fibrin and Asthma

Asthma is a prevalent respiratory disorder triggered by a variety of inhaled environmental factors, such as allergens, viruses, and pollutants. Asthma is characterized by an elevated activation of the smooth muscle surrounding the airways, as well as a propensity of the airways to narrow excessively in response to a spasmogen (i.e. contractile agonist), a feature called airway hyperresponsiveness. The level of airway smooth muscle (ASM) activation is putatively controlled by mediators released in its vicinity. In asthma, many mediators that affect ASM contractility originate from inflammatory cells that are mobilized into the airways, such as eosinophils. However, mounting evidence indicates that mediators released by remote organs can also influence the level of activation of ASM, as well as its level of responsiveness to spasmogens and relaxant agonists. These remote mediators are transported through circulating blood to act either directly on ASM or indirectly via the nervous system by tuning the level of cholinergic activation of ASM. Indeed, mediators generated from diverse organs, including the adrenals, pancreas, adipose tissue, gonads, heart, intestines, and stomach, affect the contractility of ASM. Together, these results suggest that, apart from a paracrine mode of regulation, ASM is subjected to an endocrine mode of regulation. The results also imply that defects in organs other than the lungs can contribute to asthma symptoms and severity. In this review, I suggest that the endocrine mode of regulation of ASM contractility is overlooked.

Topics: Adaptation, Physiological; Adiponectin; Androgens; Animals; Asthma; Bronchodilator Agents; Dehydroepiandrosterone; Epinephrine; Estrogens; Female; Fibrin; Gastrin-Releasing Peptide; Gastrointestinal Hormones; Glucocorticoids; Humans; Insulin; Leptin; Lung; Male; Muscle Contraction; Muscle, Smooth; Natriuretic Peptides; Progesterone; Respiratory Physiological Phenomena; Respiratory System; Theophylline; Thyroid Hormones; Urokinase-Type Plasminogen Activator

Asthma is a disease characterized by airways hyperresponsiveness (AHR), which is traditionally thought to involve the large, central airways. However, there is increasing evidence of the importance of peripheral airway involvement in asthma as well. Our group has developed particular expertise in measuring peripheral lung mechanics in both humans and mice. This presentation will review data on lung mechanics in subjects with asthma obtained by both classical means and uniquely through the wedged bronchoscope, as well as relevant experiments in mice. Our findings reveal that the lung periphery is hyperresponsive to stimuli in asthmatic subjects, with evidence of airway closure. We also show that the overall impedance of the lung is determined by a combination of peripheral airway narrowing and central airway shunting that occurs in both normal and asthmatic subjects. Experiments in mice have revealed the importance of airway closure in contributing to the phenomenon of AHR. Based on the effects of fibrin on lung mechanics, fibrin may contribute to airway closure via inactivation of surfactant. Another mechanism contributing to AHR is the heterogeneity of airway narrowing. We have explored this in humans by combining the forced oscillation technique with computerized tomography imaging of the lung, and demonstrated that heterogeneity is common to both normal and asthmatic subjects. Further experiments are ongoing and planned in both mice and humans to elucidate the role of fibrin, surfactant and heterogeneous airway narrowing and closure in contributing to AHR in asthma.

Topics: Animals; Asthma; Bronchial Hyperreactivity; Bronchoscopy; Disease Models, Animal; Fibrin; Humans; Mice; Pulmonary Surfactants; Respiratory Mechanics; Tomography, X-Ray Computed

Topics: Airway Obstruction; Animals; Asthma; Disease Models, Animal; Fibrin; Mice; Mice, Inbred BALB C

