1,721,075 research outputs found
Making a bad relationship good
No full textThere is increasing evidence of direct and/or indirect interactions between bacteria and viruses. Two new studies shed light on the mechanisms underlying these interactions with implications not only on our understanding of microbial pathogenesis but also on vaccine design
Editorial. Lung macrophages: old hands required rather than new blood?
No full textMacrophages are key sentinel cells of the lung, clearing inhaled particulates and micro-organisms from the airway. These cells perform this function without provoking inflammatory responses that could lead to pneumonias. Previous work suggested that the lung macrophage population was maintained by the recruitment of blood monocytes. However, this observation was made in transplanted lungs where macrophages had been depleted, either by hypoxia or chemotherapy. More recent work in murine models using cell fate mapping demonstrated that lung macrophages are generated early in embryonic development initially in the foetal yolk sac and slightly later in the foetal liver. Macrophages that arise from these sources then seed the lung, where they reside as a self-renewing population with little further recruitment from blood monocytes
In asthma, change is the only constant
No full textVariability is a hallmark of asthma, whether that be in morning and evening peak flow, the seasonality of exacerbations or responsiveness to treatment (1). The drivers of disease variation are manifold, but are particularly troublesome when it comes to the responsiveness to corticosteroid treatment, our mainstay of disease control. A lack of corticosteroid responsiveness is a characteristic of severe asthma (2), significantly impacting patients’ mortality and morbidity, particularly in relation to exacerbation frequency. The presence of eosinophils in blood or sputum are linked to a steroid-sensitive T2-driven inflammation and the presence of these cells are often used to guide the use of corticosteroids as well as biologic therapies (3). In contrast, sputum neutrophils are linked to activation of steroid-insensitive T1-pathways (4), but the drivers and stability of these pathways are not well understood. Further understanding of the mechanisms that lead to this corticosteroid resistance are therefore required to allow targeted treatment of these steroid unresponsive pathways to bring patient benefit. In this issue of the Journal, Fahy and colleagues provide insight into these disease mechanisms using RNA Sequencing data derived from the sputa of asthma patients in the SARP-3 study collected longitudinally (5). Additionally, sputa from a subcohort of patients was analysed following intramuscular injection of the corticosteroid, triamcinolone acetonide (TA)
Therapeutics for acute lung injury: time to call in the DRs?
No full textLung inflammation is a prominent feature of both acute and chronic respiratory syndromes. Classically, in conditions like non-pulmonary sepsis, pneumonia or chronic obstructive lung disease (COPD), this inflammation has been associated with infection, but may also result from other non-infectious insults, such as trauma or injury. Both infectious and non-infectious insults can lead to Acute Lung Injury(ALI)/Acute Respiratory Distress Syndrome (ARDS), where regardless of the underlying stimuli, the net result of the inflammation initiated is damage to the alveolar-capillary membrane which can result in respiratory failure [1]. As the underlying mechanisms unifying these diverse insults are not well understood, the development of new treatments has also lagged behind. Even where we think we understand the initiating stimulus, for example in sepsis, targeting inflammatory pathways with pleiotropic anti-inflammatory drugs such as steroids or aspirin provide little benefit and ALI/ARDS outcomes remain poor. Moreover, even ?2-agonists, which might be thought to provide some benefit due to their bronchodilator action, have not been demonstrated to provide any improvement in clinical outcomes [2]. Thus, there is a pressing need to identify new therapeutic targets to reduce ALI/ARDS morbidity and mortality
Breaching the Defenses? Mucosal-associated Invariant T Cells, Smoking, and Chronic Obstructive Pulmonary Disease
No full textThere can be little doubt that cigarette smoking is one of the primary causes of chronic obstructive pulmonary disease (COPD), however the precise mechanisms by which cigarette smoke (CS) exposure leads to COPD are yet to be elucidated. Ample evidence suggests CS causes substantial changes to the epithelial barrier (1) as well as immune cells (2) that persist in COPD. Furthermore, these changes are also associated with microbial dysbiosis in the airways of COPD patients (3), an important driver of COPD exacerbations and mortality (4, 5). In this issue of the Journal, Huber et al further investigate the impact of both smoking and COPD on the interaction between epithelial cells and mucosal-associated invariant T (MAIT) cells (6). MAIT cells are innate-like T cells, which play a role in controlling bacterial infection by recognizing non-peptide antigens derived from the bacterial vitamin B2 pathway presented by the MHC-related protein (MR)-1 (7)
Bioethics and law forum: Roeing against the wind and wadeing against the current: embryonic stem cell research and the abortion debate
No full textTranscription factors and inflammatory gene regulation: strategic approaches
No full textIn chronic inflammatory diseases, the expression of multiple genes, including those for cytokines, chemokines, adhesion molecules, receptors, and inflammatory enzymes, is often upregulated. The problem for many academic or industrial scientists is to elucidate the mechanisms behind this upregulation to further the understanding of inflammation or to explore possible means of therapeutic intervention. Common research problems faced by investigators would be to analyze the regulation of a novel gene in response to various inflammatory stimuli or alternatively to investigate the mechanisms of induction of an established gene in response to novel stimuli. Whereas the induction of many inflammatory genes is thought to occur, at least partly, at the level of increased transcription, it is important to address the possible role of posttranscriptional, translational, or even posttranslational control. For example, release or synthesis of the protein of interest from suitably stimulated cells could be examined in the presence or absence of transcriptional inhibitors, such as actinomycin D, or translational inhibitors, such as cycloheximide. Thus, a dependence on de novo transcription and/or translation may be demonstrated. Therefore, whether the protein of interest is simply released from preformed cellular stores or is synthesized from preformed mRNA can be elucidated. Northern blot analysis, reverse transcription polymerase chain reaction (RT-PCR), or ribonuclease protection assays can be used to examine steady-state mRNA levels, which if elevated gives rise to a presumption of transcriptional contro
Macrophages and neutrophils: dynamic duo or partners in crime?
