diaphorase by the formation of blue for- N02 mazans from tetrazoliums can therefore be NO3 used to localise neuronal NOS.18A form of ONOO0 cNOS distinct from the neuronal form is fL-arginine localised to vascular endothelial cells.19 20 ivones cNOS from brain and endothelial cells have iettively by been cloned'922 and these are distinct ine methyl be oxidised enzymes with about 60% homology, which are also homologous to cytochrome P-450
Sauer, Bryan G. MD, MSc, FACG; Barnes, Barrett H. MD; McGowan, Emily C. MD, PhD Author Information
Abstract Background/Aims: Biliary atresia (BA) is a progressive disease characterized by bile duct inflammation and fibrosis. The aetiology is unknown and may be due to a virus‐induced, autoimmune‐mediated injury of cholangiocytes. Cholangiocytes are not only targets of injury but may also modulate hepatic inflammation. The aim of this study was to determine the immune profile of murine cholangiocytes and the ability to function as antigen‐presenting cells (APCs) in culture with Rhesus rotavirus (RRV), poly I:C (viral mimic) or interferon‐γ/tumour necrosis factor‐α. Methods/Results: Both the cholangiocyte cell line (long‐term culture) and fresh, ex vivo cholangiocytes expressed APC surface markers major histocompatibility complex (MHC)‐class I and II and CD40, while only the cultured cell line expressed costimulatory molecules B7‐1 and B7‐2. Despite APC expression, cultured cholangiocytes were unable to function as competent APCs in T‐cell proliferation assays. Furthermore, both cultured and ex vivo cholangiocytes expressed RNA transcripts for many pro‐inflammatory cytokines and chemokines. Conclusions: Although cholangiocytes contain APC molecules, they are incompetent at antigen presentation and cannot elicit effective T‐cell activation. Upregulation of MHC‐class I and II found in BA mice may serve to prime the cholangiocyte as a target for immune‐mediated injury. Cholangiocytes produced many pro‐inflammatory cytokines and chemokines in the setting of RRV infection and T‐helper type 1 cytokine milieu, suggesting a role of cholangiocytes as immune modulators promoting the ongoing inflammation that exists in RRV‐induced BA.
I. Introduction The medications used to treat chronic obstructive pulmonary disease (COPD) are reviewed in detail in other chapters in this volume (chaps. 6 and 7). Effective management of the patient with COPD, however, requires implementation of an overall disease management strategy that integrates these medications with nonpharmacologic interventions as well as the treatment of concurrent conditions, which are frequently present in COPD patients. Currently available medications that treat COPD can improve patient well-being and prognosis in important ways. Unfortunately, the available therapies are often underused and when prescribed are often not used in ways that optimize their effectiveness. The current chapter will review the strategies of COPD management.
In COPD, the lower airways are colonised with bacteria that contribute to exacerbations. This may be due to defective macrophage phagocytosis. IFNγ is elevated in COPD and can suppress macrophage phagocytosis. IFNγ activates the JAK/STAT pathway, thus we hypothesise that inhibiting this pathway will ablate the IFNγ effect on macrophage phagocytosis. Human lung macrophages were treated with two structurally distinct JAK/STAT inhibitors (PF95 & PF13, 10-4-10-10M), stimulated with 10ng/ml IFNγ for 18h. Phagocytosis was measured after 4h exposure to beads, H. influenzae (HI) or S. pneumoniae (SP) . CXCL10 and IL-6 release after IFNγ or IFNγ+TNFα (10ng/ml) stimulation for 24h was measured by ELISA n=5. Cell viability was assessed by MTT. IFNγ increased bead phagocytosis by 30±6% which was not altered by PF95 or PF13. However IFNγ significantly inhibited uptake of HI by 24±9% and SP by 29±9%. Both PF95 and PF13 reversed these effects in a concentration-dependent manner [Table 1]. PF13, but not PF95, was cytotoxic at concentrations ≥10μM. Both PF95 and PF13 decreased CXCL10 release after IFNγ stimulation (EC50 0.31±0.17μM & 15±9.5nM respectively) and IFNγ+TNFα (EC50 0.57±0.2μM & 19±8.2nM respectively). Only PF13 decreased IL-6 after IFNγ or IFNγ+TNFα stimulation (EC50 0.45±0.72μM and 2.3±2.1μM respectively). View this table: Table 1. Effect of JAK/STAT inhibitors on IFNγ suppression of bacterial phagocytosis Inhibiting the JAK/STAT pathway diminishes the decrease in phagocytosis of HI and SP caused by IFNγ and decreases the release of inflammatory cytokines and has potential as a novel target in COPD.
