Multiple roles of the coagulation protease cascade during virus infection

Antoniak, Silvio; Mackman, Nigel

doi:10.1182/blood-2013-09-526277

Cited by 192 publications

(215 citation statements)

References 96 publications

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“…PAR1 or PAR2 activation enhanced the production of inflammatory mediators and cytokines and participated in chronic airway diseases, such as asthma, COPD, and IPF (idiopathic pulmonary fibrosis) (15). Virus infection also activated PAR1 and PAR2 to mediate innate immune, airway inflammation, and lung function (16)(17)(18). We have found that PAR2, but not PAR1, was obviously upregulated in the later stage of RSV infection in our preliminary data.…”

supporting

confidence: 48%

Pulmonary C Fibers Modulate MMP-12 Production via PAR2 and Are Involved in the Long-Term Airway Inflammation and Airway Hyperresponsiveness Induced by Respiratory Syncytial Virus Infection

Zang

Zhuang

Deng

et al. 2016

J Virol

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Children with acute respiratory syncytial virus (RSV) infection often develop sequelae of persistent airway inflammation and wheezing. Pulmonary C fibers (PCFs) are involved in the generation of airway inflammation and resistance; however, their role in persistent airway diseases after RSV is unexplored. Here, we elucidated the pathogenesis of PCF activation in RSV-induced persistent airway disorders. PCF-degenerated and intact mice were used in the current study. Airway inflammation and airway resistance were evaluated. MMP408 and FSLLRY-NH2 were the selective antagonists for MMP-12 and PAR2, respectively, to investigate the roles of MMP-12 and PAR2 in PCFs mediating airway diseases. As a result, PCF degeneration significantly reduced the following responses to RSV infection: augmenting of inflammatory cells, especially macrophages, and infiltrating of inflammatory cells in lung tissues; specific airway resistance (sRaw) response to methacholine; and upregulation of MMP-12 and PAR2 expression. Moreover, the inhibition of MMP-12 reduced the total number of cells and macrophages in bronchiolar lavage fluid (BALF), as well infiltrating inflammatory cells, and decreased the sRaw response to methacholine. In addition, PAR2 was upregulated especially at the later stage of RSV infection. Downregulation of PAR2 ameliorated airway inflammation and resistance following RSV infection and suppressed the level of MMP-12. In all, the results suggest that PCF involvement in long-term airway inflammation and airway hyperresponsiveness occurred at least partially via modulating MMP-12, and the activation of PAR2 might be related to PCF-modulated MMP-12 production. Our initial findings indicated that the inhibition of PCF activity would be targeted therapeutically for virus infection-induced long-term airway disorders. IMPORTANCEThe current study is critical to understanding that PCFs are involved in long-term airway inflammation and airway resistance after RSV infection through mediating MMP-12 production via PAR2, indicating that the inhibition of PCF activity can be targeted therapeutically for virus infection-induced long-term airway disorders. R espiratory syncytial virus (RSV) remains the leading cause of viral bronchiolitis and pneumonia in infants and young children throughout the world. Among the 1% to 3% of infants hospitalized with RSV bronchiolitis, up to 90% of children have experience 2 or more wheezing episodes, and almost 50% will be given a diagnosis of asthma by the age of 6 years (1, 2). Several studies, including epidemiology studies and animal model studies, have shown that RSV persistence in the lung of the host after RSV infection was related to long-term airway hyperresponsiveness (AHR) and inflammation (3-5). However, the mechanisms of these sequelae are poorly understood.We have reported that enhanced NGF (nerve growth factor) was partially involved in long-term airway inflammation and AHR after RSV infection (6), suggesting that neurogenic factors participate in long-term airway diseases. Eleva...

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supporting

confidence: 48%

Pulmonary C Fibers Modulate MMP-12 Production via PAR2 and Are Involved in the Long-Term Airway Inflammation and Airway Hyperresponsiveness Induced by Respiratory Syncytial Virus Infection

Zang

Zhuang

Deng

et al. 2016

J Virol

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“…[1][2][3][4] Blood-borne proteases coordinate hemostatic and innate immune responses through coagulation and complement cascades. 3,5 Under physiological conditions, the coagulation cascade is triggered by exposure of extravascular cells expressing the membrane-bound cofactor tissue factor (TF) to plasma coagulation zymogens upon vascular injury.…”

Section: Introductionmentioning

confidence: 99%

Matriptase activation connects tissue factor–dependent coagulation initiation to epithelial proteolysis and signaling

