Tissue factor as an initiator of coagulation and inflammation in the lung

Patients with severe infections almost invariably exhibit evidence of activation of the coagulation system. The lungs are amongst the most frequently affected organs during severe infection and sepsis. The abundant presence of intravascular and extravascular fibrin appears to be a specific hallmark of acute lung injury after sepsis. Tissue factor (TF) is regarded to be the primary initiator of coagulation in severe infection. Effective blockade of the TF pathway, either by recombinant TF pathway inhibitor or by anti-TF antibodies in experimental sepsis, attenuates lung injury and partially prevents pulmonary dysfunction. In addition, inhibition of the activity of TF prevents local activation of coagulation in models of pneumonia. The TF pathway can influence inflammatory signaling by activation of protease activated receptor-1 and -2. This review presents the most recent data on the crosstalk between TF-mediated coagulation and inflammation, with a specific emphasis on these processes in the lung

Diabetes and sepsis outcomes – it is not all bad news

Patients with diabetes mellitus have an increased risk of developing infections and sepsis. In this issue of Critical Care Esper and colleagues report on a large survey, involving 12.5 million sepsis cases, that examined the impact of pre-existing diabetes on organ dysfunction during sepsis. Their main conclusion was that diabetes patients, relative to non-diabetics, were less likely to develop respiratory failure and more likely to develop renal failure during the course of sepsis

Recombinant human activated protein C: current insights into its mechanism of action

Impairment of the protein C pathway plays a central role in the pathogenesis of sepsis. Administration of recombinant human activated protein C (rhAPC) may correct the dysregulated anticoagulant mechanism and prevent propagation of thrombin generation and formation of microvascular thrombosis. Furthermore, it may simultaneously modulate the inflammatory response. It is likely that the beneficial effect of rhAPC observed in experimental and clinical studies of severe sepsis results from a combination of mechanisms that modulate the entangled processes of coagulation and inflammation. This review presents an analysis of the various mechanisms of action of rhAPC in sepsis

Targeting RAGE in sepsis

The receptor of advanced glycation endproducts (RAGE) is a multiligand receptor that upon activation causes sustained activation of multiple inflammatory pathways. Recent evidence, summarized in a review by Bopp and colleagues in this issue of Critical Care, has implicated RAGE as a potential therapeutic target in sepsis. Here, we discuss several open issues that need to be addressed before anti-RAGE strategies can enter the sepsis clinical trial arena

Interleukin-27: a potential new sepsis biomarker exposed through genome-wide transcriptional profiling

Sepsis is a complex clinical condition that is driven predominantly by deviations from the orderly stereotypic immunological response to infection. Much effort has been undertaken in the search for biomarkers that can assist in discriminating critically ill patients with sterile inflammation from those with sepsis. Such biomarkers may aid the clinician in therapeutic decision making upon admission of a patient. Interleukin-27 may be such a discriminative biomarker, as suggested in the previous issue of Critical Care by a study of critically ill childre

Bench-to-bedside review: Bacterial pneumonia with influenza - pathogenesis and clinical implications

Seasonal and pandemic influenza are frequently complicated by bacterial infections, causing additional hospitalization and mortality. Secondary bacterial respiratory infection can be subdivided into combined viral/bacterial pneumonia and post-influenza pneumonia, which differ in their pathogenesis. During combined viral/bacterial infection, the virus, the bacterium and the host interact with each other. Post-influenza pneumonia may, at least in part, be due to resolution of inflammation caused by the primary viral infection. These mechanisms restore tissue homeostasis but greatly impair the host response against unrelated bacterial pathogens. In this review we summarize the underlying mechanisms leading to combined viral/bacterial infection or post-influenza pneumonia and highlight important considerations for effective treatment of bacterial pneumonia during and shortly after influenza

Impact of the factor V Leiden mutation on the outcome of pneumococcal pneumonia: a controlled laboratory study

Introduction: Streptococcus (S.) pneumoniae is the most common cause of community-acquired pneumonia. The factor V Leiden (FVL) mutation results in resistance of activated FV to inactivation by activated protein C and thereby in a prothrombotic phenotype. Human heterozygous FVL carriers have been reported to be relatively protected against sepsis-related mortality. We here determined the effect of the FVL mutation on coagulation, inflammation, bacterial outgrowth and outcome in murine pneumococcal pneumonia. Methods: Wild-type mice and mice heterozygous or homozygous for the FVL mutation were infected intranasally with 2*10(6) colony forming units of viable S. pneumoniae. Mice were euthanized after 24 or 48 hours or observed in a survival study. In separate experiments mice were treated with ceftriaxone intraperitoneally 24 hours after infection and euthanized after 48 hours or observed in a survival study. Results: The FVL mutation had no consistent effect on activation of coagulation in either the presence or absence of ceftriaxone therapy, as reflected by comparable lung and plasma levels of thrombin-antithrombin complexes and fibrin degradation products. Moreover, the FVL mutation had no effect on lung histopathology, neutrophil influx, cytokine and chemokine levels or bacterial outgrowth. Remarkably, homozygous FVL mice were strongly protected against death due to pneumococcal pneumonia when treated with ceftriaxone, which was associated with more pronounced FXIII depletion; this protective effect was not observed in the absence of antibiotic therapy. Conclusions: Homozygosity for the FVL mutation protects against lethality due to pneumococcal pneumonia in mice treated with antibiotic

