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 summary

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