To describe the characteristics of patients undergoing coronary angioplasty (PTCA) over the past 20 years and the outcome after 1 and 5 years.Prospective follow-up study.All patients who underwent a first PTCA in the Thorax centre of the Erasmus Medical Centre in Rotterdam during the period from 1 September 1980 through 30 November 1985 (group I) were compared with all patients who likewise underwent such a first PTCA during the period between 1 September 1995 and 31 December 1996 (group II). Data on the patients, the operations, any reoperations and the mortality were obtained from patient records, general practitioners and municipal archives. Cumulative percentages of survival and of not having rePTCA or coronary artery bypass surgery (CABG) were analysed by using the Kaplan-Meier-method.Group I consisted of 856 patients and group II of 840 patients. The percentage of males decreased over the years from 80% to 69%. The average age increased from 56 to 60 years; the oldest patient in group I was 75 years and the oldest in group II was 87 years. The percentage of patients with multivessel disease increased from 36% to 44%. Stent implantation occurred in 55% of the patients in group II (0% in group I). The necessity for urgent CABG due to unsuccessful PTCA decreased from 9.4% to 1%. After 1 year, the percentage of coronary revascularisations was 28.8% in group I and 22.6% in group II (p = 0.01). The perioperative mortality and the 5-year survival were not significantly different in the two groups (group I: 1.3% and 90%; group II: 2.4% and 88%, respectively). For both groups, higher age, a smaller ejection fraction, more extensive vascular disease and no treatment with statins were independent predictors of a higher mortality after 5 years. In group II, renal function disorders were the most important predictor of higher mortality.
The measurement of exhaled NO has excited considerable interest, as it may provide a simple noninvasive means of measuring airways inflammation. There is now persuasive evidence that levels of NO are increased in association with airway inflammation and are decreased with anti-inflammatory treatment. Correlation of exhaled NO with more direct measurements of inflammation in the airways, such as induced sputum, bronchoalveolar lavage and bronchial biopsies, is needed. The great advantage of exhaled NO is that the measurement is completely noninvasive. It can, therefore, be performed repeatedly, and also in children and patients with severe airflow obstruction, where more invasive techniques are not possible. However, the measurement is not specific, and exhaled NO is increased in inflammation due to asthma, bronchiectasis, and respiratory tract infections. This means that absolute values are less important than serial measurements in individual patients. The value of this approach has been demonstrated in asthmatic patients, where the dose of inhaled steroid is changed, resulting in increased levels when the dose is reduced and lower levels when the dose is increased. Because exhaled NO is reduced by anti-inflammatory treatments, it may be of use in monitoring whether therapy is adequate. The technique may also have application in the monitoring of the anti-inflammatory effects of new antiasthma drugs, such as selective phosphodiesterase inhibitors, leukotriene antagonists and synthesis inhibitors, and immunomodulators. Because the measurement is precise and reasonably reproducible, it may facilitate the measurement of dose-response effects with anti-inflammatory treatments, which is difficult at present. The analysers for exhaled NO that are currently available are expensive, but in the future it is likely that technological advances will make it possible to miniaturize these analysers, so that they are portable and may even be used at home in conjunction with peak flow meters. -his may lead to their application in epidemiological research, which may be a useful screening measurement for community studies. Although we have discussed exhaled nitric oxide, other volatile substances may also be detected in exhaled air. Thus, ethane and pentane, which are volatile products of lipid peroxidation, and hydrogen peroxide, may be used to detect oxidant stress in the respiratory tract and may also be useful as markers of inflammation. There is little doubt that this is a rapidly expanding area of research.
