Coagulation factors in the airways in moderate and severe asthma and the effect of inhaled steroids

Brims, Fraser; Chauhan, Anoop; Higgins, Bernard; Shute, Janis K.

doi:10.1136/thx.2009.114439

Cited by 69 publications

(74 citation statements)

References 55 publications

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“…The regulation of t-PA gene expression is not well described. t-PA is produced by a number of airway cells, including mast cells, macrophages, fibroblasts, endothelial cells, glandular cells, and epithelial cells (38,39). Our immunohistochemistry data demonstrated that t-PA staining was most prominently Figure 7.…”

Section: Discussionmentioning

confidence: 79%

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

141

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: 79%

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

141

205

View full text Add to dashboard Cite

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“…This has been observed in animal models, in the lung tissue of humans with acute lung injury [28] and in patients with pneumonia [29]. Also, there is evidence of activation of the extrinsic coagulation cascade in the asthmatic airway, with involvement of both plasma and locally derived factors [7,8]. This is supported by a recent finding showing local vascular inflammation in asthma and COPD [30], as well as the observation of a higher incidence of PE than DVT in COPD patients [22], and evidence that in other chronic inflammatory disorders, such as diabetes, rheumatoid arthritis and ulcerative colitis, a higher incidence of PE has not been observed [3][4][5].…”

Section: Discussionmentioning

confidence: 88%

“…This has been shown for inflammatory bowel disease [3], rheumatoid arthritis [4], diabetes mellitus [5] and chronic obstructive pulmonary disease (COPD) [6]. Asthma has also been associated with a procoagulant and antifibrinolytic activity in the airways [7,8]. However, whether this procoagulant shift translates into a higher risk of symptomatic VTE is unknown.…”

Section: Introductionmentioning

confidence: 99%

Risk of deep vein thrombosis and pulmonary embolism in asthma

Majoor

Kamphuisen

Zwinderman³

et al. 2012

Eur Respir J

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Increasing evidence suggests that patients with asthma have activated coagulation within the airways. Whether this leads to an increase in venous thromboembolic events is unknown. We therefore assessed the incidence of venous thromboembolic events in patients with mild-to-moderate and severe asthma as compared with an age-and sex-matched reference population.648 patients with asthma (283 with severe and 365 patients with mild-to-moderate asthma) visiting three Dutch outpatient asthma clinics were studied. All patients completed a questionnaire about a diagnosis of deep vein thrombosis and pulmonary embolism in the past, their risk factors, history of asthma and medication use. All venous thromboembolic events were objectively verified.In total, 35 venous thromboembolic events (16 deep vein thrombosis and 19 pulmonary embolism) occurred at a median age of 39 (range 20-63) years. The incidence of pulmonary embolism in patients with severe asthma was 0.93 (95% CI 0.42-1.44) per 1000 person-years, 0.33 (95% CI 0.07-0.60) in mild-tomoderate asthma and 0.18 (95% CI 0.03-0.33) in the general population, respectively. Severe asthma and oral corticosteroid use were independent risk factors of pulmonary embolism (hazard ratios 3.33 (1.16-9.93) and 2.82 (1.09-7.30), respectively). Asthma was not associated with deep vein thrombosis.Severe asthma greatly enhances the risk of pulmonary embolism, particularly if chronic corticosteroids are used. @ERSpublications Severe asthma greatly enhances the risk of pulmonary embolism, particularly if chronic corticosteroids are used

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“…Although coagulation is classically thought to happen in blood vessels, coagulation also occurs on the luminal surface of the airway epithelium (14). Compared with control subjects, coagulation activity and the concentrations of coagulation-associated mediators, including thrombin, thrombin-antithrombin complex, and tissue factor (TF) are elevated in sputum and bronchoalveolar lavage (BAL) fluid from patients with asthma (15)(16)(17). TF is a 47-kD transmembrane protein that functions as the primary cellular initiator of blood coagulation by binding Factor VII/Factor VIIa (FVII/FVIIa) (18,19).…”

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confidence: 99%

IL-13 Augments Compressive Stress–Induced Tissue Factor Expression in Human Airway Epithelial Cells

Mitchel¹,

Antoniak

Kim

et al. 2016

Am J Respir Cell Mol Biol

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Tissue factor (TF) is best known as a cellular initiator of coagulation, but it is also a multifunctional protein that has been implicated in multiple pathophysiologic conditions, including asthma. In the lung, airway epithelial cells express TF, but it is unknown how TF expression is regulated by asthma-associated mediators. We investigated the role of IL-13, a type 2 cytokine, alone and in combination with compressive stress, which mimics asthmatic bronchoconstriction, on TF expression and release of TF-positive extracellular vesicles from primary normal human bronchial epithelial cells. Well-differentiated normal human bronchial epithelial cells were treated with IL-13 and compressive stress, alone and in combination. TF mRNA, protein and activity were measured in the cells and conditioned media. TF was also measured in the bronchoalveolar lavage (BAL) fluid of allergen-challenged mice and patients with asthma. IL-13 and compressive stress increased TF expression, but only compressive stress induced TF-positive extracellular vesicle release. Pretreatment with IL-13 augmented compressive stress-induced TF expression and release. TF protein and activity in BAL fluid were increased in allergen-sensitized and -challenged mice. TF was elevated in the BAL fluid of patients with mild asthma after an allergen challenge. Our in vitro and in vivo data indicate close cooperation between mechanical and inflammatory stimuli on TF expression and release of TF-positive extracellular vesicles in the lungs, which may contribute to pathophysiology of asthma.Keywords: asthma; bronchoconstriction; mechanotransduction; coagulation; airway epithelium Clinical RelevanceTwo critical components of asthma-IL-13 and bronchoconstriction-cooperatively work to induce tissue factor (TF) expression and release of TF-positive extracellular vesicles from well-differentiated human bronchial epithelial cells. Furthermore, in both mice and humans, allergen challenge increases the release of TF into bronchoalveolar lavage fluid.Asthma is characterized by chronic airway inflammation and airway hyperresponsiveness (1, 2). Although the immune system is certainly implicated in asthma, a growing body of evidence suggests that airway epithelial cells also initiate and perpetuate disease (3, 4). During asthma exacerbations, airway smooth muscle contracts excessively and the airway becomes narrowed, resulting in buckling of the airway epithelium (5, 6). Epithelial cells in such buckled airways are subjected to a compressive mechanical stress of approximately 30 cm H 2 O (7). Using an in vitro system mimicking the Correspondence and requests for reprints should be addressed to Jin

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Coagulation factors in the airways in moderate and severe asthma and the effect of inhaled steroids

Cited by 69 publications

References 55 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

Risk of deep vein thrombosis and pulmonary embolism in asthma

IL-13 Augments Compressive Stress–Induced Tissue Factor Expression in Human Airway Epithelial Cells

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