Inhibition of granulocyte migration by tiotropium bromide

<p>Abstract</p> <p>Study objectives</p> <p>Neutrophil influx into the airways is an important mechanism in the pathophysiology of the inflammatory process in the airways of patients with chronic obstructive pulmonary disease (COPD). Previously it was shown that anticholinergic drugs reduce the release of non-neuronal paracrine mediators, which modulate inflammation in the airways. On this basis, we investigated the ability of the long-acting anticholinergic tiotropium bromide to inhibit a) alveolar macrophage (AM)-mediated chemotaxis of neutrophils, and b) cellular release of reactive oxygen species (ROS).</p> <p>Method</p> <p>AM and neutrophils were collected from 71 COPD patients. Nanomolar concentrations of tiotropium bromide were tested in AM cultured up to 20 h with LPS (1 μg/ml). AM supernatant was tested for TNFα, IL8, IL6, LTB4, GM-CSF, MIPα/β and ROS. It was further used in a 96-well chemotaxis chamber to stimulate the migration of fluorescence labelled neutrophils. Control stimulants consisted of acetylcholine (ACh), carbachol, muscarine or oxotremorine and in part PMA (phorbol myristate acetate, 0.1 μg/ml). Potential contribution of M_1-3-receptors was ascertained by a) analysis of mRNA transcription by RT-PCR, and b) co-incubation with selective M-receptor inhibitors.</p> <p>Results</p> <p>Supernatant from AM stimulated with LPS induced neutrophilic migration which could be reduced by tiotropium in a dose dependent manner: 22.1 ± 10.2 (3 nM), 26.5 ± 18,4 (30 nM), and 37.8 ± 24.0 (300 nM, p < 0.001 compared to non-LPS activated AM). Concomitantly TNFα release of stimulated AM dropped by 19.2 ± 7.2% of control (p = 0.001). Tiotropium bromide did not affect cellular IL8, IL6, LTB4, GM-CSF and MIPα/β release in this setting. Tiotropium (30 nM) reduced ROS release of LPS stimulated AM by 36.1 ± 15.2% (p = 0.002) and in carbachol stimulated AM by 46.2 ± 30.2 (p < 0.001). M3R gene expression dominated over M2R and M1R. Chemotaxis inhibitory effect of tiotropium bromide was mainly driven by M3R inhibition.</p> <p>Conclusion</p> <p>Our data confirm that inhibiting muscarinic cholinergic receptors with tiotropium bromide reduces TNFα mediated chemotactic properties and ROS release of human AM, and thus may contribute to lessen cellular inflammation.</p

Real time geotechnical field data acquistion using a distributed approach

A distributed geotechnical remote analysis of data system (Distributed G-RAD) can benefit both owners and contractors in providing better quality control and assurance on geotechnical projects. The Distributed G-RAD approach involves efficient data acquisition using PDAs with GPS capability, radio frequency identification (RFID) tags for labeling soil samples, laser scanning for measuring lift thickness and volumes of stockpiles and borrow pits. Spatial data storage is provided using a geographic information system (GIS). Portions of this system are already developed while other parts are still being considered. This paper also describes how RFID and laser scanning technologies can be used in the larger Distributed G-RAD system

Chronic hypoventilation syndromes and sleep-related hypoventilation

Chronic hypoventilation affects patients with disorders on any level of the respiratory system. The generation of respiratory impulses can be impaired in congenital disorders, such as central congenital alveolar hypoventilation, in alterations of the brain stem or complex diseases like obesity hypoventilation. The translation of the impulses via spinal cord and nerves to the respiratory muscles can be impaired in neurological diseases. Thoraco-skeletal or muscular diseases may inhibit the execution of the impulses. All hypoventilation disorders are characterized by a reduction of the minute ventilation with an increase of daytime hypercapnia. As sleep reduces minute ventilation substantially in healthy persons and much more pronounced in patients with underlying thoraco-pulmonary diseases, hypoventilation manifests firstly during sleep. Therefore, sleep related hypoventilation may be an early stage of chronic hypoventilation disorders. After treatment of any prevailing underlying disease, symptomatic therapy with non-invasive ventilation (NIV) is required. The adaptation of the treatment should be performed under close medical supervision. Pressure support algorithms have become most frequently used. The most recent devices automatically apply pressure support and vary inspiratory and expiratory pressures and breathing frequency in order to stabilize upper airways, normalize ventilation, achieve best synchronicity between patient and device and aim at optimizing patients' adherence

Severity stages of obesity-related breathing disorders - a cross-sectional cohort study

Introduction: There is a general underappreciation of the spectrum of obesity-related breathing disorders and their consequences. We therefore compared characteristics of obese patients with eucapnic obstructive sleep apnea (OSA), OSA with obesity-related sleep hypoventilation (ORSH) or obesity hypoventilation syndrome (OHS) to identify the major determinants of hypoventilation. Patients and methods: In this prospective, diagnostic study (NCT04570540), obese patients with OSA, ORSH or OHS were characterized applying polysomnography with transcutaneous capnometry, blood gas analyses, bodyplethysmography and measurement of hypercapnic ventilatory response (HCVR). Pathophysiological variables known to contribute to hypoventilation and differing significantly between the groups were specified as potential independent variables in a multivariable logistic regression to identify major determinants of hypoventilation. Results: Twenty, 43 and 19 patients were in the OSA, ORSH and OHS group, respectively. BMI was significantly lower in OSA as compared to OHS. The extent of SRBD was significantly higher in OHS as compared to OSA or ORSH. Patients with ORSH or OHS showed a significantly decreased forced expiratory volume in 1 s and forced vital capacity compared to OSA. HCVR was significantly lower in OHS and identified as the major determinant of hypoventilation in a multivariable logistic regression (Nagelkerke R-2 = 0.346, p = 0.050, odds ratio (95%-confidence interval) 0.129 (0.017-1.004)). Conclusion: Although there were differences in BMI, respiratory mechanics and severity of upper airway obstruction between groups, our data support HCVR as the major determinant of obesity-associated hypoventilation. (C) 2022 Elsevier B.V. All rights reserved