Extravascular fibrin, plasminogen activator, plasminogen activator inhibitors, and airway hyperresponsiveness

Wagers, Scott; Norton, Ryan J.; Rinaldi, Lisa; Bates, Jason H. T.; Sobel, Burton E.; Irvin, Charles G.

doi:10.1172/jci19569

Cited by 116 publications

(136 citation statements)

References 54 publications

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“…Our data are in agreement with a previous study demonstrating a significant correlation between sputum concentrations of eosinophilic cationic protein and sputum TAT levels in human asthmatics (29). This relationship warrants further investigation because disordered coagulation and fibrinolysis, including the accumulation of fibrin and thrombin in the airway, have been associated with AHR (30).…”

Section: Discussionsupporting

confidence: 93%

A central regulatory role for eosinophils and the eotaxin/CCR3 axis in chronic experimental allergic airway inflammation

Fulkerson

Fischetti

McBride

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

194

173

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To clarify the role and regulation of eosinophils, we subjected several key eosinophil-related genetically engineered mice to a chronic model of allergic airway inflammation aiming to identify results that were independent of the genetic targeting strategy. In particular, mice with defects in eosinophil development (⌬dbl-GATA) and eosinophil recruitment [mice deficient in CCR3 (CCR3 knockout) and mice deficient in both eotaxin-1 and eotaxin-2 (eotaxin-1͞2 double knockout)] were subjected to Aspergillus fumigatus-induced allergic airway inflammation. Allergen-induced eosinophil recruitment into the airway was abolished by 98%, 94%, and 99% in eotaxin-1͞2 double knockout, CCR3 knockout, and ⌬dbl-GATA mice, respectively. Importantly, allergen-induced type II T helper lymphocyte cytokine production was impaired in the lungs of eosinophil-and CCR3-deficient mice. The absence of eosinophils correlated with reduction in allergen-induced mucus production. Notably, by using global transcript expression profile analysis, a large subset (29%) of allergen-induced genes was eosinophil-and CCR3-dependent; pathways downstream from eosinophils were identified, including in situ activation of coagulation in the lung. In summary, we present multiple lines of independent evidence that eosinophils via CCR3 have a central role in chronic allergic airway disease.allergy ͉ asthma ͉ chemokine ͉ cytokine

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Section: Discussionsupporting

confidence: 93%

A central regulatory role for eosinophils and the eotaxin/CCR3 axis in chronic experimental allergic airway inflammation

Fulkerson

Fischetti

McBride

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

194

173

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“…Because fibrin is considered inflammatory in general, enhanced fibrinolysis should lead to less inflammation. 32 But the opposite was observed. The amount of fibrin deposition and inflammation was significantly enhanced in proCPB Ϫ/Ϫ mice compared with WT.…”

Section: Discussionmentioning

confidence: 91%

Thrombin-activatable procarboxypeptidase B regulates activated complement C5a in vivo

Nishimura

Myles

Piliposky

et al. 2006

Blood

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Plasma procarboxypeptidase B (proCPB)is activated by the endothelial thrombinprothrombomodulin complex. Activated (CPB) functions as a fibrinolysis inhibitor, but it may play a broader role by inactivating inflammatory mediators. To test this hypothesis, C5a-induced alveolitis was studied in wild-type (WT) and proCPBdeficient mice (proCPB ؊/؊ ). C5a-induced alveolitis, as measured by cell counts and total protein contents in bronchoalveolar lavage fluids, was markedly enhanced in the proCPB ؊/؊ mice. E229K thrombin, a thrombin mutant with minimal clotting activity but retaining its ability to activate protein C and proCPB, attenuated C5a-induced alveolitis in WT but not in proCPB ؊/؊ mice, indicating that its beneficial effect is mediated primarily by its activation of proCPB. Lung tissue histology confirmed these cellular inflammatory responses. Delayed administration of E229K thrombin after the C5a instillation was ineffective in reducing alveolitis in WT mice, suggesting that the beneficial effect of E229K thrombin is due to the direct inhibition of C5a by CPB. Our studies show that thrombin-activatable proCPB, in addition to its role in fibrinolysis, has intrinsic anti-inflammatory functions. Its activation, along with protein C, by the endothelial thrombin-TM complex represents a homeostatic response to counteract the inflammatory mediators generated at the site of vascular injury. IntroductionThe complement system is part of the innate immune system and plays a major role in the host defense against pyrogenic bacterial infection. 1,2 It is also involved in a wide variety of acute and chronic inflammatory disorders, including sepsis, acute respiratory distress syndrome, rheumatoid arthritis, and glomerulonephritis. The complement system consists of multiple proteins in plasma and on cell surfaces and can be activated by 3 distinct pathways, all converging on the cleavage of C3 into C3a and C3b. C3b in turn becomes an essential component of the C5 convertase enzyme complex, leading to cleavage of C5 into C5a and C5b. Both C3a and C5a are strong chemoattractants. 1,2 They cause oxidative burst and enhance phagocytosis and granule enzyme release in neutrophils. They are vasodilators at sites of inflammation. C3a and C5a exert their effects through binding to cellular C3a receptors (C3aR) and C5a receptors (C5aR), respectively. C5aR are found on circulating myeloid cells, including neutrophils, monocytes, eosinophils, and basophils, as well as nonmyeloid cells in many organs, especially in the lung and the liver. 2-4 Widespread up-regulation of the C5aR occurs during sepsis, and mice deficient in C5aR succumbed to bacterial pneumonias in animal models, indicating that C5a/ C5aR signaling is essential in host defenses in the lung and other organs. 5,6 Both C3a and C5a are inhibited by carboxypeptidase N (CPN), a constitutively active plasma carboxypeptidase.Thrombin-activatable procarboxypeptidase B (proCPB), also known as procarboxypeptidase U, procarboxypeptidase R, and thrombin-activatable fibrinolysis inhib...

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“…Activation of coagulation and fibrin deposition as a consequence of tissue inflammation are fundamental for host defense to confine infections and for repair processes (8). However, the proinflammatory effects of fibrin or the failure to degrade deposited fibrin may play an etiologic role in many diseases, including rheumatoid arthritis, multiple sclerosis, status asthmaticus, adult respiratory distress syndrome, and ligneous conjunctivitis (8)(9)(10)(11)(12).…”

Section: What This Study Adds To the Fieldmentioning

confidence: 99%

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

148

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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Extravascular fibrin, plasminogen activator, plasminogen activator inhibitors, and airway hyperresponsiveness

Cited by 116 publications

References 54 publications

A central regulatory role for eosinophils and the eotaxin/CCR3 axis in chronic experimental allergic airway inflammation

A central regulatory role for eosinophils and the eotaxin/CCR3 axis in chronic experimental allergic airway inflammation

Thrombin-activatable procarboxypeptidase B regulates activated complement C5a in vivo

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

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