Protection of Plasminogen Activator Inhibitor-1-Deficient Mice from Nasal Allergy

Sejima, Takayuki; Madoiwa, Seiji; Mimuro, Jun; Sugo, Teruko; Okada, Kiyotaka; Ueshima, Shigeru; Matsuo, Osamu; Ishida, Takashi; Ichimura, Keiichi; Sakata, Yoichi

doi:10.4049/jimmunol.174.12.8135

Cited by 40 publications

(39 citation statements)

References 45 publications

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“…In this latter investigation, OVA-sensitized mice demonstrated increased PAI-1 levels in nasal washings upon intranasal OVA challenge; this locally produced PAI-1 contributed to a Th2 response as reflected by Th1-biased responses in sensitized PAI-1 Ϫ/Ϫ mice characterized by reduced OVA-specific circulating IgE and elevated plasma IgG2a levels, as well as lower IL-4 and IL-5 and higher IFN-␥ concentrations in nasal lavage fluid (23). Our present findings extend and are partly in line with these results: naive PAI-1 Ϫ/Ϫ mice displayed enhanced systemic IFN-␥ release after i.p.…”

Section: Discussionmentioning

confidence: 99%

Plasminogen Activator Inhibitor Type-1-Deficient Mice Have an Enhanced IFN-γ Response to Lipopolysaccharide and Staphylococcal Enterotoxin B

Renckens

Pater

Poll

2006

The Journal of Immunology

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Plasminogen activator inhibitor type-1 (PAI-1) is a major inhibitor of fibrinolysis by virtue of its capacity to inhibit urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA). Systemic inflammation is invariably associated with elevated circulating levels of PAI-1, and during human sepsis plasma PAI-1 concentrations predict an unfavorable outcome. Knowledge about the functional role of PAI-1 in a systemic inflammatory response syndrome is highly limited. In this study, we determined the role of endogenous PAI-1 in cytokine release induced by administration of LPS or staphylococcal enterotoxin B (SEB). Both LPS and SEB elicited secretion of PAI-1 into the circulation of normal wild-type (Wt) mice. Relative to Wt mice, PAI-1 gene-deficient (PAI-1−/−) mice demonstrated strongly elevated plasma IFN-γ concentrations after injection of either LPS or SEB. In addition, PAI-1−/− splenocytes released more IFN-γ after incubation with LPS or SEB than Wt splenocytes. Both PAI-1−/− CD4+ and CD8+ T cells produced more IFN-γ upon stimulation with SEB. LPS-induced IFN-γ release in mice deficient for uPA, the uPA receptor, or tPA was not different from IFN-γ release in LPS-treated Wt mice. These results identify a novel function of PAI-1 during systemic inflammation, where endogenous PAI-1 serves to inhibit IFN-γ release by a mechanism that does not depend on its interaction with uPA/uPA receptor or tPA.

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Section: Discussionmentioning

confidence: 99%

Plasminogen Activator Inhibitor Type-1-Deficient Mice Have an Enhanced IFN-γ Response to Lipopolysaccharide and Staphylococcal Enterotoxin B

Renckens

Pater

Poll

2006

The Journal of Immunology

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“…It has been reported that the Th2 response was downregulated and the immune response shifted from a Th2-dominant to a Th1-dominant reaction in PAI-1 Ϫ/Ϫ mice (30). The reduction of airway inflammation that occurs with increased fibrinolysis may be one mechanism by which the uPA/plasmin system reduces airway remodeling and fibrogenic factors such as TGF-␤.…”

Section: Discussionmentioning

confidence: 99%

Inhalation of urokinase-type plasminogen activator reduces airway remodeling in a murine asthma model

Kuramoto¹,

Nishiuma²,

Kobayashi³

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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Inhalation of urokinase-type plasminogen activator reduces airway remodeling in a murine asthma model. Am J Physiol Lung Cell Mol Physiol 296: L337-L346, 2009. First published December 19, 2008 doi:10.1152/ajplung.90434.2008.-The airway remodeling that occurs in asthma is characterized by an excess of extracellular matrix deposition in the submucosa, hyperplasia/hypertrophy of smooth muscle, goblet cell metaplasia, and accumulation of fibroblasts/myofibroblasts. The urokinase-type plasminogen activator (uPA)/plasmin system participates in pericellular proteolysis and is capable of directly degrading matrix components, activating latent proteinases, and activating growth factors. In a mouse ovalbumin (OVA) asthma model, we increased plasminogen activator activity in the lung by administering exogenous uPA or by using mice genetically deficient in the uPA inhibitor plasminogen activator inhibitor-1 (PAI-1) to assess the role of this system in asthma pathogenesis. After intraperitoneal OVA sensitization, mice inhaled OVA plus uPA (500 IU/ mouse) or saline by ultrasonic nebulization for 3 wk. When studied 24 h after the final exposure, the groups with upregulated plasmin activity had significantly reduced subepithelial fibrosis within the airway walls and had decreased airway hyperresponsiveness (AHR) to methacholine. Morphometric analysis showed that subepithelial wall thickening of the bronchi (subepithelial area ratio) was also reduced, as were collagen and ␣-smooth muscle actin. Upregulation of plasmin activity also increased the level of hepatocyte growth factor activity in bronchoalveolar lavage fluid, whereas the release of transforming growth factor-␤ was decreased. The administration of uPA 1 wk after the last OVA inhalation also significantly reduced lung hydroxyproline content and AHR. These results show that enhancing uPA/ plasmin activity lessens the airway remodeling in a murine asthma model.