Chronic rhinosinusitis with nasal polyps (CRSwNP) is often comorbid with asthma and resistant to therapeutic interventions. We recently reported that excessive fibrin deposition caused by impairment of fibrinolysis might play pivotal role in forming nasal polyp. Nattokinase (NK), a serine protease produced by Bacillus subtilis, has been reported to be a strong fibrinolytic enzyme. NK could be a promising drug candidate for use in the treatment of both CRSwNP and asthma. The objective of this study was to investigate the effects of NK on nasal polyp tissues from patients with CRSwNP. The nasal discharge from patients with CRSwNP and sputum from subjects with asthma were also used to investigate whether NK influences the viscosity of mucus.. To examine the effects on NK on nasal polyp tissues, pieces of nasal polyps were incubated either with saline or NK (10-1000 FU/ml) at 37 °C for 24 h. We assessed the presence of fibrin in nasal polyp tissue incubated with NK by means of immunohistochemistry. To examine the effects of NK on nasal discharge and sputum from patients with CRSwNP and asthma, respectively, were incubated with NK solution at 37 °C for 1 h.. NK effectively shrinks the nasal polyp tissue through fibrin degradation. We also found that the viscosity of the nasal discharge and sputum from patients with CRSwNP and asthma, respectively, was significantly reduced by incubation with NK solution.. NK may be an effective alternative therapeutic option in patients with CRSwNP and comorbid asthma by causing fibrin degradation.

Topics: Adult; Aged; Animals; Asthma; Chronic Disease; Disease Models, Animal; Eosinophils; Female; Fibrin; Humans; Immunoglobulin E; Leukocyte Count; Male; Mice; Middle Aged; Mucus; Nasal Mucosa; Nasal Polyps; Proteolysis; Rhinitis; Sinusitis; Subtilisins; Viscosity

Myocardial infarction and ischemic stroke are associated with formation of dense fibrin clots resistant to lysis. Although pro- and antithrombotic alterations have been reported in atopy, fibrin clot function has not been studied in atopic patients. The aim of the current study was to investigate fibrin clot properties in patients with atopic dermatitis (AD). Plasma fibrin clot permeability, turbidity and clot lysis were assessed in 130 consecutive AD patients, aged 29.7 +/- 11 [+/-SD] years (mean SCORAD index, 32.4 +/- 14.9), free of thrombotic events. A control group comprised 130 healthy controls matched for demographics. Patients with AD had lower clot permeability (7.12 +/- 1.87 vs. 9.32 +/- 0.86 x 10(-9) cm(2); P < 0.0001), increased fiber thickness (maximum clot absorbancy at 405 nm, 4.03 +/- 0.54 vs. 3.47 +/- 0.25), faster clot formation (the lag phase, 39.16 +/- 4.61 vs. 43.05 +/- 4.56 s), higher maximum D-dimer levels released from clots, reflecting increased clot mass (4.05 +/- 0.57 vs. 3.47 +/- 0.25 mg/l; P < 0.0001), lower rate of D-dimer release (0.073 +/- 0.01 vs. 0.078 +/- 0.01 mg/l/min; P < 0.0001), and prolonged fibrinolysis time (9.26 +/- 1.47 vs. 7.81 +/- 1.17 min; P < 0.0001) compared with controls. Concomitant asthma (n = 36; 27.7%) was related to a higher rate of D-dimer release from clots than the remainder (0.075 +/- 0.01 vs. 0.072 +/- 0.01 mg/l/min, respectively; P = 0.03). Altered plasma fibrin clot properties associated with reduced efficiency of fibrinolysis can be detected in AD patients, which might represent a novel mechanism that modulates a hemostatic balance in atopy.

Topics: Adolescent; Adult; Asthma; Biomarkers; Blood Coagulation Tests; Case-Control Studies; Chi-Square Distribution; Dermatitis, Atopic; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinolysis; Humans; Logistic Models; Male; Poland; Thrombosis; Young Adult

