Secondary pneumococcal pneumonia is a serious complication during and shortly after influenza infection. We established a mouse model to study postinfluenza pneumococcal pneumonia and evaluated the role of IL-10 in host defense against Streptococcus pneumoniae after recovery from influenza infection. C57BL/6 mice were intranasally inoculated with 10 median tissue culture infective doses of influenza A (A/PR/8/34) or PBS (control) on day 0. By day 14 mice had regained their normal body weight and had cleared influenza virus from the lungs, as determined by real-time quantitative PCR. On day 14 after viral infection, mice received 104 CFU of S. pneumoniae (serotype 3) intranasally. Mice recovered from influenza infection were highly susceptible to subsequent pneumococcal pneumonia, as reflected by a 100% lethality on day 3 after bacterial infection, whereas control mice showed 17% lethality on day 3 and 83% lethality on day 6 after pneumococcal infection. Furthermore, 1000-fold higher bacterial counts at 48 h after infection with S. pneumoniae and, particularly, 50-fold higher pulmonary levels of IL-10 were observed in influenza-recovered mice than in control mice. Treatment with an anti-IL-10 mAb 1 h before bacterial inoculation resulted in reduced bacterial outgrowth and markedly reduced lethality during secondary bacterial pneumonia compared with those in IgG1 control mice. In conclusion, mild self-limiting influenza A infection renders normal immunocompetent mice highly susceptible to pneumococcal pneumonia. This increased susceptibility to secondary bacterial pneumonia is at least in part caused by excessive IL-10 production and reduced neutrophil function in the lungs.

Independent studies have shown that CD27, 4-1BB, and OX40 can all promote survival of activated CD8+ T cells. We have therefore compared their impact on CD8+ memory T cell formation and responsiveness within one, physiologically relevant model system. Recombinant mice, selectively lacking input of one or two receptors, were challenged intranasally with influenza virus, and the immunodominant virus-specific CD8+ T cell response was quantified at priming and effector sites. Upon primary infection, CD27 and (to a lesser extent) 4-1BB made nonredundant contributions to accumulation of CD8+ virus-specific T cells in draining lymph nodes and lung, while OX40 had no effect. Interestingly though, in the memory response, accumulation of virus-specific CD8+ T cells in spleen and lung critically depended on all three receptor systems. This was explained by two observations: 1) CD27, 4-1BB, and OX40 were collectively responsible for generation of the same memory CD8+ T cell pool; 2) CD27, 4-1BB, and OX40 collectively determined the extent of secondary expansion, as shown by adoptive transfers with standardized numbers of memory cells. Surprisingly, wild-type CD8+ memory T cells expanded normally in primed OX40 ligand- or 4-1BB ligand-deficient mice. However, when wild-type memory cells were generated in OX40 ligand- or 4-1BB ligand-deficient mice, their secondary expansion was impaired. This provides the novel concept that stimulation of CD8+ T cells by OX40 and 4-1BB ligand during priming imprints into them the capacity for secondary expansion. Our data argue that ligand on dendritic cells and/or B cells may be critical for this.

Purpose Systemic levels of soluble urokinase-type plasminogen activator receptor (suPAR) positively correlate with the activation level of the immune system. We reviewed the usefulness of systemic levels of suPAR in the care of critically ill patients with sepsis, SIRS, and bacteremia, focusing on its diagnostic and prognostic value. Methods A PubMed search on suPAR was conducted, including manual cross-referencing. The list of papers was narrowed to original studies of critically ill patients. Ten papers on original studies of critically ill patients were identified that report on suPAR in sepsis, SIRS, or bacteremia. Results Systematic levels of suPAR have little diagnostic value in critically ill patients with sepsis, SIRS, or bacteremia. Systemic levels of suPAR, however, have superior prognostic power over other commonly used biological markers in these patients. Mortality prediction by other biological markers or severity-of-disease classification system scores improves when combining them with suPAR. Systemic levels of suPAR correlate positively with markers of organ dysfunction and severity-of-disease classification system scores. Finally, systemic levels of suPAR remain elevated for prolonged periods after admission and only tend to decline after several weeks. Notably, the type of assay used to measure suPAR as well as the age of the patients and underlying disease affect systemic levels of suPAR. Conclusions The diagnostic value of suPAR is low in patients with sepsis. Systemic levels of suPAR have prognostic value, and may add to prognostication of patients with sepsis or SIRS complementing severity-of-disease classification systems and other biological markers.

