Theophylline minimally inhibits bronchoconstriction induced by dry cold air inhalation in asthmatic subjects

The aim of this study was to evaluate the effect of a sustained-release theophylline preparation on bronchial responsiveness to cold dry air inhalation in asthmatic subjects. Sixteen adult subjects with asthma in a clinical steady state underwent 3 isocapnic cold air challenges on 3 consecutive days at a time when they had not received oral theophylline medication over the past 3 days. The dose of cold air causing a 20% (PD20) fall in FEV1 was obtained from each subject's dose-response curve. Subjects were then administered active or placebo sustained-release theophylline preparations according to a double-blind, randomized, two-treatment crossover design. Medication was given for a minimum of 3 consecutive days. PD20 was reassessed on 4 different days, 3 to 4 h after receiving active or placebo medication (two visits for each medication). We found a significant bronchodilator effect of theophylline as compared to the placebo (mean +/- SD differences in changes of FEV1 of 8.8 +/- 1.9%). We also documented a significant blocking effect of the active medication as opposed to the placebo on PD20 (p = 0.01). This difference (mean = 0.18 on the loge scale) was statistically beyond the intraindividual between-day variability observed on the 3 control days (p less than 0.001) but was physiologically minimal. This blocking effect was also partially related to changes in airway caliber. We conclude that theophylline showed a blocking effect on bronchial responsiveness to dry cold air, which was physiologically minimal and was partially related to changes in airway caliber.     

Acute bronchoconstriction is not a stimulus for sympatho-adrenal activation in asthmatic or healthy subjects

Bronchoconstriction has been found to cause little sympathoadrenal activation in asthmatic patients. It has been questioned whether this is due to blunted sympatho-adrenal reactivity in asthmatics or if bronchoconstriction is a stimulus for sympatho-adrenal activation at all. We therefore compared sympatho-adrenal responses in eight asthmatic patients and 12 healthy subjects by measurements of plasma adrenaline and noradrenaline concentrations before, during and after methacholine-induced bronchoconstriction. Significant bronchoconstriction was obtained in eight of the healthy subjects and in all of the asthmatics. Considerably higher concentrations of methacholine were required to evoke bronchoconstriction in the healthy subjects but the relative magnitudes of bronchoconstriction were similar in the two groups: peak expiratory flow (PEF) decreased by approximately 24 and approximately 28% and specific airway conductance (sGaw) decreased by approximately 68 and approximately 70% in asthmatics and controls, respectively). Methacholine-induced bronchoconstriction did not alter plasma catecholamine levels significantly in either group. In addition, plasma concentrations of catecholamines and neuropeptide Y-like immunoreactivity (NPY-LI) were measured before and during bronchoconstriction induced by histamine or allergen in 8 and 5 asthmatic subjects, respectively. Plasma noradrenaline, adrenaline and NPY-LI remained unchanged up to 30 min after bronchoconstriction induced by histamine or allergen. We, therefore, conclude that bronchoconstriction is not a stimulus for sympatho-adrenal activation and that the lack of an adrenaline response to bronchoconstriction is not likely to be related to NPY release.     

Terbutaline acts at multiple sites to inhibit bronchoconstriction induced by dry air in canine peripheral airways.

We examined the effect of the beta 2-agonist terbutaline on dry airflow-induced bronchoconstriction (AIB) in the canine lung periphery. Using a wedged bronchoscope technique, collateral resistance (Rcs) and airway wall temperature (Taw) were measured before and after a 2-min exposure to dry air. When sublobar segments were challenged with dry air, Taw fell during challenge (p less than 0.001), and Rcs increased 5 min postchallenge (p less than 0.01). Pretreatment with terbutaline (100 micrograms/kg) reduced the fall induced by dry-air challenge in Taw by 37% and the subsequent rise in Rcs by 87%. Terbutaline significantly reduced the concentrations of thromboxane B2 (TxB2) and prostaglandin D2 (PGD2), and decreased the concentration of epithelial cells recovered in bronchoalveolar lavage fluid 5 min postchallenge. In addition, terbutaline attenuated histamine- and PGD2-induced constriction. Finally, peripheral lung sensitivity (as assessed by delta Rcs/delta Taw) to challenge after treatment with terbutaline was significantly less than that calculated for untreated control animals (p less than 0.05). These data are consistent with the idea that terbutaline attenuates AIB by (1) facilitating replacement of water lost during exposure to dry air, (2) inhibiting mediator production and release from osmosensitive cells, and (3) reducing smooth muscle responsiveness.     

Respiratory heat and moisture loss is associated with eosinophilic inflammation in asthma.

