IL-13R alpha 2 reverses the effects of IL-13 and IL-4 on bronchial reactivity and acetylcholine-induced Ca2+ signaling

Background: The interleukins IL-4 and IL-13 play a key role in the pathophysiology of asthma. The interleukin receptor IL-13R alpha 2 is believed to act as a decoy receptor, but until now, the functional significance of IL-13R alpha 2 remains vague. Methods: Bronchial reactivity was quantified in murine lung slices by digital video microscopy and acetylcholine (ACH)-induced Ca2+ signaling was measured in human airway smooth muscle cells (ASMC) using fluorescence microscopy. Results: IL-4 or IL-13 up to 50 ng/ml induced bronchial hyperreactivity. But after incubation with 100 ng/ml this effect was lost and bronchial responsiveness was again comparable to the control level. The effects of IL-4 and IL-13 on bronchial reactivity were paralleled by the effects on ASMC proliferation. Fifty nanograms per milliliter of IL-4 and IL-13 increased the Ca2+ response of human ASMC to ACH. At 100 ng/ml, however, the effects of the cytokines on the Ca2+ response were no longer evident. The expression of IL-13R alpha 2 increased with increasing concentrations of IL-4 or IL-13, reaching its maximum at 100 ng/ml. Blocking IL-13R alpha 2, the loss of the effect of IL-4 and IL-13 at 100 ng/ml on human ASMC proliferation and the ACH-induced Ca2+ response were no longer present. Conclusions: IL-4 and IL-13 induce bronchial hyperreactivity by changing the Ca2+ homeostasis of ASMC. These effects are counteracted by IL-13R alpha 2. The biological significance of IL-13R alpha 2 might be a protective function by regulating IL-13- and IL-4-mediated signal transduction and thereby limiting pathological alterations in Th2-mediated inflammatory diseases. Copyright (c) 2007 S. Karger AG, Basel

Independent Information of Nonspecific Biomarkers in Exhaled Breath Condensate

Background: Exhaled breath condensate (EBC) has been used for diagnosing and monitoring respiratory disorders. For clinical purposes the assessment of easy-to-obtain nonspecific markers seems particularly interesting. Objectives: As these measures are related to each other, our objective was to extract the independent information in global EBC markers across a range of respiratory disorders. Methods: EBC was collected from patients with asthma (n = 18), chronic obstructive pulmonary disease (n = 17), and cystic fibrosis (n = 46), as well as from lung transplant (LTX) recipients (n = 14) and healthy controls (n = 26). Samples were assessed for electrical conductivity, ammonia, pH, and nitrite/nitrate. pH was measured after both deaeration with argon and CO(2) standardization. Additionally, the fraction of exhaled nitric oxide (FE(NO)) was assessed. Factor analysis was applied to identify major factors concerning these measures. Results: Three independent factors were detected; the first comprised conductivity, ammonia, and pH, especially when standardized using CO(2), the second nitrite/nitrate, and the third FE(NO). Conductivity and ammonia were highly correlated (r = 0.968; p < 0.001). FE(NO) provided independent information mainly in asthma. The nonspecific EBC markers showed considerable overlap between patient groups and healthy subjects. However, conductivity, ammonia, pH standardized for CO(2) and nitrite/nitrate were increased in LTX recipients compared to healthy controls (p < 0.05 each). Conclusions: A panel of nonspecific easy-to-obtain exhaled breath markers could be reduced to 3 independent factors. The information content of conductivity, ammonia, and pH after CO(2) equilibration appeared to be similar, while FE(NO) was independent. The increased levels of these biomarkers in LTX might indicate a potential for their use in these patients. Copyright (C) 2010 S. Karger AG, Base

Effect of Growth Hormone (hGH) Replacement Therapy on Physical Work Capacity and Cardiac and Pulmonary Function in Patients with hGH Deficiency Acquired in Adulthood.