IntroductionDendritic cells (DCs) are key regulators of adaptive immunity by selectively promoting or suppressing T-cell responses. 1 One of the suppressive mechanisms involves the expression of the enzyme indoleamine 2,3-dioxygenase (IDO) by DCs. 2 IDO degrades the essential amino acid tryptophan into kynurenine, which leads to tryptophan depletion resulting in suppression of T-cell proliferation 3-5 or induction of apoptosis in activated T cells both in vitro and in vivo, 6 and, consequently, the induction of tolerance. 7,8 IDO can be induced in DCs by a variety of stimuli, including ligation of CD40 or CD80/CD86 by, respectively, CD40L 3,9,10 or CTLA-4 11,12 on activated T cells, as well as soluble factors such as IFN-␥ and IL-1 (reviewed in Mellor and Munn 2 ). Some other factors, such as LPS, require additional signals such as IFN-␥ to effectively induce IDO in DCs. 3,13 Remarkably, the conditions resulting in the expression of anti-inflammatory IDO also result in the expression of proinflammatory cytokines.NF-B transcription factors are essential for the expression of proinflammatory cytokines in DCs 14 and have been implicated in IDO induction. 15 NF-B can be activated via 2 distinct signal transduction pathways. The canonical (also known as classical) NF-B pathway requires activation of the IKK complex, consisting of the catalytic subunits IKK␣ and IKK␤, and the regulatory subunit NEMO/IKK␥, and controls NF-B activation in response to proinflammatory stimuli such as LPS, TNF␣, and CD40L. [16][17][18][19] Activation of this pathway results predominantly in the activation, nuclear translocation, and DNA binding of the classical NF-B dimer p50-RelA. In this pathway, IKK␤ is essential for NF-B activation, whereas IKK␣ is dispensable for the activation and induction of NF-B DNA-binding activity in most cell types. [19][20][21] In contrast, the noncanonical (also known as alternative) pathway is strictly dependent on IKK␣ homodimers and requires neither IKK␤ nor NEMO/IKK␥. 22,23 The target for IKK␣ homodimers is NF-B2/p100, which upon activation of IKK␣ by NF-B-inducing kinase (NIK) is incompletely degraded into p52, resulting in the release and nuclear translocation of mainly p52-RelB dimers. This pathway can be triggered by the activation of members of the TNF-receptor superfamily such as the lymphotoxin ␤ receptor, B-cell activating factor belonging to the TNF family (BAFF) receptor, and CD40 (which also induce canonical NF-B signaling), but not via pattern recognition receptors such as Toll-like receptor 4 (TLR4), the receptor for LPS. 24 It has been suggested that the canonical and noncanonical NF-B pathways play distinct roles in immunity (reviewed in Bonizzi and Karin 25 ). Recent literature proposes a role for the noncanonical pathway in the regulation of immune responses, as IKK␣ is implicated in the negative regulation of inflammation 26,27 and NIK has a role in the development of regulatory T cells (Tregs). 28 In addition, it has been demonstrated that IKK␣ has an important function in thymic organo...

Mechanical ventilation induced a NLRP3 inflammasome dependent pulmonary inflammatory response. NLRP3 inflammasome deficiency partially protected mice from VILI.

To cite this article: Glas GJ, van der Sluijs KF, Schultz MJ, Hofstra J-JH, van der Poll T, Levi M. Bronchoalveolar hemostasis in lung injury and acute respiratory distress syndrome. J Thromb Haemost 2013; 11: 17-25.Summary. Enhanced intrapulmonary fibrin deposition as a result of abnormal broncho-alveolar fibrin turnover is a hallmark of acute respiratory distress syndrome (ARDS), pneumonia and ventilator-induced lung injury (VILI), and is important to the pathogenesis of these conditions. 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. There is an intense and bidirectional interaction between coagulation and inflammatory pathways in the bronchoalveolar compartment. Systemic or local administration of anticoagulant agents (including activated protein C, antithrombin and heparin) and profibrinolytic agents (such as plasminogen activators) attenuate pulmonary coagulopathy. Several preclinical studies show additional anti-inflammatory effects of these therapies in ARDS and pneumonia.

Abstract-Influenza infections increase the risk of diseases associated with a prothrombotic state, such as venous thrombosis and atherothrombotic diseases. However, it is unclear whether influenza leads to a prothrombotic state in vivo. To determine whether influenza activates coagulation, we measured coagulation and fibrinolysis in influenzainfected C57BL/6 mice. We found that influenza increased thrombin generation, fibrin deposition, and fibrinolysis. In addition, we used various anti-and prothrombotic models to study pathways involved in the influenza-induced prothrombotic state. A reduced capacity to generate activated protein C in TM pro/pro mice increased thrombin generation and fibrinolysis, whereas treatment with heparin decreased thrombin generation in influenza-infected C57Bl/6 mice. Thrombin generation was not changed in hyperfibrinolytic mice, deficient in plasminogen activator inhibitor type-1 (PAI-1 Ϫ/Ϫ ); however, increased fibrin degradation was seen. Treatment with tranexamic acid reduced fibrinolysis, but thrombin generation was unchanged. We conclude that influenza infection generates thrombin, increased by reduced levels of protein C and decreased by heparin. The fibrinolytic system appears not to be important for thrombin generation. These findings suggest that influenza leads to a prothrombotic state by coagulation activation. Heparin treatment reduces the influenza induced prothrombotic state.

No abstract