No full textAs spring emerges from the shadows of a cold, dark winter we are again left to reflect on the ravages of another influenza season. Based on the emergent data from Australia1, the 2017-18 outbreak in the Northern Hemisphere was predicted to be particularly severe an so it proved to be. Disease severity can be driven by a number of factors, including shifts in the viral genome, but host innate immune responses also play a role, most notably in the lethal cytokine storm response to avian influenza strains2.Macrophages are the predominant innate immune cell in the human airway and critical for an appropriate protective response to bacterial, fungal and viral infections. These cells enhance viral clearance, being essential for both viral antigen presentation to mucosal T cells3 and the development of neutralising antibodies4. Furthermore, when macrophages are depleted, there is increased lung pathology5 in response to viral infection demonstrating the central role of macrophages in ensuring that virus control does not compromise host survival. In the majority of cases, such mechanisms ensure that lung inflammation is kept to a minimum so that pneumonias do not develop. However, it is known that influenza infection can lead to both primary and secondary bacterial pneumonias6, although whether as a result of virus or host factors is unclear. Pneumonias are primarily associated with massive neutrophil influx into the lung leading to compromised gas exchange but there are conflicting reports as to whether the role of the neutrophil in viral infections is protective or pathologic7
Coadministration of the cyanobacterial lipopolysaccharide antagonist CyP with antibiotic inhibits cytokine production by an in vitro meningitis model infected with Neisseria meningitidis
No full textIn this study, the objective was to determine the anti-inflammatory properties of CyP, a cyanobacterial lipopolysaccharide (LPS) antagonist, used in combination with antibiotic chemotherapy during infection of an in vitro meningitis model infected with Neisseria meningitidis (meningococcus). Monocultures of human meningioma cells and meningioma-primary human macrophage co-cultures were infected with meningococci (10(2)-10(8) cfu/monolayer) or treated with isolated outer membranes or purified LPS (0.1-100 ng/monolayer) from N. meningitidis. CyP (1-20 mug/monolayer) was added at intervals from t?=?0 to 4 h, with and without benzylpenicillin (1-20 mug/monolayer). The antagonistic effect of CyP and its adjunctive properties to benzylpenicillin administration was determined by measuring cytokine levels in culture supernatants after 24 h. CyP significantly inhibited (P?<?0.05) the secretion of interleukin (IL)-6, IL-8, monocyte chemoattractant protein (MCP)-1 and RANTES ('regulated upon activation, normal T cell expressed and secreted') (overall reduction levels from 50% to >95%) by meningioma cell lines and meningioma-macrophage co-cultures challenged with either live meningococci or bacterial components. Inhibition was effective when CyP was added within 2 h of challenge (P?<?0.05) and was still pronounced by 4 h. In the co-culture model, CyP alone partially inhibited IL-1beta secretion, but did not prevent tumour necrosis factor (TNF)-alpha secretion, whereas penicillin alone inhibited IL-1beta and TNF-alpha but conversely did not reduce MCP-1 and RANTES secretion. However, coadministration of CyP and penicillin in both models had an additive effect and restored the overall inhibitory profile. CyP inhibits cytokine production in an in vitro meningitis model and augments the anti-inflammatory response when combined with benzylpenicillin. Administration of an LPS antagonist with antibiotic merits consideration in the emergency treatment of patients presenting with meningococcal infection
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