Local activation of coagulation and inhibition of fibrinolysis in the lung during ventilator associated pneumonia

Schultz, Marcus J.; Millo, Julian; Levi, Marcel; Hack, C. E.; Weverling, Gerrit Jan; Garrard, C S; Poll, Tom van der

doi:10.1136/thorax.2003.013888

Cited by 132 publications

(135 citation statements)

References 19 publications

(32 reference statements)

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“…Earlier it has been demonstrated that pulmonary coagulopathy is an important feature of pulmonary infection (38,39), with changes in fibrin generation being restricted to the site of infection in patients with community-acquired pneumonia caused by S. pneumoniae (46) or ventilator-associated pneumonia caused by several pathogens, among others P. aeruginosa (47,48). Pulmonary coagulopathy now gains more and more interest as a new target in therapeutic studies of acute lung injury of pneumonia (49)(50)(51).…”

Section: Discussionmentioning

confidence: 99%

Platelet-Activating Factor Receptor Contributes to Host Defense against Pseudomonas aeruginosa Pneumonia but Is Not Essential for the Accompanying Inflammatory and Procoagulant Response

Zoelen

Florquin²,

Meijers

et al. 2008

The Journal of Immunology

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Pseudomonas aeruginosa is a major cause of nosocomial pneumonia, which is associated with high morbidity and mortality. Because of its ubiquitous nature and its ability to develop resistance to antibiotics, it is a problematic pathogen from a treatment perspective. Platelet-activating factor receptor (PAFR) is involved in phagocytosis of several pathogens. To determine the role of PAFR in the innate immune response to P. aeruginosa pneumonia, pafr gene-deficient (PAFR−/−) mice and normal wild-type (Wt) mice were intranasally inoculated with P. aeruginosa. PAFR deficiency impaired host defense as reflected by increased bacterial outgrowth and dissemination in mice with a targeted deletion of the PAFR gene. PAFR−/− neutrophils showed a diminished phagocytosing capacity of P. aeruginosa in vitro. Relative to Wt mice, PAFR−/− mice demonstrated increased lung inflammation and injury as reflected by histopathology, relative lung weights and total protein concentrations in bronchoalveolar lavage fluid, which was accompanied by higher levels of proinflammatory cytokines in lung homogenates and plasma. In addition, PAFR deficiency was associated with exaggerated local and systemic activation of coagulation as determined by fibrin staining of lung tissue and pulmonary and plasma concentrations of thrombin-antithrombin complexes and D-dimer. These data suggest that PAFR is an essential component of an effective host response to P. aeruginosa pneumonia, at least partly via its contribution to the phagocytic properties of professional granulocytes. Additionally, our results indicate that PAFR signaling is not essential for the induction of a local and systemic inflammatory and procoagulant response to Pseudomonas pneumonia.

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Section: Discussionmentioning

confidence: 99%

Platelet-Activating Factor Receptor Contributes to Host Defense against Pseudomonas aeruginosa Pneumonia but Is Not Essential for the Accompanying Inflammatory and Procoagulant Response

Zoelen

Florquin²,

Meijers

et al. 2008

The Journal of Immunology

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“…Ontology analysis of the candidate genes demonstrates that the major mechanical stretch-related ALI biological process was blood coagulation with genes in this ontology including fibrinogen A, coagulation factor III, plasminogen activator, urokinase receptor (uPAR), tissue factor, and PAI-1 ( Figure 3). Many of these same genes have been implicated elsewhere as potential candidate genes in ALI (13,28,29) and in VALI (30,31). In addition to coagulation, there was prominent representation of genes involved in innate immunity (MIF, CD14, TNF, IL-1RA, C5aR, IL-6).…”

Section: Cross-species Gene Expression Profiling and Identification Omentioning

confidence: 96%

Functional Genomic Insights into Acute Lung Injury: Role of Ventilators and Mechanical Stress

