Alveolar macrophages in asthma and chronic obstructive pulmonary disease : modulation of cellular activity

Asthma and chronic obstructive pulmonary disease (COPD) affect over 10 % of the population in industrialized countries and its prevelance and mortality is still rising in stead of decreasing despite intensive drug therapy. This may be caused by the fact that both diseases are more than just bronchoconstriction but are the clinical manifestation of (a) very complex pathophysiological process(es). Indeed, over the past few years, investigators of several disciplins have focussed their attention to the underlying mechanisms that lead to the typical characteristics of both pulmonary diseases. One of the most striking similarities between asthma and COPD is their association with pulmonary inflammation which is regarded a fundamental event in the pathophysiology of asthma and COPD. This is reflected in the treatment of both diseases which, over the past few years, is clearly shifted !rom relief of symptoms (bronchodilators) towards a more causal therapy (anti-inflammatory drugs). Still, due to the complexity of mechanisms involved in pulmonary inflammation, asthma and COPD remain difficult to treat. Pulmonary inflammation can be regarded as a complex puzzle consisting of an, as yet, unknown number of different pieces. Curing asthma and COPD or at least an adequate treatment of the disease implicates the full or partial elucidation of the puzzle. Since we do not know the full size or shape of the puzzle, one way to accomplish this, is gathering knowledge about the individual pieces which make up the unknown puzzle and trying to figure out how they fit together. In the pathophysiology of pulmonary inflammation the greater part of pieces consists of pulmonary cells and the interactions between them. Communication between cells is provided by means of interactions of a variety of mediators they produce which is attained through binding to cell-surface receptors. These receptors are part of ingenious mechanisms (transmembrane signalling systems) which translate external information into intracellular signals (second messengers). In turn, alterations in the concentration of second messengers modulate in a complex way the activity of the cell. Having simplified a small part of the complexity of pulmonary inflammation to cells, mediators and second messengers, we have confined our study to the modulation of cellular activity of alveolar macrophages (AM), cells which exhibit an important key function in the processes of pulmonary inflammation. In the second part of this thesis (the first part contains a general introduction), the mechanisms by which inflammatory mediators and B-adrenergic agonists interact with AM adenylyl cyclase (the transmembrane signalling system which produces the second messenger cyclic AMP) and its modulation by immunologic challenge (sensitization and antigen challenge) are described. In the third part, the interactions of the lipid mediator platelet activating factor and AM are considered in more detail with a special reference to cAMP-production and arachidonic acid metabolism. In part four, the knowledge gathered from the previous parts has been employed to study the modulation of functional activity of human AM in which differences between AM from control subjects and COPD patients and asthmatics are emphasized. The thesis ends with part five which includes a general discussion and a summar

Cyclic AMP enhancing drugs modulate eicosanoid release from human alveolar macrophages

The effect of the phosphodiesterase inhibitor isobutyl-methylxanthine (IBMX), salbutamol and sodium nitroprusside was evaluated regarding PGE2 and LTB4 release and cAMP and cGMP level in human alveolar macrophages obtained from controls and COPD patients. Basal levels per five million control-respectively COPD alveolar macrophages: cAMP 1.2 and 1.0 pmole; cGMP 8.4 and 9.1 fmole; PGE2 120 and 63 pg and LTB4 19.2 and 14.8 pg. In both populations IBMX increased cAMP level by 55–93% and salbutamol+IBMX by 285-252%. Except for the 61% rise in LTB4 release by salbutamol+IBMX the drugs hardly affected PGE2 and LTB4 release from control macrophages. In COPD alveolar macrophages, however, IBMX and IBMX+salbutamol largely reduced PGE2 release (63 vs 11 pg per 106 cells) but less efficiently increased LTB4. In both macrophage populations sodium nitroprusside (SNP) substantially increased (3–4 fold) cGMP level but did not affect eicosanoid production. Present results indicate that drugs which enhance cAMP level decrease PGE2 release from COPD macrophages and stimulate the release of LTB4 a chemotactic mediator involved in bronchial inflammatory reactions