Gall

Szabo

Lee

et al. 2016

Blood

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The coagulation cascade is designed to sense tissue injury by physical separation of the membrane-anchored cofactor tissue factor (TF) from inactive precursors of coagulation proteases circulating in plasma. Once TF on epithelial and other extravascular cells is exposed to plasma, sequential activation of coagulation proteases coordinates hemostasis and contributes to host defense and tissue repair. Membrane-anchored serine proteases (MASPs) play critical roles in the development and homeostasis of epithelial barrier tissues; how MASPs are activated in mature epithelia is unknown. We here report that proteases of the extrinsic pathway of blood coagulation transactivate the MASP matriptase, thus connecting coagulation initiation to epithelial proteolysis and signaling. Exposure of TF-expressing cells to factors (F) VIIa and Xa triggered the conversion of latent pro-matriptase to an active protease, which in turn cleaved the pericellular substrates protease-activated receptor-2 (PAR2) and pro-urokinase. An activation pathway-selective PAR2 mutant resistant to direct cleavage by TF:FVIIa and FXa was activated by these proteases when cells co-expressed pro-matriptase, and matriptase transactivation was necessary for efficient cleavage and activation of wild-type PAR2 by physiological concentrations of TF:FVIIa and FXa. The coagulation initiation complex induced rapid and prolonged enhancement of the barrier function of epithelial monolayers that was dependent on matriptase transactivation and PAR2 signaling. These observations suggest that the coagulation cascade engages matriptase to help coordinate epithelial defense and repair programs after injury or infection, and that matriptase may contribute to TF-driven pathogenesis in cancer and inflammation.

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“…MVs are particularly prothrombotic when displaying tissue factor (TF) (4). Viruses, such as influenza, induce TF expression in monocytes and endothelial cells and activate the coagulation cascade, which can result in DIC (5). Influenza virus H1N1 also activates platelets and induces the release of MVs (6).…”

Section: Introductionmentioning

confidence: 99%

Microvesicle Tissue Factor Activity and Interleukin-8 Levels are Associated with Mortality in Patients with Influenza A/H1N1 Infection

Rondina

Tatsumi

Bastarache

et al. 2016

Critical Care Medicine

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Objective To identify plasma biomarkers that can be early predictors of mortality in critically ill patients with primary influenza A/H1N1. Design A prospective, multicenter, case-cohort pilot study. Setting Three academic ICUs. Patients Fifteen patients with primary influenza A/H1N1 that included 7 survivors and 8 non-survivors. For comparison, age- and gender-matched healthy controls (n=27) were also studied. Interventions Plasma was prepared from whole blood drawn upon ICU admission in influenza patients (ICU day 1). Microvesicle tissue factor (MV-TF) activity, thrombin-antithrombin complexes (TATc), and D-dimers were measured as procoagulant markers and markers of activation of coagulation. Plasma cytokine levels were measured on the same blood samples in a subset of 12 influenza patients using the Luminex Multi-Analyte Profiling system. Patients were followed for the primary outcome of 28-day mortality. Measurements and Main Results The average admission APACHE II score of the patients was 25.5±9.3, 60% of patients had shock, and the 28-day mortality rate was 53.3% (n=8/15). Influenza patients had dysregulated indices of coagulation and inflammation compared to controls. Among the markers of activation of coagulation measured on ICU day 1, only increased MV-TF activity was significantly associated with subsequent influenza-related mortality (5.6±1.2 pg/ml in non-survivors vs. 1.8±0.8 pg/mL in survivors, p < 0.05). IL-8 was significantly higher in non-survivors compared with survivors (71.8±29.1 pg/ml, n=5 vs. 17.3±3.7 pg/mL, n=7, p < 0.05). In addition, MV-TF activity and IL-8 levels were significantly and positively correlated (r2 = 0.60, P=0.003). Other cytokines, TATc, and D-dimer were not different between non-survivors and survivors and did not correlate with illness severity or mortality. Conclusions This study identifies an association between plasma IL-8 and MV-TF activity measured upon admission in patients with severe, primary influenza A/H1N1 infection and subsequent mortality. Thus, these biomarkers may serve as very early prognostic markers for patients with influenza A/H1N1.

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Multiple roles of the coagulation protease cascade during virus infection

Cited by 192 publications

References 96 publications

Pulmonary C Fibers Modulate MMP-12 Production via PAR2 and Are Involved in the Long-Term Airway Inflammation and Airway Hyperresponsiveness Induced by Respiratory Syncytial Virus Infection

Pulmonary C Fibers Modulate MMP-12 Production via PAR2 and Are Involved in the Long-Term Airway Inflammation and Airway Hyperresponsiveness Induced by Respiratory Syncytial Virus Infection

Matriptase activation connects tissue factor–dependent coagulation initiation to epithelial proteolysis and signaling

Microvesicle Tissue Factor Activity and Interleukin-8 Levels are Associated with Mortality in Patients with Influenza A/H1N1 Infection

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