http://nova.newcastle.edu.au/vital/access/services/Feed ${session.getAttribute("locale")} 5 http://nova.newcastle.edu.au/vital/access/manager/Repository/uon:11339 The mechanisms underlying the exaggerated distal airway inflammation and hyperresponsiveness that characterize acute exacerbations of asthma are largely unknown. Using BALB/c mouse experimental models, we demonstrated a potentially important role for alveolar macrophages (AM) in the development of an allergeninduced exacerbation of asthma. To induce features of airway inflammation and remodeling characteristic of mild chronic asthma, animals were systemically sensitized and exposed to low mass concentrations (≈3 mg/m³) of aerosolized ovalbumin for 30 minutes per day, 3 days per week, for 4 weeks. A subsequent single moderate-level challenge (≈30 mg/m³) was used to trigger an acute exacerbation. In chronically challenged animals,cytokine expression by AM was not increased, whereas after an acute exacerbation, AM exhibited significantly enhanced expression of proinflammatory cytokines, including interleukin (IL) 1β, IL-6, CXCL-1, and tumor necrosis factor α. In parallel, there was a marked increase in the expression of several cytokines by CD4⁺ T-lymphocytes, notably the Th2 cytokines IL-4 and IL-13. Importantly, AM from an acute exacerbation stimulated the expression of Th2 cytokines when cocultured with CD4⁺ cells from chronically challenged animals, and their ability to do so was significantly greater than AM from either chronically challenged or naïve controls. Stimulation was partly dependent on interactions involving CD80/86. We conclude that in an acute exacerbation of asthma, enhanced cytokine expression by AM may play a critical role in triggering increased expression of cytokines by pulmonary CD4⁺ T-lymphocytes. 2012-08-24T00:10:56.218Z ]]> http://nova.newcastle.edu.au/vital/access/manager/Repository/uon:9439 Background Airway hyperresponsiveness (AHR) in asthmatics includes a variable component that persists following an allergen challenge. This may be dissociated from inflammatory cell recruitment, implying a role for resident pulmonary cells in regulating the response. Objective Using improved methods of assessing AHR in a mouse model of allergic airway disease, to investigate the basis of the development of prolonged AHR. Method BALB/c mice were systemically sensitized and then challenged with aerosolized ovalbumin (OVA). Airway and tissue responsiveness were measured at baseline and at 1 day, and 1, 2 and 3 weeks after the last OVA challenge. Inflammatory cell numbers in BALF and levels of mRNA for eotaxin-1 and -2, IFN-γ , IL-5 and -13 in the lung were measured at each time-point. In further experiments, the roles of IFN-γ and of CCR3⁺ and CD4⁺ cells in the development of prolonged AHR were assessed by blockade or depletion with monoclonal antibodies. The role of pulmonary macrophages was assessed by selective chemical depletion of these cells. Results Airway responsiveness was increased above baseline at 1 day after the last OVA challenge, and this was sustained for 1 week. In contrast, tissue-specific responsiveness was only significantly increased above baseline at 1 day. Development of prolonged AHR was inhibited by neutralization of IFN-γ or by depletion of pulmonary macrophages, but not by depletion of either CD4⁺ T cells or CCR3⁺ eosinophils. Conclusion An interaction between IFN-γ and pulmonary macrophages contributed to the prolongation of airway hyperresponsiveness. In contrast, T cells and eosinophils did not contribute to prolongation of AHR. These findings emphasize the importance of the innate host response in the development of manifestations of asthma, as well as its potential relevance as a target for therapeutic intervention. 2011-11-21T05:00:03.783Z ]]> http://nova.newcastle.edu.au/vital/access/manager/Repository/uon:4801 At term, amniotic fluid contents may mediate the onset of labor through the activation of amniotic fluid macrophages and their migration into the myometrium. To test this concept, the authors examine the histological changes that occur in myometrial biopsies at term prior to (n = 53) and during (n = 15) labor. Biopsies were stained with an antimacrophage antibody, anti-CD34 (endothelial cells), and anti-caspase 3 (apoptotic cells). The samples showed a variable inflammatory infiltrate of neutrophils and macrophages, with a greater infiltrate in the samples obtained during labor (P<.001, Fisher exact test). Prior to labor, there were prominent changes in the myometrial fibers that reflected shearing, shrinkage, edema, and particularly apoptosis; endothelial cells of thin-walled vessels prominent