These findings demonstrate that TLR3 activation by poly(I:C) modulates the local inflammatory response in the lung and suggest a critical role of TLR3 activation in driving lung function impairment. Thus, TLR3 activation may be one mechanism through which viral infections contribute toward exacerbation of respiratory disease.

BackgroundAcute respiratory distress syndrome (ARDS) is a disease associated with a high mortality rate. The initial phase is characterized by induction of inflammatory cytokines and chemokines and influx of circulating inflammatory cells, including macrophages which play a pivotal role in the innate and adaptive immune responses to injury. Growing evidence points to phenotypic heterogeneity and plasticity between various macrophage activation states.MethodsIn this study, gene expression in alveolar macrophages and circulating leukocytes from healthy control subjects and patients with ARDS was assessed by mRNA microarray analysis.ResultsBoth alveolar macrophages and circulating leukocytes demonstrated up-regulation of genes encoding chemotactic factors, antimicrobial peptides, chemokine receptors, and matrix metalloproteinases. Two genes, the pro-inflammatory S100A12 and the anti-inflammatory IL-1 decoy receptor IL-1R2 were significantly induced in both cell populations in ARDS patients, which was confirmed by protein quantification. Although S100A12 levels did not correlate with disease severity, there was a significant association between early plasma levels of IL-1R2 and APACHE III scores at presentation. Moreover, higher levels of IL-1R2 in plasma were observed in non-survivors as compared to survivors at later stages of ARDS.ConclusionsThese results suggest a hybrid state of alveolar macrophage activation in ARDS, with features of both alternative activation and immune tolerance/deactivation.. Furthermore, we have identified a novel plasma biomarker candidate in ARDS that correlates with the severity of systemic illness and mortality.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-015-0190-x) contains supplementary material, which is available to authorized users.

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Doripenem is a carbapenem with potent broad-spectrum activity against Gram-negative pathogens, including antibiotic-resistant Enterobacteriaceae. As the incidence of extended-spectrum ␤-lactamase (ESBL)-producing Gram-negative bacilli is increasing, it was of interest to examine the in vivo comparative efficacy of doripenem, imipenem, and meropenem against a Klebsiella pneumoniae isolate expressing the TEM-26 ESBL enzyme. In a murine lethal lower respiratory infection model, doripenem reduced the Klebsiella lung burden by 2 log 10 CFU/g lung tissue over the first 48 h of the infection. Treatment of mice with meropenem or imipenem yielded reductions of approximately 1.5 log 10 CFU/g during this time period. Seven days postinfection, Klebsiella titers in the lungs of treated mice decreased an additional 2 log 10 CFU/g relative to those in the lungs of untreated control animals. Lipopolysaccharide (LPS) endotoxin release assays indicated that 6 h postinfection, meropenem-and imipenemtreated animals had 10-fold more endotoxin in lung homogenates and sera than doripenem-treated mice. Following doripenem treatment, the maximum endotoxin release postinfection (6 h) was 53,000 endotoxin units (EU)/ml, which was 2.7-and 6-fold lower than imipenem or meropenem-treated animals, respectively. While the levels of several proinflammatory cytokines increased in both the lungs and sera following intranasal K. pneumoniae inoculation, doripenem treatment, but not meropenem or imipenem treatment, resulted in significantly increased interleukin 6 levels in lung homogenates relative to those in lung homogenates of untreated controls, which may contribute to enhanced neutrophil killing of bacteria in the lung. Histological examination of tissue sections indicated less overall inflammation and tissue damage in doripenem-treated mice, consistent with improved antibacterial efficacy, reduced LPS endotoxin release, and the observed cytokine induction profile.Bacterial infections of the lower respiratory tract continue to be a major cause of morbidity and mortality despite the development of broad-spectrum antibiotics (11). Infections originating in the lung more frequently lead to sepsis than those originating in the abdomen or the urinary tract, with community-acquired pneumonia (CAP) emerging as one of the leading causes of death worldwide (4). Klebsiella pneumoniae is an increasingly important CAP pathogen, particularly in individuals with impaired pulmonary defenses, and is also a key pathogen in nosocomial pneumonia (42). Pulmonary infections caused by K. pneumoniae are often characterized by a rapid clinical course that includes multilobar involvement, formation of abscesses, and dissemination of bacteria from the pulmonary air space into the bloodstream, leading to widespread systemic effects and death (27,31,43). Treatment of K. pneumoniae infections can be complicated by the presence of extended-spectrum ␤-lactamases (ESBLs), which confer resistance to many broad-spectrum penicillin and cephalosporin antibiotics. K. pneumoniae i...

Introduction: Immunotherapies are focused on strategies that alter immune responses, using antibodies that binds to receptors on different immune cell subsets and either activate or suppress their functions depending on the immune response being targeted. Hence, the necessity of developing assays that assess the functional and biological effect of a therapeutic on its target. When incorporated into high-parameter flow cytometry panels, receptor occupancy assay can simultaneously evaluate receptor expression and drug occupancy on defined cell subsets, which can provide information related to functional effects, and safety. Areas covered: This review focuses on the importance of developing, optimizing, and validating a robust Receptor Occupancy Assay (ROA) to improve dose selection, pharmacology monitoring and safety mainly in clinical settings. Expert opinion: The designing of an ROA can be challenging and can lead to exaggerated pharmacology if not accurately developed, optimized, and validated. However, improvements in our understanding of epitopes, binding, affinities, and pharmacological effects may lead to improved antibody drug targeting and receptor evaluation.