The effects of 6 months of replacement therapy with recombinant human GH (hGH) on physical work capacity and cardiac structure and function were investigated in 20 patients with hGH deficiency of adult onset in a double blind, placebo-controlled trial. The GH dose of 12.5 micrograms/kg BW was self-administered daily sc. Oxygen consumption (VO2), CO2 production, and ventilatory volumes were measured during exercise on a bicycle spiroergometer. M-Mode echocardiography was performed using standard techniques. The VO2 max data, expressed per kg BW (mL/min.kg BW) showed a significant increase from 23.2 +/- 2.4 to 30.0 +/- 2.3 (P < 0.01) in the hGH-treated group, whereas the VO2 max data, expressed per lean body mass (milliliters per min/kg lean body mass) did not change significantly in either group. Maximal O2 pulse (milliliters per beat) increased significantly from 15.2 +/- 5.6 to 19.6 +/- 3.3 mL/beat (P < 0.01), but remained constant in the placebo group. The maximal power output (watts +/- SE) increased significantly (P < 0.01) from 192.5 +/- 13.5 to 227.5 +/- 11.5 in the hGH-treated group, but remained constant in the placebo group. Cardiac structure (left ventricular posterior wall, interventricular septum thickness, left ventricular mass, left ventricular end-systolic dimension, and left ventricular end-diastolic dimension) as well as echocardiographically assessed cardiac function did not change significantly after 6 months of treatment in either group. We conclude that hGH replacement in hGH-deficient adults improves oxygen uptake and exercise capacity. These improvements in pulmonary parameters might be due to an increase in respiratory muscle strength and partly to the changes in muscle volume per se observed during hGH replacement therapy. Furthermore, an increased cardiac output might contribute to the improvement in exercise performance during hGH treatment. According to our data, hGH replacement therapy leads to an improvement of exercise capacity and maximal oxygen uptake, but has no significant effect on cardiac structure

Mechanisms altering airway smooth muscle cell Ca(2+) homeostasis in two asthma models

Background: Asthma is characterized by airway remodeling, altered mucus production and airway smooth muscle cell (ASMC) contraction causing extensive airway narrowing. In particular, alterations of ASMC contractility seem to be of crucial importance. The elevation of the cytoplasmic Ca(2+) concentration is a key event leading to ASMC contraction and changes in the agonist- induced Ca(2+) increase in ASMC have been reported in asthma. Objective: The aim of this study was to investigate mechanisms underlying these changes. Methods: Murine tracheal smooth muscle cells (MTSMC) from T- bet KO mice and human bronchial smooth muscle cells (HBSMC) incubated with IL-13 and IL-4 served as asthma models. Acetylcholine- induced changes in the cytoplasmic Ca(2+) concentration were recorded using fluorescence microscopy and the expression of Ca(2+) homeostasis regulating proteins was investigated with Western blot analysis. Results: Acetylcholine- induced Ca(2+) transients were elevated in both asthma models. This correlated with an increased Ca(2+) content of the sarcoplasmic reticulum (SR). In MTSMC from T-bet KO mice, the expression of the SR Ca(2+) buffers calreticulin and calsequestrin was higher compared to wild- type mice. In HBSMC incubated with IL-13 or IL-4, the expression of ryanodine receptors, inositol-3-phosphate receptors and sarcoplasmic/ endoplasmic reticulum Ca 2+ ATPases 2 was increased compared to HBSMC without incubation with interleukins. The enlarged acetylcholine- induced Ca(2+) transients could be reversed by blocking inositol-3- phosphate receptors. Conclusions: We conclude that in the murine asthma model the SR Ca(2+) buffer capacity is increased, while in the human asthma model the expression of SR Ca(2+) channels is altered. The investigation of the Ca(2+) homeostasis of ASMC has the potential to provide new therapeutical options in asthma. Copyright (C) 2008 S. Karger AG, Basel

Reference values of impulse oscillometric lung function indices in adults of advanced age.

Impulse oscillometry (IOS) is a non-demanding lung function test. Its diagnostic use may be particularly useful in patients of advanced age with physical or mental limitations unable to perform spirometry. Only few reference equations are available for Caucasians, none of them covering the old age. Here, we provide reference equations up to advanced age and compare them with currently available equations. IOS was performed in a population-based sample of 1990 subjects, aged 45-91 years, from KORA cohorts (Augsburg, Germany). From those, 397 never-smoking, lung healthy subjects with normal spirometry were identified and sex-specific quantile regression models with age, height and body weight as predictors for respiratory system impedance, resistance, reactance, and other parameters of IOS applied. Women (n = 243) showed higher resistance values than men (n = 154), while reactance at low frequencies (up to 20 Hz) was lower (p<0.05). A significant age dependency was observed for the difference between resistance values at 5 Hz and 20 Hz (R5-R20), the integrated area of low-frequency reactance (AX), and resonant frequency (Fres) in both sexes whereas reactance at 5 Hz (X5) was age dependent only in females. In the healthy subjects (n = 397), mean differences between observed values and predictions for resistance (5 Hz and 20 Hz) and reactance (5 Hz) ranged between -1% and 5% when using the present model. In contrast, differences based on the currently applied equations (Vogel & Smidt 1994) ranged between -34% and 76%. Regarding our equations the indices were beyond the limits of normal in 8.1% to 18.6% of the entire KORA cohort (n = 1990), and in 0.7% to 9.4% with the currently applied equations. Our study provides up-to-date reference equations for IOS in Caucasians aged 45 to 85 years. We suggest the use of the present equations particularly in advanced age in order to detect airway dysfunction