Subject(s)
Anti-Inflammatory Agents/therapeutic use , Asthma/drug therapy , Dexamethasone/therapeutic use , Fatty Acids, Omega-3/metabolism , Hypersensitivity/drug therapy , Inflammation/drug therapy , Respiratory Hypersensitivity/drug therapy , Animals , Arachidonate 12-Lipoxygenase/genetics , Arachidonate 15-Lipoxygenase/genetics , Dinoprostone/metabolism , Disease Models, Animal , Humans , Inflammation/complications , Mice , Mice, Inbred C57BL , Mice, Knockout , Prostaglandin D2/metabolismABSTRACT
BACKGROUND: Although acute exacerbations, mostly triggered by viruses, account for the majority of hospitalizations in asthmatic patients, there is still very little known about the pathophysiologic mechanisms involved. Plasmacytoid dendritic cells (pDCs), prominent cells of antiviral immunity, exhibit proinflammatory or tolerogenic functions depending on the context, yet their involvement in asthma exacerbations remains unexplored. OBJECTIVES: We sought to investigate the role of pDCs in allergic airway inflammation and acute asthma exacerbations. METHODS: Animal models of allergic airway disease (AAD) and virus-induced AAD exacerbations were used to dissect pDC function in vivo and unwind the potential mechanisms involved. Sputum from asthmatic patients with stable disease or acute exacerbations was further studied to determine the presence of pDCs and correlation with inflammation. RESULTS: pDCs were key mediators of the immunoinflammatory cascade that drives asthma exacerbations. In animal models of AAD and rhinovirus-induced AAD exacerbations, pDCs were recruited to the lung during inflammation and migrated to the draining lymph nodes to boost TH2-mediated effector responses. Accordingly, pDC depletion after allergen challenge or during rhinovirus infection abrogated exacerbation of inflammation and disease. Central to this process was IL-25, which was induced by allergen challenge or rhinovirus infection and conditioned pDCs for proinflammatory function. Consistently, in asthmatic patients pDC numbers were markedly increased during exacerbations and correlated with the severity of inflammation and the risk for asthma attacks. CONCLUSIONS: Our studies uncover a previously unsuspected role of pDCs in asthma exacerbations with potential diagnostic and prognostic implications. They also propose the therapeutic targeting of pDCs and IL-25 for the treatment of acute asthma.
Subject(s)
Asthma/immunology , Dendritic Cells/immunology , Interleukins/metabolism , Picornaviridae Infections/immunology , Respiratory Hypersensitivity/immunology , Rhinovirus/physiology , Th2 Cells/immunology , Acute Disease , Animals , Asthma/complications , Cell Movement , Cells, Cultured , Disease Models, Animal , Disease Progression , Humans , Lymphocyte Activation , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Picornaviridae Infections/complications , Respiratory Hypersensitivity/complicationsABSTRACT
Although specialized pro-resolving mediators (SPMs) biosynthesized from polyunsaturated fatty acids are critical for the resolution of acute inflammation, the molecules and pathways that induce their production remain elusive. Here, we show that TLR7, a receptor recognizing viral ssRNA and damaged self-RNA, mobilizes the docosahexaenoic acid (DHA)-derived biosynthetic pathways that lead to the generation of D-series SPMs. In mouse macrophages and human monocytes, TLR7 activation triggered production of DHA-derived monohydroxy metabolome markers and generation of protectin D1 (PD1) and resolvin D1 (RvD1). In mouse allergic airway inflammation, TLR7 activation enhanced production of DHA-derived SPMs including PD1 and accelerated the catabasis of Th2-mediated inflammation. D-series SPMs were critical for TLR7-mediated resolution of airway inflammation as this effect was lost in Alox15(-/-) mice, while resolution was enhanced after local administration of PD1 or RvD1. Together, our findings reveal a new previously unsuspected role of TLR7 in the generation of D-series SPMs and the resolution of allergic airway inflammation. They also identify TLR stimulation as a new approach to drive SPMs and resolution of inflammatory diseases.
Subject(s)
Inflammation Mediators/metabolism , Toll-Like Receptor 7/metabolism , Animals , Arachidonate 12-Lipoxygenase/deficiency , Arachidonate 12-Lipoxygenase/genetics , Arachidonate 12-Lipoxygenase/metabolism , Arachidonate 15-Lipoxygenase/deficiency , Arachidonate 15-Lipoxygenase/genetics , Arachidonate 15-Lipoxygenase/metabolism , Arachidonate 5-Lipoxygenase/metabolism , Bronchoalveolar Lavage Fluid/cytology , Cells, Cultured , Docosahexaenoic Acids/metabolism , Humans , Inflammation/metabolism , Inflammation/therapy , Macrophages/cytology , Macrophages/immunology , Macrophages/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Monocytes/immunology , Monocytes/metabolismABSTRACT
INTRODUCTION: Ideally, there will be reproducible markers easily and non-invasively available to test for malignancy, or alternative procedures when there is no accurate marker available. For prostate cancer, one of the most common cancers in men, levels of prostate-specific antigen (PSA) lack specificity and sensitivity for the determination of malignancy when they fall within a range of values termed the 'grey zone'. OBJECTIVE: To examine the predictive value of sialic acid in prostate neoplasms. STUDY DESIGN: In our study of diagnostic accuracy we recruited 70 men complaining of urinary symptoms who presented in the urology department as outpatients or inpatients. All patients were checked with biopsy and pathology in order to relate benign and malignant lesions of the prostate to levels of sialic acid, a member of a family of acetylated products of neuraminic acid, which has so far proved to be a very sensitive and accurate marker of malignancy. RESULTS: The sialic acid level was found to be elevated in patients with prostate cancer (mean 75.06±10.4 mg/dl) and reduced in patients with benign prostate hyperplasia (mean 57.086±8.7 mg/dl) (p<0.01); it had a sensitivity of 86% and specificity of 84% in diagnosing malignancy. CONCLUSION: Sialic acid can be used as an adjunct in predicting prostate malignancy when PSA values fall in the grey zone.
