5 research outputs found
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
Identification of β2-adrenoceptors on guinea pig alveolar macrophages using (-)-3-[125I]iodocyanopindolol
The β-adrenoceptor antagonist (-)-3-[125I]iodocyanopindolol ([125I]ICYP) binds with high affinity and in a saturable way to membranes of guinea pig alveolar macrophages. The equilibrium dissociation constant for [125I]ICYP is 24.3 ± 1.2 pM, and the number of binding sites is 166.3 ± 13.7 fmol/mg protein (N=4, ±SEM). Displacement studies with selective antagonists showed that [125I]ICYP labels β2-adrenoceptors on guinea pig alveolar macrophages
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