Plasminogen Activator Inhibitor-Type I Gene Deficient Mice Show Reduced Influx of Neutrophils in Ventilator-Induced Lung Injury

Ventilator-induced lung injury (VILI) is associated with inhibition of the fibrinolytic system secondary to increased production of plasminogen activator inhibitor- (PAI-)1. To determine the role of PAI-1 on pulmonary coagulopathy and inflammation during mechanical ventilation, PAI-1 gene-deficient mice and their wild-type littermates were anesthetized (control), or anesthetized, tracheotomized and subsequently ventilated for 5 hours with either low tidal volumes (LVT) or high tidal volumes (HVT). VILI was assessed by pulmonary coagulopathy, lung wet-to-dry ratios, total protein level in bronchoalveolar lavage fluid, neutrophil influx, histopathology, and pulmonary and plasma cytokine levels. Ventilation resulted in pulmonary coagulopathy and inflammation, with more injury following ventilation with HVT as compared to LVT. In PAI-1 gene-deficient mice, the influx of neutrophils in the pulmonary compartment was attenuated, while increased levels of pulmonary cytokines were found. Other endpoints of VILI were not different between PAI-1 gene-deficient and wild-type mice. These data indicate that a defect fibrinolytic response attenuates recruitment of neutrophils in VILI

Host Transcription Profile in Nasal Epithelium and Whole Blood of Hospitalized Children Under 2 Years of Age With Respiratory Syncytial Virus Infection.

BACKGROUND: Most insights into the cascade of immune events after acute respiratory syncytial virus (RSV) infection have been obtained from animal experiments or in vitro models. METHODS: In this study, we investigated host gene expression profiles in nasopharyngeal (NP) swabs and whole blood samples during natural RSV and rhinovirus (hRV) infection (acute versus early recovery phase) in 83 hospitalized patients <2 years old with lower respiratory tract infections. RESULTS: Respiratory syncytial virus infection induced strong and persistent innate immune responses including interferon signaling and pathways related to chemokine/cytokine signaling in both compartments. Interferon-α/β, NOTCH1 signaling pathways and potential biomarkers HIST1H4E, IL7R, ISG15 in NP samples, or BCL6, HIST2H2AC, CCNA1 in blood are leading pathways and hub genes that were associated with both RSV load and severity. The observed RSV-induced gene expression patterns did not differ significantly in NP swab and blood specimens. In contrast, hRV infection did not as strongly induce expression of innate immunity pathways, and significant differences were observed between NP swab and blood specimens. CONCLUSIONS: We conclude that RSV induced strong and persistent innate immune responses and that RSV severity may be related to development of T follicular helper cells and antiviral inflammatory sequelae derived from high activation of BCL6

The role of bronchoalveolar hemostasis in the pathogenesis of acute lung injury

Disturbed alveolar fibrin turnover is intrinsic to acute lung injury/acute respiratory distress syndrome (ALI/ARDS) and pneumonia and is important to its pathogenesis. Recent studies also suggest disturbed alveolar fibrin turnover to be a feature of ventilator-induced lung injury (VILI). The mechanisms that contribute to alveolar coagulopathy are localized tissue factor-mediated thrombin generation, impaired activity of natural coagulation inhibitors, and depression of bronchoalveolar urokinase plasminogen activator-mediated fibrinolysis, caused by the increase of plasminogen activator inhibitors. Administration of anticoagulant agents (including activated protein C, antithrombin, tissue factor-factor VIIa pathway inhibitors, and heparin) and profibrinolytic agents (including plasminogen activators) attenuate pulmonary coagulopathy. Several preclinical studies show additional anti-inflammatory effects of these therapies in ALI/ARDS and pneumonia. In this article, we review the involvement of coagulation and fibrinolysis in the pathogenesis of ALI/ARDS pneumonia and VILI and the potential of anticoagulant and profibrinolytic strategies to reverse pulmonary coagulopathy and pulmonary inflammatory responses

Recombinant human activated protein C inhibits local and systemic activation of coagulation without influencing inflammation during Pseudomonas aeruginosa pneumonia in rats

OBJECTIVE: Alveolar fibrin deposition is a hallmark of pneumonia. It has been proposed that recombinant human activated protein C exerts lung-protective effects via anticoagulant and anti-inflammatory pathways. We investigated the role of the protein C system in pneumonia caused by Pseudomonas aeruginosa, the organism that is predominantly involved in ventilator-associated pneumonia. DESIGN: An observational clinical study and a controlled, in vivo laboratory study. SETTING: Multidisciplinary intensive care unit and a research laboratory of a university hospital. PATIENTS AND SUBJECTS: Patients with unilateral ventilator-associated pneumonia and male Sprague-Dawley rats. INTERVENTIONS: Bilateral bronchoalveolar lavage was performed in five patients with unilateral ventilator-associated pneumonia. A total of 62 rats were challenged with intratracheal P. aeruginosa (10 colony-forming units), inducing pneumonia. Rats were randomized to treatment with normal saline, recombinant human activated protein C, heparin, or recombinant tissue plasminogen activator. MEASUREMENTS AND MAIN RESULTS: Patients with pneumonia demonstrated suppressed levels of protein C and activated protein C in bronchoalveolar lavage fluid obtained from the infected site compared with the contralateral uninfected site. Intravenous administration of recombinant human activated protein C in rats with P. aeruginosa pneumonia limited bronchoalveolar generation of thrombin-antithrombin complexes, largely preserving local antithrombin activity. However, recombinant human activated protein C did not have effects on neutrophil influx and activity, expression of pulmonary cytokines, or bacterial clearance. CONCLUSIONS: In patients with ventilator-associated pneumonia, the pulmonary protein C pathway is impaired at the site of infection, and local anticoagulant activity may be insufficient. Recombinant human activated protein C prevents procoagulant changes in the lung; however, it does not seem to alter the pulmonary host defense against P. aeruginosa pneumonia

Antithrombin inhibits bronchoalveolar activation of coagulation and limits lung injury during Streptococcus pneumoniae pneumonia in rats

Objective: Alveolar fibrin deposition is a hallmark of pneumonia. It has been proposed that natural inhibitors of coagulation, including activated protein C, antithrombin, and tissue factor pathway inhibitor, exert lung-protective effects via anticoagulant and possibly anti-inflammatory pathways. We investigated the role of these natural anticoagulants in Streptococcus pneumoniae pneumonia. Design: A controlled in vivo laboratory.study. Setting. Research laboratory of a university hospital. Subjects. Total of 98 male Sprague-Dawley rats. Interventions. Rats were challenged intratracheally with S. pneumoniae (serotype 3, 106 colony forming units), inducing pneumonia. Rats were randomized to intravenous treatment with normal saline, activated protein C, antithrombin, tissue factor pathway inhibitor, heparin, or tissue-type plasminogen activator. Measurements and Main Results: Rats infected with S. pneumoniae had increased thrombin-antithrombin complexes in bronchoalveolar lavage fluid, with decreased levels of antithrombin activity and fibrin degradation products. Administration of activated protein C, antithrombin, and tissue factor pathway inhibitor significantly limited these procoagulant changes. Furthermore, antithrombin treatment resulted in less bacterial outgrowth of S. pneumoniae and less histopathologic damage in lungs. Conclusions. Anticoagulant treatment attenuates pulmonary coagulopathy during S. pneumoniae pneumonia. Antithrombin seems to exert significant lung-protective effects in pneumococcal pneumonia in rat