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“…78 PAI-1 has been implicated as a mediator of the allergic immune response: in a murine allergic rhinitis model, PAI-1-deficient mice showed a suppressed Th2 response and fewer symptoms. 85 In addition, PAI-1-deficient mice displayed a reduced airway hyper-responsiveness in the ovalbumin-induced allergic lung inflammation model. 82 In a model of chronic asthma produced by exposure to aerosolized ovalbumin during 4 weeks, PAI-1 deficiency did not influence peribronchial eosinophilic infiltration, goblet cell hyperplasia, or ovalbumin-specific IgE levels.…”

Section: Fibrinolysis In Asthmamentioning

confidence: 99%

Asthma and coagulation

Boer

Majoor²,

Veer

et al. 2012

Blood

145

140

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Asthma is a chronic airway disease characterized by paroxysmal airflow obstruction evoked by irritative stimuli on a background of allergic lung inflammation. Currently, there is no cure for asthma, only symptomatic treatment. In recent years, our understanding of the involvement of coagulation and anticoagulant pathways, the fibrinolytic system, and platelets in the pathophysiology of asthma has increased considerably. Asthma is associated with a procoagulant state in the bronchoalveolar space, further aggravated by impaired local activities of the anticoagulant protein C system and fibrinolysis. Protease-activated receptors have been implicated as the molecular link between coagulation and allergic inflammation in asthma. This review summarizes current knowledge of the impact of the disturbed hemostatic balance in the lungs on asthma severity and manifestations and identifies new possible targets for asthma treatment. (Blood. 2012;119(14):3236-3244) IntroductionAsthma is a disease of chronic airway inflammation causing symptoms of paroxysmal airflow obstruction, airway hyperresponsiveness to irritative stimuli, wheezing, chest tightness, and coughing. 1 These symptoms occur against a background of allergic inflammation, characterized by infiltration of mast cells, eosinophils, and T-helper 2 (Th2) lymphocytes into the airway wall and mucus hypersecretion. Many patients with chronic asthma show progressive decline of lung function that is thought to be the result of structural remodeling of the airway wall 2 and have frequent exacerbations and steroid resistance, 3 posing a major clinical challenge and health problem. 4 New therapeutic approaches need to be developed targeting the inflammatory background that triggers asthma symptoms. 5 Historically, coagulation and fibrinolysis have been considered as processes that take place in the vascular compartment. It is now appreciated that the airways represent a body compartment in which coagulation and anticoagulant mechanisms can be initiated and regulated locally. 6 In addition to the activation of coagulation in lung inflammatory disorders that is probably induced by leakage of plasma proteins into the bronchoalveolar space, essential mediators of coagulation can be found locally in the lung, including tissue factor (TF) that initiates coagulation and thrombin, which transforms fibrinogen to fibrin. 7 Several diseases associated with abundant lung inflammation, including acute respiratory distress syndrome, pneumonia, and lung fibrosis, 6,8 have been shown to result in similar changes in bronchoalveolar levels of proteins implicated in coagulation and fibrinolysis, tipping the physiologic equilibrium of preventing fibrin clot formation toward a net procoagulant state. In particular, for asthma this disturbed hemostatic balance in the airways is of importance for the perpetuation of allergic inflammation (Figure 1) in which cytokines and protease-activated receptors (PARs) play an important role. In addition, platelets have been found to actively participate in ma...

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Protection of Plasminogen Activator Inhibitor-1-Deficient Mice from Nasal Allergy

Cited by 40 publications

References 45 publications

Plasminogen Activator Inhibitor Type-1-Deficient Mice Have an Enhanced IFN-γ Response to Lipopolysaccharide and Staphylococcal Enterotoxin B

Plasminogen Activator Inhibitor Type-1-Deficient Mice Have an Enhanced IFN-γ Response to Lipopolysaccharide and Staphylococcal Enterotoxin B

Inhalation of urokinase-type plasminogen activator reduces airway remodeling in a murine asthma model

Asthma and coagulation

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