Kinase Activity Profiling of Gram-Negative Pneumonia

Pneumonia is a severe disease with high morbidity and mortality. A major causative pathogen is the Gram-negative bacterium Klebsiella (K.) pneumoniae. Kinases play an integral role in the transduction of intracellular signaling cascades and regulate a diverse array of biological processes essential to immune cells. The current study explored signal transduction events during murine Gram-negative pneumonia using a systems biology approach. Kinase activity arrays enable the analysis of 1,024 consensus sequences of protein kinase substrates. Using a kinase activity array on whole lung lysates, cellular kinase activities were determined in a mouse model of K. pneumoniae pneumonia. Notable kinase activities also were validated with phospho-specific Western blots. On the basis of the profiling data, mitogen-activated protein kinase (MAPK) signaling via p42 mitogen-activated protein kinase (p42) and p38 mitogen-activated protein kinase (p38) and transforming growth factor β (TGFβ) activity were reduced during infection, whereas v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian) (SRC) activity generally was enhanced. AKT signaling was represented in both metabolic and inflammatory (mitogen-activated protein kinase kinase 2 [MKK], apoptosis signal-regulating kinase/mitogen-activated protein kinase kinase kinase 5 [ASK] and v-raf murine sarcoma viral oncogene homolog B1 [b-RAF]) context. This study reaffirms the importance of classic inflammation pathways, such as MAPK and TGFβ signaling and reveals less known involvement of glycogen synthase kinase 3β (GSK-3β), AKT and SRC signaling cassettes in pneumonia

Interleukin-6 Gene-Deficient Mice Show Impaired Defense against Pneumococcal Pneumonia

Induction of pneumonia in C57Bl/6 mice by intranasal inoculation with 106 cfu of Streptococcus pneumoniae resulted in sustained expression of interleukin (IL)-6 mRNA in lungs and increases in lung and plasma IL-6 concentrations. In IL-6-deficient (IL-6−/−) mice, pneumonia was associated with higher lung levels of the proinflammatory cytokines tumor necrosis factor-α, IL-1β, and interferon-γ and of the antiinflammatory cytokine IL-10 than in wild type (IL-6+/+) mice (all P < .05). Also, the plasma concentrations of soluble tumor necrosis factor receptors were higher in IL-6−/− mice (P < .05), while the acute-phase protein response was strongly attenuated (P < .01). Lungs harvested from IL-6−/− mice 40 h after inoculation contained more S. pneumoniae colonies (P < .05). IL-6−/− mice died significantly earlier from pneumococcal pneumonia than did IL-6+/+ mice (P < .05). During pneumococcal pneumonia, IL-6 down-regulates the activation of the cytokine network in the lung and contributes to host defens

Role of Toll-Like Receptors 2 and 4 in Pulmonary Inflammation and Injury Induced by Pneumolysin in Mice

Background: Pneumolysin (PLN) is an intracellular toxin of Streptococcus pneumoniae that has been implicated as a major virulence factor in infections caused by this pathogen. Conserved bacterial motifs are recognized by the immune system by pattern recognition receptors among which the family of Toll-like receptors (TLRs) prominently features. The primary objective of the present study was to determine the role of TLR2 and TLR4 in lung inflammation induced by intrapulmonary delivery of PLN. Methodology/Results: First, we confirmed that purified PLN activates cells via TLR4 (not via TLR2) in vitro, using human embryonic kidney cells transfected with either TLR2 or TLR4. Intranasal administration of PLN induced an inflammatory response in the pulmonary compartment of mice in vivo, as reflected by influx of neutrophils, release of proinflammatory cytokines and chemokines, and a rise in total protein concentrations in bronchoalveolar lavage fluid. These PLN-induced responses were dependent in part, not only on TLR4, but also on TLR2, as indicated by studies using TLR deficient mice. Conclusion: These data suggest that although purified PLN is recognized by TLR4 in vitro, PLN elicits lung inflammation i