Plasminogen activator inhibitor type–1 deficiency does not influence the outcome of murine pneumococcal pneumonia

Rijneveld, Anita W.; Florquin, Sandrine; Bresser, Paul; Levi, Marcel; Waard, Vivian de; Lijnen, Roger; Zee, Jaring S. van der; Speelman, Peter; Carmeliet, Peter; Poll, Tom van der

doi:10.1182/blood-2003-01-0227

Cited by 81 publications

(94 citation statements)

References 55 publications

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“…Our findings, however, are in contrast to those of Rijneveld et al (30), which found no decrease in alveolar neutrophil recruitment in PAI-1 Ϫ/Ϫ mice administered S. pneumoniae. At least two potential possibilities explain the differences in our findings compared with Rijneveld et al First, assessment of pulmonary neutrophil influx was only examined 48 h after S. pneumoniae inoculation in the study by Rijneveld et al, thereby possibly missing an early effect of PAI-1 Ϫ/Ϫ on neutrophil recruitment, as seen in our study (30). Second, the inflammatory mediators used in the two studies are different.…”

Section: Discussioncontrasting

confidence: 57%

“…Septal thickening, lung inflammation, and overall mortality were improved in PAI-1-deficient mice in a hyperoxia model of lung injury, although a direct assessment of neutrophil recruitment to the alveolar compartment was not performed in that study (29). In contrast, neutrophil recruitment to the lung was not diminished in PAI-1-deficient mice after intratracheal (IT) inoculation of Streptococcus pneumoniae (30), or in a model of chronic LPS exposure (31). Several pathways have been described that regulate PAI-1 expression, including the MAPK family (32,33).…”

Section: P Lasminogen Activator Inhibitor-1 (Pai-1)mentioning

confidence: 92%

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Regulation of Lipopolysaccharide-Induced Lung Inflammation by Plasminogen Activator Inhibitor-1 through a JNK-Mediated Pathway

Arndt

Young

Worthen

2005

The Journal of Immunology

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The neutrophil is of undoubted importance in lung inflammation after exposure to LPS. We have shown recently that systemic inhibition of JNK decreased neutrophil recruitment to the lung after exposure to LPS, although the mechanisms underlying this inhibition are incompletely understood. As plasminogen activator inhibitor-1 (PAI-1) accentuates cell migration, with JNK activation recently shown to up-regulate PAI-1 expression, this suggested that systemic JNK inhibition may down-regulate LPS-induced pulmonary neutrophil recruitment through a decrease in PAI-1 expression. We show in this study that exposure of mice to aerosolized LPS increased PAI-1 expression in the lung and alveolar compartment, which was decreased by pretreatment with the JNK inhibitor SP600125. Exogenous, intratracheally administered PAI-1 prevented the inhibition of pulmonary neutrophil recruitment in the setting of systemic JNK inhibition, thereby suggesting a role for PAI-1 in the JNK-mediated pathway regulating LPS-induced neutrophil recruitment. In addition, PAI-1−/− mice had a decrease in neutrophil recruitment to the alveolar compartment after exposure to LPS, compared with wild-type controls, further suggesting a role for PAI-1 in LPS-induced lung inflammation. An increase in the intravascular level of KC is a likely mechanism for the inhibition of pulmonary neutrophil recruitment after LPS exposure in the setting of decreased PAI-1 expression, as systemic KC levels after exposure to LPS were increased in PAI-1-deficient mice and in mice pretreated with SP600125, with augmentation of intravascular KC levels inhibiting neutrophil recruitment to the lung after exposure to LPS.

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Section: Discussioncontrasting

confidence: 57%

Section: P Lasminogen Activator Inhibitor-1 (Pai-1)mentioning

confidence: 92%

Regulation of Lipopolysaccharide-Induced Lung Inflammation by Plasminogen Activator Inhibitor-1 through a JNK-Mediated Pathway

Arndt

Young

Worthen

2005

The Journal of Immunology

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“…Persistent increases in pulmonary concentrations of uPA have also been found in patients with pneumonia (5,6). However, in both animals and humans exposed to pulmonary LPS, as well as in patients with pneumonia, pulmonary concentrations of plasminogen activator inhibitor 1 (PAI-1) are elevated to an even greater degree than are those of uPA (5,6,(31)(32)(33)(34). The relatively greater levels of PAI-1 as compared with uPA appear to be largely responsible for the inhibition of the fibrinolytic activity of uPA in these settings.…”