in the biopsies displayed marked nuclear biotinylation, and the vascular lumen contained fibrin and platelet thrombi, microparticles, desquamated endothelial cells, amniotic squamous cells, and mucoid material. These changes were also present in samples obtained during labor. In an additional 10 patients in labor with male fetuses, myometrial samples were examined for the presence of macrophages carrying a Y chromosome indicative of a fetal origin, but none were observed. These findings suggest that endothelial cell damage and amniotic fluid embolism are very common at term prior to clinical labor and provide a mechanism by which surfactant protein A and phospholipids present in the amniotic fluid may access myometrial cells and provoke the inflammatory response that occurs during parturition. The authors' studies give no support to the suggestion that fetal macrophages might invade the human myometrium at term. 2010-04-27T05:33:34.457Z ]]> http://nova.newcastle.edu.au/vital/access/manager/Repository/uon:4347 Background: Rhinovirus infection is responsible for considerable morbidity and mortality as the major cause of exacerbations of asthma, and is also known to induce exacerbations of cystic fibrosis and chronic obstructive pulmonary disease. Exacerbations of these diseases are also frequently associated with bacterial and atypical bacterial infection. Alveolar macrophages are the major immune cells in the airways and are important in defence against bacterial infections. Methods: The authors investigated whether rhinovirus modifies cytokine release, the pattern recognition receptor expression and phagocytosis by human alveolar macrophages in response to bacterial products. Results: Viable rhinovirus was detected in macrophages up to 3 days after exposure and viral RNA expression persisted for 10 days. Infectious but not UV inactivated rhinovirus increased tumour necrosis factor α (TNFα) and interleukin (IL)8 release by macrophages. In contrast, infectious rhinovirus impaired lipopolysaccharide and lipoteichoic acid induced TNFα and IL8 secretion by macrophages. Rhinovirus induced impairment of macrophage antibacterial immune responses did not involve IL10, prostaglandin E₂or downregulation of Toll-like receptor 2. Furthermore, the macrophage phagocytic response to labelled bacterial particles, but not to latex beads, was impaired. Conclusion: The authors have identified impairment of cytokine responses to bacterial lipopolysaccharide and lipoteichoic acid by alveolar macrophages in response to infectious rhinovirus. Virus induced impairment of antibacterial host defence has important implications in the pathogenesis of exacerbations of respiratory diseases. 2010-04-27T05:04:33.626Z ]]> http://nova.newcastle.edu.au/vital/access/manager/Repository/uon:4489 Aim: To demonstrate that so-called "caseous necrosis" is the result of apoptosis and investigate the association of B and T cells, and macrophages with the granulomas and their relationship to some apoptosis-related proteins. Methods: Cervical lymph node biopsy specimens from 55 HIV-infected Thai patients with caseating granulomas, confluent caseating granulomas, sarcoid-like granulomas, foamy macrophage response, pseudo-inflammatory tumour response or non-specific lymphoid hyperplasia were examined histologically and for apoptosis by immunostaining for caspase 3 and TUNEL. Classic tuberculoid caseating granulomas in cervical lymph node and lungs from non-HIV-infected patients were also stained with caspase 3. Results: All areas of caseous necrosis frequently displayed extensive apoptosis that readily accounted for the so-called "necrosis". Small foci of apoptosis were present in the other reaction patterns and fibrotic granulomas often showed residual apoptosis. The extent of apoptosis was inversely related to the numbers of identifiable acid-fast bacilli; all epithelioid macrophages revealed strong immunoexpression of the pro-apoptotic proteins Bax and Fas, whereas the anti-apoptotic protein Bcl-2 was not present. Apoptosis occurred in CD68+ macrophages and CD3+ CD8+ T cells; all nodes were deficient of CD4+ cells. CD8+ T cells were intimately related to the apoptotic foci, suggesting a role in the process, particularly in the absence of CD4+ cells. In non-HIV-infected cases, similar extensive apoptosis was confirmed with caspase 3. Conclusions: So-called "caseous necrosis" is shown for the first time to be the result of apoptosis. In the absence of CD4+ cells the findings negate many of the postulated mechanisms of apoptosis in the murine model and have implications for the treatment of mycobacterial infections. 2010-04-27T04:58:04.255Z ]]>