In the normal airway, the hemostatic balance is antithrombotic and favors fibrinolysis. Acute asthma is associated with inflammatory cell infiltrate and plasma exudation in the airways. Postmortem specimens following status asthmaticus suggest a role for the activation of the extrinsic coagulation cascade and intraluminal fibrin formation. The authors report a chance observation of fibrin formation in the airways of a patient with moderate asthma 5 days before a severe exacerbation requiring hospital admission.. Alpha-2 macroglobulin, an index of plasma leakage, coagulation factors, and D-dimers were measured by enzyme-linked immunosorbent assay (ELISA) in hypertonic saline-induced sputum, as part of a study into airway repair in stable asthma. All subjects were required to have stable symptoms and measures of asthma prior to sampling.. The subject's baseline forced expiratory volume in one second (FEV(1)) was 94% predicted and fraction of exhaled nitric oxide (FeNO) level was 30 ppb prior to sputum induction. Differential sputum cell count revealed an airways neutrophilia (neutrophils 81.1%, eosinophils 0.19%). D-dimers were 70-fold and 22-fold higher than the median value for patients with stable moderate and severe asthma, respectively. Plasma exudation was 42-fold higher than in stable moderate asthma, but on a par with levels found in severe stable asthma, and locally produced coagulation factors may therefore be involved. Levels of fibrinogen, plasminogen, plasminogen activator inhibitor (PAI)-1 and thrombin-activatable fibrinolysis inhibitor (TAFI) were all at least an order of magnitude higher than those seen in stable moderate or severe asthma.. Acute exacerbation of moderate asthma appears to be associated with a shift to a profibrinogenic, possibly antifibrinolytic, environment in the airways.

Topics: Aged; Asthma; Blood Coagulation; Carboxypeptidase B2; Eosinophils; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Humans; Male; Neutrophils; Plasminogen; Plasminogen Activator Inhibitor 1; Sputum; Up-Regulation

Platelets and fibrin play an important role in allergic processes, including allergic asthma. The asthmatic BALB/c mouse model was used to induce asthma, and asthmatic mice were treated with the anti-inflammatory plant Withania somnifera, separately and in combination with the antioxidant selenium. Selenium is an important supplement in asthma, because asthmatics may have a selenium deficiency. Hydrocortisone was used as positive control. Results indicate control mice possess major thick fibers, minor thin fibers, and tight round activated platelets with typical pseudopodia formation. Minor fibers of asthmatic mice have a netlike appearance covering the major fibers whereas the platelets form loosely connected, granular aggregates. Hydrocortisone made the fibrin more fragile and platelet morphology changes from a tight activated platelet to a more granular activated platelet, not closely fused to each other. The plant extracts, separately and in combination with selenium did not affect the fragility of the fibrin and reversed the formation of the dense minor netlike layer over the major fibers, and the platelets formed a dense aggregate. Asthmatic mice treated with selenium showed a dense minor fibrin layer; however, the platelets formed a dense aggregate. We conclude that the anti-inflammatory products affect the stability of fibrin networks but not platelet stability (seen with hydrocortisone). Selenium does not affect the stability of the fibrin networks, but affects platelet stability. These results suggests that asthmatic patients should indeed use an antioxidant supplement, e.g. selenium, because it stabilizes activated platelets, together with anti-inflammatory products.

Topics: Animals; Antioxidants; Asthma; Blood Platelets; Drug Therapy, Combination; Female; Fibrin; Leukocyte Count; Mice; Mice, Inbred BALB C; Microscopy, Electron, Scanning; Phytotherapy; Plant Extracts; Selenium; Withania