Increased mucosal vascularity is a hallmark of airway inflammation in asthma. It was hypothesised that this would lead to a detectable increase in respiratory heat and moisture loss (RHML), which would reflect the degree of airway inflammation present. A total of 23 subjects with asthma and 18 healthy controls had RHML measured in a cross-sectional study. The measurements were made using a device that combines temperature and humidity measurement during inspiration and expiration and allows precise control over inspirate conditions and ventilatory pattern. The subjects with asthma underwent parallel measurements of exhaled nitric oxide, sputum eosinophil percentage and exhaled breath condensate pH. Mean+/-SD RHML was elevated in patients with asthma (98.1+/-7.3 J.L(-1)) compared with control subjects (91.9+/-4.5 J.L(-1)). RHML measurement in asthma correlated with sputum eosinophil percentage. This novel correlation between thermal and cellular measurements in asthma suggests that both of these noninvasive indices are sensitive to the degree of underlying chronic airway inflammation.     

Respiratory heat/water loss alone does not determine the severity of exercise-induced asthma

Respiratory heat loss (RHL) or water loss (RWL) have been proposed as possible triggering factors in exercise and hyperventilation-induced asthma (EIA and HIA). It has recently been demonstrated that exercise intensity and climatic factors are both important in determining the severity of EIA. Eight young asthmatics performed both exercise and isocapnic hyperventilation (IHV) manoeuvres under identical climatic conditions, as part of our investigation of these interactive factors which determine the severity of the asthmatic response. It was found that, when challenged at low ventilatory levels, exercise produced a significantly attenuated asthmatic response compared to IHV. The fall in forced expired volume in 1 sec (delta FEV1) following exercise was 15 +/- 4% as compared with 27 +/- 3% after IHV (p less than 0.002). It is concluded that while the hypernoea in exercise may serve as a trigger, exercise per se introduces an additional factor which serves to limit the full response seen with IHV. This attenuated response is revealed at low ventilatory levels but is masked at high levels.     

Duration of action of inhaled terbutaline at two different doses and of albuterol in protecting against bronchoconstriction induced by hyperventilation of dry cold air in asthmatic subjects

Although several studies have examined the duration of the bronchodilator effect of several inhaled beta-2-adrenergic agents, the duration of the blocking effect on bronchial hyperresponsiveness, another key feature of asthma, has seldom been studied. We investigated this problem in eight adult asthmatic subjects who underwent hyperventilation tests with dry cold air on 4 different days. On the first day, five hyperventilation tests with assessment of the level of ventilation causing a 20% fall in FEV1 (PD20) were obtained to evaluate the within-day variability of the test. On the three other visits, after a baseline hyperventilation test, albuterol 200 micrograms, terbutaline 500 micrograms, and terbutaline 1,500 micrograms were administered in a double-blind, randomized way. Hyperventilation tests were carried out 1, 2, 4, and 6 h later. The blocking effect on the treatment days, as assessed by the differences in PD20 for each test compared with baseline PD20 for that day, was corrected for the within-day variability of the control day. There was a significant bronchodilator effect 1 h after administering the drug; it was equivalent for albuterol 200 micrograms (25.6 +/- 14.7%) and terbutaline 1,500 micrograms (21.7 +/- 13.5%) and significantly less for terbutaline 500 micrograms (14.1 +/- 10.0%). Complete or partial blockade on bronchial responsiveness was obtained in the majority (six to seven of eight) of the subjects 1 h after inhaling the bronchodilator, with progressive reduction in the effect later on. Four subjects still showed a blocking effect 6 h after terbutaline 1,500 micrograms was administered, one subject after terbutaline 500 micrograms, and no subjects after albuterol (chi square = 6.6, p = 0.04).(ABSTRACT TRUNCATED AT 250 WORDS)     

Leptin administration does not prevent the bone mineral metabolism changes induced by weight loss

The objective was to examine the effects of weight loss and leptin administration following weight loss on calciotropic hormones and bone turnover. This was a prospective, single-blinded study of 12 subjects (8 women, 4 men; 2 nonobese, 10 obese; age range, 19-46 years) who were studied on an inpatient basis while maintaining their usual weight [Wt_initial] and during maintenance of 10% weight loss while receiving twice-daily injections of either a placebo [Wt_−10%P] or replacement doses of leptin [Wt_−10%L]. The main outcome measures were markers of bone formation (bone alkaline phosphatase and procollagen type 1 amino terminal propeptide) and resorption (N-telopeptide) as well as parathyroid hormone, calcium, and 25-hydroxy vitamin D measured from fasting morning serum. As expected, serum leptin declined with weight loss. Bone alkaline phosphatase decreased by 12.3% ± 3.9% between Wt_initial and Wt_−10%P and remained suppressed after leptin administration (both P < .01 compared with baseline). N-telopeptides increased by 37.2% ± 11.3% from Wt_initial to Wt_−10%L (P < .01). Procollagen type 1 amino terminal propeptide, parathyroid hormone, calcium, and 25-hydroxy vitamin D did not change. These results suggest that both decreased bone formation and increased bone resorption underlie bone loss associated with weight loss. Leptin administration did not prevent the uncoupling of bone remodeling that accompanies weight loss.     

