP组组织纤溶酶原激活物（t-PA） mRNA和蛋白表达水平较UT组显著降低（P < 0.01）。免疫组织化学显示NP中t-PA明显减少，主要在上皮和腺体中。Th2细胞因子刺激培养的气道上皮细胞显示t-PA下调，提示Th2在NP中的潜在机制。结论：th2介导的t-PA减少可能导致NP粘膜下层纤维蛋白过度沉积，参与CRS合并鼻息肉的组织重塑和发病机制。
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.