There is evidence of activation of the extrinsic coagulation cascade in the asthmatic airway, and both plasma and locally derived factors may be involved. The hypothesis that the normal haemostatic balance of healthy airways sampled by sputum induction favours fibrin formation in asthmatic airways, and that inhaled corticosteroids (ICS) and plasma exudation influence this balance, was tested.. ELISA and activity assays were used to measure alpha(2)-macroglobulin (an index of plasma leakage) and coagulation factors in hypertonic saline-induced sputum of 30 stable subjects (10 controls, 10 with moderate asthma and 10 with severe asthma). Additionally, the moderate cohort were weaned off their ICS, followed by further sputum induction 5 days after cessation of steroids.. ICS wean induced a significant rise in plasminogen (median (interquartile range (IQR)): 13.92 (6.12-16.17) vs 4.82 (2.14-13.32) ng/ml; 95% CI 0.003 to 8.596, p = 0.0499) and tissue plasminogen activator (tPA; 5.57 (3.57-14.35) vs 3.88 (1.74-4.05) ng/ml; 95% CI 0.828 to 9.972, p = 0.0261) levels in sputum, such that tPA in untreated moderate asthma was significantly (p = 0.0029) higher than normal (2.14 (0.0-2.53) ng/ml). Subjects with severe asthma had significantly more alpha(2)-macroglobulin (p = 0.0003), tissue factor (p = 0.023), plasminogen activator inhibitor (p = 0.0091), thrombin-activatable fibrinolysis inhibitor (p = 0.0031) and fibrin degradation products (p = 0.0293) in their sputum than control subjects.. Untreated moderate asthma is associated with increased fibrinolysis that is corrected by ICS. Severe asthma and high dose corticosteroid therapy is associated with a profibrinogenic, antifibrinolytic environment in the airways. This study suggests that inhibition of fibrin deposition in severe asthma may be a therapeutic approach.

Topics: Administration, Inhalation; Adult; Asthma; Blood Coagulation; Blood Coagulation Factors; Epidemiologic Methods; Female; Fibrin; Fibrinolysis; Glucocorticoids; Humans; Male; Middle Aged; Sputum

Platelets and fibrin networks play an important role in asthma and the BALB/c asthmatic mouse model has previously been successfully used to study platelet ultrastructure. In control BALB/c mice, major, thick fibers and minor thin fibers and tight, platelet aggregates with typical pseudopodia formation, are present. Minor fibers of asthmatic mice have a netlike appearance covering the major fibers, whereas the platelets seem to form loosely connected, granular aggregates. The question that now arises is whether platelets and fibrin networks of humans with asthma will have the same ultrastructure as seen in the BALB/c asthmatic model. In order to answer this question, ultrastructure of platelets and fibrin networks from two participants (controlled asthma and uncontrolled, chronic asthma) were studied and compared with that of human controls and BALB/c asthmatic mice. Peak flow measurements of the controls and patients were also assessed. Results showed that similar platelet and fibrin network ultrastructure is found in uncontrolled, human participants and BALB/c asthmatic animals. The challenge when using animal models is always whether the model adequately mimics the human disease; the current research, therefore, shows morphological support for the use of this model in the study of asthma. These morphological results may also provide additional information to plan treatment regimes for sufferers of this very debilitating disease.

Topics: Adolescent; Adult; Animals; Asthma; Blood Platelets; Disease Models, Animal; Female; Fibrin; Humans; Male; Mice; Mice, Inbred BALB C

The murine Balb/c asthma model has been used successfully for a number of in vivo immunological applications and for testing novel therapeutics, and it is a reliable, clinically relevant facsimile of the human disease. Here we investigate whether this model can be used to study other components of the human body, e.g. ultrastructure. In particular, we investigate the effect of the phytomedicine Euphorbia hirta (used to treat asthma), on the ultrastructure of fibrin as well as platelets, cellular structures that both play an important role in the coagulation process. Hydrocortisone is used as positive control. Ultrastructure of the fibrin networks and platelets of control mice were compared to mice that were asthmatic, treated with two concentrations of hydrocortisone and one concentration of the plant material. Results indicate control mice possess major, thick fibers and minor thin fibers as well as tight round platelet aggregates with typical pseudopodia formation. Minor fibers of asthmatic mice have a netlike appearance covering the major fibers, while the platelets seem to form loosely connected, granular aggregates. Both concentrations of hydrocortisone make the fibrin more fragile and that platelet morphology changes form a tight platelet aggregate to a more granular aggregate not closely fused to each other. We conclude that E. hirta does not impact on the fragility of the fibrin and that it prevents the minor fibers to form the dense netlike layer over the major fibers, as is seen in untreated asthmatic mice. This ultrastructural morphology might give us better insight into asthma and the possible new treatment regimes.