MyD88 is a key mediator of anorexia, but not weight loss, induced by lipopolysaccharide and interleukin-1 beta

Systemic inflammatory signals can disrupt the physiological regulation of energy balance, causing anorexia and weight loss. In the current studies, we investigated whether MyD88, the primary, but not exclusive, intracellular signal transduction pathway for Toll-like receptor 4 and IL-1 receptor I, is necessary for anorexia and weight loss to occur in response to stimuli that activate these key innate immune receptors. Our findings demonstrate that the absence of MyD88 signaling confers complete protection against anorexia induced by either lipopolysaccharide (LPS) (20 h food intake in MyD88-/- mice 5.4 +/- 0.3 vs. 3.3 +/- 0.4 g in MyD88+/+ control mice, P < 0.001) or IL-1 beta (20 h food intake in MyD88-/- mice 4.9 +/- 0.5 vs. 4.0 +/- 0.3 g in MyD88+/+ control mice, P < 0.001). However, absent MyD88 signaling does not prevent these inflammatory mediators from causing weight loss (LPS, -0.4 +/- 0.1 g; IL1 beta, -0.1 +/- 0.1 g, both P < 0.01 vs. vehicle-injected MyD88-/- mice, +0.4 +/- 0.2 g). Furthermore, LPS-induced weight loss occurs in the absence of adipsia, fever, or hypothalamus-pituitary-adrenal axis activation in MyD88-deficient mice. In addition, the peripheral inflammatory response to LPS is surprisingly intact in mice lacking MyD88. Together, these observations indicate that LPS reduces food intake via a mechanism that is dissociated from its effect on peripheral cytokine production, and whereas the presence of circulating proinflammatory cytokines per se is insufficient to cause anorexia in the absence of MyD88 signaling, it may contribute to LPS-induced weight loss.     

Interleukin 5 is required for the blood and tissue eosinophilia but not granuloma formation induced by infection with Schistosoma mansoni.

Eosinophils are thought to play a major role in the immunobiology of schistosomiasis. To investigate the immunologic basis of the eosinophil response and directly assess the function of eosinophils in egg-induced pathology, mice infected with Schistosoma mansoni were injected with a monoclonal antibody produced against interleukin 5 (IL-5), a cytokine previously shown to stimulate eosinophil differentiation in vitro. This treatment suppressed the generation of eosinophil myelocyte precursors in the bone marrow and reduced to background levels the numbers of mature eosinophils in the marrow, in circulation, and within acute schistosome egg granulomas. Nevertheless, granulomas in the anti-IL-5-treated/eosinophil-depleted mice at 8 weeks of infection were only marginally smaller than those in animals injected with control monoclonal antibody, and hepatic fibrosis was comparable in the two groups. Additional parameters such as worm burden, egg output, and serum IgE levels were unaltered by the anti-IL-5 treatment. In contrast, infected animals injected with monoclonal antibody against gamma interferon (IFN-gamma) displayed circulating eosinophil levels that were elevated with respect to control mice, possibly because of an enhanced release of mature eosinophils from the marrow, and developed egg granulomas that were indistinguishable in size and cellular composition from those in control animals. Immunologic assays revealed that lymphocytes from acutely infected mice produce large quantities of IL-5 but minimal IFN-gamma when stimulated with either egg antigen or mitogen. Taken together, these results indicate that neither IL-5 nor eosinophils are essential for egg-induced pathology but suggest that lymphocytes that belong to the IL-5-producing TH2 subset predominate during acute infection and may induce granuloma formation by the production of other cytokines.     

Vision loss in granulomatosis with polyangiitis: when prednisone is the problem,not the solution

Clinical Rheumatology -     

Cardiac damage induced by immunization with heat‐killed Trypanosoma cruzi is not antibody mediated

Cardiac inflammation that develops during infection with Trypanosoma cruzi may result in part from autoimmunity, which may occur after bystander activation, after parasite‐induced cardiomyocyte damage, or molecular mimicry. A/J mice infected with T. cruzi or immunized with heat‐killed T. cruzi (HKTC) develop strong autoimmunity accompanied by cardiac damage. To determine whether this cardiac damage occurs via an antibody‐dependent mechanism, we analysed T. cruzi‐infected and HKTC‐immunized mice for the presence of autoantibodies, cardiac antibody deposition, and serum cardiac troponin I as a measure of cardiac damage. We also performed a serum transfer experiment in which sera from T. cruzi‐infected and T. cruzi‐immunized mice (and controls) were transferred into naïve recipients, which were then analysed for the presence of antibodies and serum troponin. Unlike T. cruzi‐infected mice, T. cruzi‐immunized mice did not show significant antibody deposition in the myocardium. These results indicate that antibody deposition does not precede cardiac damage and inflammation in mice immunized with or infected with T. cruzi. Serum adoptive transfer did not induce cardiac damage in any recipients. Based on these findings, we conclude that the cardiac damage induced by immunization with HKTC is not mediated by antibodies.     