Section: Discussionmentioning

confidence: 97%

Involvement of the Urokinase Kringle Domain in Lipopolysaccharide-Induced Acute Lung Injury

Wang

Bdeir

Yarovoi

et al. 2006

The Journal of Immunology

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Urokinase plasminogen activator (uPA) plays a major role in fibrinolytic processes and also can potentiate LPS-induced neutrophil activation through interactions with its kringle domain (KD). To investigate the role of the uPA KD in modulating acute inflammatory processes in vivo, we cloned and then developed Abs to the murine uPA KD. Increased pulmonary expression of uPA and the uPA KD was present in the lungs after LPS exposure. Administration of anti-kringle Abs diminished LPS-induced up-regulation of uPA and uPA KD in the lungs, and also decreased the severity of LPS-induced acute lung injury, as determined by development of lung edema, pulmonary neutrophil accumulation, histology, and lung IL-6, MIP-2, and TNF-α cytokine levels. These proinflammatory effects of the uPA KD appeared to be mediated through activation of Akt and NF-κB. The present studies indicate that the uPA KD plays a major role in the development of TLR4-mediated acute inflammatory processes, including lung injury. Blockade of the uPA KD may prevent the development or ameliorate the severity of acute lung injury induced through TLR4-dependent mechanisms, such as would occur in the setting of Gram-negative pulmonary or systemic infection.

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“…We measured circulating levels of a select group of coagulation markers thought to be important in the coagulation response to infection (28,(37)(38)(39). In addition to the changes we observed, changes may well occur at the local level (31,40) or within other coagulation system components or factors that are not reflected in our selection of biomarkers.…”

Section: Discussionmentioning

confidence: 99%

Prevalence and Significance of Coagulation Abnormalities in Community-Acquired Pneumonia

Milbrandt

Reade

Lee

et al. 2009

Mol Med

126

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Coagulation abnormalities are common in severe pneumonia and sepsis, yet little is known about the presence of coagulopathy or its significance in patients with lesser illness severity. We examined coagulation abnormalities in 939 subjects hospitalized with community-acquired pneumonia (CAP) in 28 US hospitals, hypothesizing that abnormalities would increase with illness severity and poor outcomes. We measured plasma coagulation markers (D-dimer, plasminogen activator inhibitor [PAI], antithrombin, factor IX, and thrombin-antithrombin complex [TAT]) at the time of patient presentation to the emergency department and daily during the first wk of hospitalization. Day-1 clinical laboratory test results for international normalized ratio, activated partial thromboplastin time, and platelet count were recorded from the medical record. In our cohort, 32.5% of patients developed severe sepsis and 11.1% died by d 90. Day-1 coagulation abnormalities were common, especially for D-dimer (80.6%) and TAT (36.0%), and increased with illness severity and poor outcomes. However, abnormalities also occurred in those patients who never developed organ dysfunction and differences between groups were modest. The proportion of patients with abnormalities changed over time, yet the magnitude of change was small and not always in the direction of normality. Many patients remaining in the hospital continued to manifest coagulation abnormalities on d 7, especially for D-dimer (86.5%) and TAT (36.9%). In conclusion, coagulation abnormalities were common and persistent in CAP patients, even among the least ill. These findings underscore the complexity of the coagulation response to infection and may offer insights into coagulation-based therapeutics in clinical sepsis trials.

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Plasminogen activator inhibitor type–1 deficiency does not influence the outcome of murine pneumococcal pneumonia

Cited by 81 publications

References 55 publications

Regulation of Lipopolysaccharide-Induced Lung Inflammation by Plasminogen Activator Inhibitor-1 through a JNK-Mediated Pathway

Regulation of Lipopolysaccharide-Induced Lung Inflammation by Plasminogen Activator Inhibitor-1 through a JNK-Mediated Pathway

Involvement of the Urokinase Kringle Domain in Lipopolysaccharide-Induced Acute Lung Injury

Prevalence and Significance of Coagulation Abnormalities in Community-Acquired Pneumonia

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