Topics: Allergens; Animals; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Blood Platelets; Disease Models, Animal; Dose-Response Relationship, Drug; Euphorbia; Fibrin; Hydrocortisone; Male; Mice; Mice, Inbred BALB C; Microscopy, Electron, Scanning; Ovalbumin; Phytotherapy; Plant Extracts

Fibrin deposition in the mucus plugs of asthmatic patients has long been known, and asthmatic sputum has been held to be important in the pathogenesis of bronchial obstruction. We examined the coagulation activity in the airways of asthmatic patients. Albumin as an index of plasma leakage into the bronchial lumen, thrombin antithrombin III complex (TAT), tissue factor, FDP, D-dimer and the TAT/D-dimer ratio as indices of coagulation and fibrinolytic markers were determined in expectorated or hypertonic saline-induced sputum from patients with acute and stable asthma, and with chronic bronchitis, and from normal control subjects. Patients with acute asthma, in comparison with patients with stable asthma or chronic bronchitis and normal control subjects, had significantly higher levels of albumin, TAT and TAT/D-dimer. The fibrin antigen was more positively stained immunohistochemically in sputum from acute asthmatics than in other sputa. In both patients with acute asthma and those with stable asthma, there was a significant positive correlation between albumin and TAT or albumin and TAT/D-dimer in the sputum. However, in normal control subjects, there was no correlation between these markers. These results suggest that the coagulation system in the airways of acute asthmatic patients is activated, that this favors fibrin deposition in the bronchial lumen and that coagulation pathways in the bronchial compartment and the degree of plasma exudation into the airways are dependently regulated in patients with asthma but not in normal control subjects.

Topics: Adult; Aged; Antithrombin III; Asthma; Blood Coagulation; Bronchi; Fibrin; Fibrinolysis; Formycins; Humans; Male; Middle Aged; Peptide Hydrolases; Ribonucleotides; Sputum

Dysregulation of matrix metalloproteinases (MMPs) and ineffective fibrinolysis are associated with the deposition of extracellular matrix (ECM). We hypothesized that elevated plasminogen activator inhibitor (PAI)-1 promotes ECM deposition in the asthmatic airway by inhibiting MMP-9 activity and fibrinolysis. Degree of airway inflammation was similar in PAI-1(-/-) and wild type (WT) mice after ovalbumin (OVA) challenge. PAI-1 production, deposition of collagen and fibrin, and MMP-9 activity in the lung tissue or airways were greater after OVA challenge compared with saline challenge. However, in PAI-1(-/-) mice, collagen deposition was 2-fold less, fibrin deposition was 4-fold less, and MMP-9 activity was 3-fold higher. This is the first direct evidence that the plasmin system regulates ECM deposition in the airways of a murine asthma model, independently of the effect of PAI-1 on inflammatory cells. The results suggest that the PAI-1-dependent inhibition of MMP-9 activity and fibrinolysis is a major mechanism by which ECM deposition occurs.

Topics: Animals; Asthma; Bronchoalveolar Lavage Fluid; Collagen; Extracellular Matrix; Fibrin; Immunoglobulin E; Lung; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Mice, Knockout; Ovalbumin; Plasminogen Activator Inhibitor 1

Topics: Adult; Aged; Airway Resistance; Asthma; Basement Membrane; Bronchi; Female; Fibrin; Fluorescent Antibody Technique; Forced Expiratory Volume; Humans; Immunoenzyme Techniques; Male; Middle Aged; Mucous Membrane

Topics: Acetylcysteine; Asthma; Bronchial Diseases; Cysteine; Cystic Fibrosis; Expectorants; Fibrin; Humans; Lung Diseases; Mucus; Sputum; Toxicology

Topics: Administration, Intravenous; Allergens; Asthma; Fibrin; Humans; Hypersensitivity; Rhinitis, Allergic, Seasonal