Obesity is associated with increased post-prandial GIP levels which are not reduced by dietary restriction and weight loss

Obesity is characterised by fasting and post-prandial hyperinsulinaemia. One factor which may contribute to this is overactivity of the enteroinsular axis. Glucose tolerance, beta-cell response and GIP profiles were therefore compared during oral glucose (OGTT), mixed meal (MTT) and intravenous glucose tolerance tests (IVGTT) in both lean (IBW less than 120%) and obese (IBW greater than 120%) healthy subjects. The tests were repeated in the obese group after a period of dietary restriction and weight loss. Fasting GIP concentrations were similar, but postprandial levels were significantly greater in the obese subjects during both the OGTT and MTT. Glucose profiles were similar but associated with basal and stimulated hyperinsulinaemia in the obese subjects indicating insulin resistance. GIP levels did not change during the IVGTT and were similar in the two groups throughout the test. Following diet and weight-reduction there was a significant decrease in both fasting and post-prandial insulin levels in the obese subjects but there were no significant changes in glucose or GIP concentrations. In conclusion the endogenously stimulated plasma GIP response is exaggerated in obese healthy subjects but this increased response is not decreased by short term diet and weight loss. The increased GIP concentrations may contribute the observed hyperinsulinaemia in obesity, but its contribution is likely to be small in view of the decrease in insulin concentrations following diet and weight-loss which was independent of any change in GIP.     

Magnesium and acute myocardial infarction. Transient hypomagnesemia not induced by renal magnesium loss in patients with acute myocardial infarction

Serum magnesium concentrations and the rate of urine magnesium excretion were studied in 24 patients with suspected acute myocardial infarction (AMI). Blood and urine samples were taken on admission, at three-hour intervals for the first 24 hours after admission, and every eight hours for the next 24 hours. Thirteen of the patients were found to have AMI, and the 11 who did not have AMI served as a control. During the first 32 hours, the AMI group had significantly low serum magnesium concentrations. The serum magnesium concentrations were unchanged in the control group. Results of the urine samples disproved our hypothesis that the drop in serum magnesium concentrations was due to an increased renal magnesium loss. These results indicate a magnesium migration associated with AMI, from extracellular to intracellular space.     

Endothelial inflammation induced by excess glucose is associated with cytosolic glucose 6-phosphate but not increased mitochondrial respiration

Aims/hypothesis  Exposure of endothelial cells to high glucose levels suppresses responses to insulin, including induction of endothelial nitric oxide synthase activity, through pro-inflammatory signalling via the inhibitor of nuclear factor kappaB (IκB)α-nuclear factor kappaB (NF-κB) pathway. In the current study, we aimed to identify metabolic responses to glucose excess that mediate endothelial cell inflammation and insulin resistance. Since endothelial cells decrease their oxygen consumption rate (OCR) in response to glucose, we hypothesised that increased mitochondrial function would not mediate these cells’ response to excess substrate. Methods  The effects of glycolytic and mitochondrial fuels on metabolic intermediates and end-products of glycolytic and oxidative metabolism, including glucose 6-phosphate (G6P), lactate, CO₂, NAD(P)H and OCR, were measured in cultured human microvascular endothelial cells and correlated with IκBα phosphorylation. Results  In response to increases in glucose concentration from low to physiological levels (0–5 mmol/l), production of G6P, lactate, NAD(P)H and CO₂ each increased as expected, while OCR was sharply reduced. IκBα activation was detected at glucose concentrations >5 mmol/l, which was associated with parallel increases of G6P levels, whereas downstream metabolic pathways were insensitive to excess substrate. Conclusions/interpretation  Phosphorylation of IκBα by excess glucose correlates with increased levels of the glycolytic intermediate G6P, but not with lactate generation or OCR, which are inhibited well below saturation levels at physiological glucose concentrations. These findings suggest that oxidative stress due to increased mitochondrial respiration is unlikely to mediate endothelial inflammation induced by excess glucose and suggests instead the involvement of G6P accumulation in the adverse effects of hyperglycaemia on endothelial cells.