Methods to assess the stability of a bicycle rider system

The SOFIE (Intelligent Assisted Bicycles) project wishes to create performance and design guidelines for mechatronic appliances which improve the stability of electric bicycles, so-called intelligent stability assist devices (IAD). To achieve this goal, a stability hypothesis, an advanced rider/bicycle model and bicycle stability test bench, will be created. This paper describes the development of these components and its goal is to present the project design. The stability hypothesis is based on the concept that the Centre of Mass (CoM) of the bicycle/rider system stays within certain lateral margins from the heading of a bicycle. The rider/bicycle model is created in Adams for multi-body dynamic simulations. The bicycle stability test bench is designed to be interchangeable between bicycles. The model, the test bench and the stability hypothesis will be used to validate the effectiveness of the IAD’s and assist in their design

Pulmonary granulocyte influx and impaired alveolar macrophage adenylyl cyclase responsiveness in developing respiratory distress

Alveolar macrophages have recently been postulated as being involved in the aetiology of adult respiratory distress syndrome (ARDS). To evaluate their role, basal cyclic AMP levels and responsiveness of adenylyl cyclase alveolar macrophages were determined at four intermediate stages of developing respiratory distress in piglets using a protocol with repeated lung lavage. Examination of alveolar cells recovered from the subsequent lavages reveals an influx of granulocytes (neutrophils and eosinophils) within 1 h of two intensive lung lavages. During the developing respiratory distress the basal cyclic AMPlevel of alveolar macrophages increases and adenylyl cyclase responsiveness to prostaglandin E2 (PGE2) and isoprelanaline diminishes. The previously observed impairment of macrophage activity can then be explained at a subcellular level

Anthropometry for WorldSID A World-Harmonized Midsize Male Side Impact Crash Dummy

The WorldSID project is a global effort to design a new generation side impact crash test dummy under the direction of the International Organization for Standardization (ISO). The first WorldSID crash dummy will represent a world-harmonized mid-size adult male. This paper discusses the research and rationale undertaken to define the anthropometry of a world standard midsize male in the typical automotive seated posture. Various anthropometry databases are compared region by region and in terms of the key dimensions needed for crash dummy design. The Anthropometry for Motor Vehicle Occupants (AMVO) dataset, as established by the University of Michigan Transportation Research Institute (UMTRI), is selected as the basis for the WorldSID mid-size male, updated to include revisions to the pelvis bone location. The proposed mass of the dummy is 77.3kg with full arms. The rationale for the selected mass is discussed. The joint location and surface landmark database is appended to this paper

Stimulation of cyclic AMP production in human alveolar macrophages induced by inflammatory mediators and β-sympathicomimetics

Abstract We have investigated the effects of inflammatory mediators and β-adrenoceptor agonists on the adenylyl cyclase responsiveness in alveolar macrophages from control subjects, patients suffering from chronic obstructive pulmonary disease (COPD) and asthmatics. Basal cyclic AMP (cAMP) levels in alveolar macrophages from COPD patients were significantly elevated (plus 42%) as compared to controls. In addition, the adenylyl cyclase responsiveness to prostaglandin E2, histamine and the β-adrenoceptor agonist salbutamol was significantly impaired in alveolar macrophages from COPD patients and asthmatics. The lipid mediator platelet activating factor showed no effect on cAMP production in all three alveolar macrophage populations. Furthermore, the cAMP-enhancing effects of isoprenaline, salbutamol and histamine appeared to be mediated via β2-adrenoceptors and histamine H2-receptor subtypes respectively. Taken together, these data suggest an intrinsic desensitization phenomenon in alveolar macrophages from COPD patients and asthmatics

Causes and consequences of psychological distress among orphans in eastern Zimbabwe.

Substantial resources are invested in psychological support for children orphaned or otherwise made vulnerable in the context of HIV/AIDS (OVC). However, there is still only limited scientific evidence for greater psychological distress amongst orphans and even less evidence for the effectiveness of current support strategies. Furthermore, programmes that address established mechanisms through which orphanhood can lead to greater psychological distress should be more effective. We use quantitative and qualitative data from Eastern Zimbabwe to measure the effects of orphanhood on psychological distress and to test mechanisms for greater distress amongst orphans suggested in a recently published theoretical framework