Nonas

Finigan

Gao

et al. 2005

Proceedings of the American Thoracic Society

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Acute lung injury (ALI) is a complex and devastating illness, often occurring in the setting of sepsis and trauma. Despite recent advances in the understanding and treatment of ALI, pathogenic mechanisms and genetic modifiers in ALI remain incompletely understood. Furthermore, there has been increasing interest in the identification of genetic variations that contribute to ALI susceptibility and severity in order to gain unique insights into ALI pathogenesis and to design novel treatment strategies. However, the sporadic nature of ALI and the lack of family-based cohort studies preclude conventional genomic approaches such as linkage mapping (or "positional cloning"). We have used a "candidate gene approach" with extensive gene expression profiling studies in animal (rat, murine, canine) and human models of ALI to identify potential ALI candidate genes associated with sepsis and ventilator-associated lung injury. These studies, when combined with innovative in silico bioinformatics approaches, revealed both novel (pre-B-cell colony enhancing factor, myosin light chain kinase) and previously identified (interleukin 6, macrophage migration inhibitory factor) gene candidates. Subsequent single nucleotide polymorphism discovery and genotyping studies revealed polymorphisms that demonstrate an influence on ALI susceptibility in patients. These studies indicate that the candidate gene approach is a robust strategy to provide novel insights into the genetic basis of ALI, and the identification of potentially novel therapeutic targets.Keywords: single nucleotide polymorphism; interleukin 6; pre-B-cell colony enhancing factor Acute lung injury (ALI) is a common and devastating illness in patients with sepsis, pneumonia, or trauma, and carries an annual mortality rate of 30 to 50% (1). Marked by profound inflammation, increased vascular permeability, and alveolar flooding, the acute respiratory failure that is associated with ALI invariably requires mechanically assisted ventilation. Despite advances in care for patients with ALI, the development of sophisticated hemodynamic monitoring technologies, and new insights into the pathogenesis underlying sepsis and ALI, there remains a significant gap in the full translation of this progress into increased ALI survival (2). Furthermore, improved understanding of ALI at both the molecular and population level has not reconciled the heterogeneity in patient susceptibility to ALI or ALI outcomes. Until recently, studies focused on understanding the molecular basis of complex disorders such as ALI were limited to a gene-by-gene approach. However, the capacity for high-throughput sequencing coupled with the mapping of the human genome heralded additional revolutionary technologic breakthroughs with tools for a large-scale analysis of the genome, including rapid, high-throughput gene expression profiling and genotyping (3, 4). Access to the complete genome sequences of prokaryotes, eukaryotic model organisms, as well as the mouse, rat, and dog has sparked efforts to identify specific...

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“…Depressed fibrinolytic activity is related to high pulmonary concentrations of the main inhibitor of fibrinolysis in lung tissue, plasminogen activator inhibitor type 1 (PAI-1). The importance of the fibrinolytic system in the pathogenesis of pneumonia is underscored by the observation that a depression of bronchoalveolar fibrinolysis precedes the clinical occurrence of pneumonia by several days (7). Bronchoalveolar fluid levels of PAI-1 are increased in burn patients with inhalation trauma and in patients with ARDS (12,31) and is probably secreted by lung epithelial cells, fibroblasts, and endothelial cells (32,33).…”

Section: Fibrinolysismentioning

confidence: 99%

“…In association with enhanced fibrin production, fibrinolytic activity is depressed in alveolar fluids of patients with pneumonia (7,20,22), patients with inhalation trauma (12), and patients with ARDS (6). Depressed fibrinolytic activity is related to high pulmonary concentrations of the main inhibitor of fibrinolysis in lung tissue, plasminogen activator inhibitor type 1 (PAI-1).…”

Section: Fibrinolysismentioning

confidence: 99%

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Nebulized anticoagulants in lung injury in critically ill patients—an updated systematic review of preclinical and clinical studies

et al. 2017

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Pneumonia, inhalation trauma and acute respiratory distress syndrome (ARDS), typical causes of lung injury in critically ill patients, are all three characterized by dysregulated inflammation and coagulation in the lungs. Nebulized anticoagulants are thought to have beneficial effects as they could attenuate pulmonary coagulopathy and maybe even affect pulmonary inflammation. A systematic search of the medical literature was performed using terms referring to aspects of the condition ('pneumonia', 'inhalation trauma' and 'ARDS'), the intervention ('nebulized', 'vaporized', and 'aerosolized') and anticoagulants limited to agents that are commercially available and frequently given or tested in critically ill patients ['heparin', 'danaparoid', 'activated protein C' (APC), 'antithrombin' (AT) and 'tissue factor pathway inhibitor' (TFPI)].The systematic search identified 16 articles reporting on preclinical studies and 11 articles reporting on human trials. All nebulized anticoagulants attenuate pulmonary coagulopathy in preclinical studies using various models for lung injury, but the effects on inflammation are less consistent. Nebulized heparin, danaparoid and TFPI, but not APC and AT also reduced systemic coagulation. Nebulized heparin in lung injury patients shows contradictory results, and there is concern over systemic side effects of this strategy.Future studies need to focus on the way to nebulize anticoagulants, as well as on efficient but safe dosages, and other side effects.

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Local activation of coagulation and inhibition of fibrinolysis in the lung during ventilator associated pneumonia

Cited by 132 publications

References 19 publications

Platelet-Activating Factor Receptor Contributes to Host Defense against Pseudomonas aeruginosa Pneumonia but Is Not Essential for the Accompanying Inflammatory and Procoagulant Response

Platelet-Activating Factor Receptor Contributes to Host Defense against Pseudomonas aeruginosa Pneumonia but Is Not Essential for the Accompanying Inflammatory and Procoagulant Response

Functional Genomic Insights into Acute Lung Injury: Role of Ventilators and Mechanical Stress

Nebulized anticoagulants in lung injury in critically ill patients—an updated systematic review of preclinical and clinical studies

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