   Congress    Sponsors  Search Write About màj 23/07/98 |
Airway Smooth Muscle
Presentation
of the Group -Involvement in asthma research |
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Congress Sponsors Search Write About màj 23/07/98 |
Airway Smooth Muscle
Presentation
of the Group -Involvement in asthma research |
||||||||||||||
Recent
experimental results and current investigation
In the field of airway
smooth muscle physiology, we have characterized the calcium
signalling of this cell (1, 2). Regarding bronchial hyperresponsiveness
pathophysiology, we have established the dose-effect relationship
for atmospheric pollutants (3)
and examined the cellular mechanisms implicated in the increase
in airway reactivity induced by pollutants (4). Of direct relevance to asthma, one of
the aspects of bronchial hyperresponsiveness investigated in the
laboratory deals with the role of IgE in passive sensitization of
human bronchi. Passive sensitization of human isolated airways
with serum from allergic asthmatic patients provides a good
opportunity to study the role of IgE in bronchial reactivity. In
agreement with findings from several research teams, we have
observed that passive sensitization with serum containing high
concentration of IgE alters the mechanical response of human
isolated airways to nonspecific agonists such as histamine, KCl,
tachykinins or to relaxant compounds (5, 6). Passive sensitization of human airways
can be mimicked using monoclonal IgE and an anti-IgE challenge (7) but the direct role of IgE in the
hyperresponsiveness induced by the sensitizing procedure remains
controversial. In a recent study, we found that passive
sensitization was mainly related to mast cells bearing the IgE
molecule in both submucosal and smooth muscle layers (8). Mast cell-derived products could
therefore play an important role in IgE-induced
hyperresponsiveness. Current functional studies performed in the
laboratory indicate that mast cell-derived tryptase enhances the
contractile response of human isolated airways to non specific
agonists and that the tryptase inhibitor benzamidine could
abolish the alteration of contractile response induced by passive
sensitization (unpublished results). Taken together these results
suggest that mast cell-derived proteases could contribute to
sensitization-induced hyperresponsiveness. Further studies on
mast cell activation during the passive sensitization procedure
are now undertaken.
Relevance to
severe asthma
Some aspects of our
research could be relevant to severe asthma study:
References
Ref (1): Roux E., Guibert C., Savineau J.P., Marthan R. [Ca2+] oscillation induced by muscarinic stimulation in airway smooth muscle cells: receptor subtypes and correlation with the mechanical activity. British Journal of Pharmacology, 1997, 120, 1294-1301. (partial abstract from http://www.healthy.net/library/search/medline.htm )
Author : Roux E; Guibert C; Savineau JP; Marthan R
Address : Laboratoire de Physiologie Cellulaire Respiratoire,
Université Bordeaux 2, France.
Source : Br J Pharmacol, 120(7):1294-301 1997 Apr
Abstract :
1. Cytosolic calcium concentration ([Ca2+]i) by indo 1
microspectrofluorimetry in freshly isolatedcells and isometric
contraction of isolated rings were measured in response to
muscarinic cholinoceptor stimulation in rat tracheal smooth
muscle. 2. In isolated myocytes, acetylcholine (ACh, 0.03-1
microM) caused a rapid and graded increase in [Ca2+]i
up to a net amplitude of 492 +/- 26 nM (n = 19) which gradually
declined. The EC50 for ACh was 0.13 microM. This first [Ca2+]i
peak was followed, when the ACh concentration increased, in
approximately 50-60% of the cells, by successive peaks of
decreased amplitude ([Ca2+]i oscillations)
superimposed on the plateau phase. Whereas the percentage of
cells exhibiting [Ca2+]i oscillations remained
consistent, the frequency of these oscillations increased to up
to 10 min-1 with an ACh concentration of 100 microM. 3. Removal
of extracellular calcium (in the presence of EGTA, 0.4 mM) or
addition of the voltage-dependent Ca(2+)-channel
blocker verapamil (10 microM) did not alter the first [Ca2+]i
peak, the plateau or the oscillations induced by ACh or
carbachol. In contrast, the specific inhibitor of the
sarcoplasmic Ca(2+)-ATPase, thapsigargin (1 microM),
completely abolished the [Ca2+]i response....
... for the complete abstract, please enquire http://www.healthy.net/library/search/medline.htm
Ref (2): Savineau J.P., Marthan R. Modulation of the calcium sensitivity of the smooth muscle contractile apparatus: molecular mechanisms, pharmacological and pathophysiological implications. Fundamental and Clinical Pharmacology, 1997, 11, 289-299. (partial abstract from http://www.healthy.net/library/search/medline.htm )
Author : Savineau JP; Marthan R
Address : Laboratoire de Physiologie Cellulaire Respiratoire,
Université-Victor Ségalen-Bordeaux 2, France.
Source : Fundam Clin Pharmacol, 11(4):289-99 1997
Abstract : Smooth
muscle contraction is the basis of the physiological reactivity
of several systems (vascular, respiratory, gastrointestinal,
urogenital ...). Hyperresponsiveness of smooth muscle may also
contribute to a variety of problems such as arterial
hypertension, asthma and spontaneous abortion. An increase in
cytoplasmic calcium concentration ([Ca2+]i) is the key
event in excitation-contraction coupling in smooth muscle and the
relationship linking the [Ca2+]i value to the force of
contraction represents the calcium sensitivity of the contractile
apparatus (CaSCA). Recently, it has become evident that CaSCA can
be modified upon the action of agonists or drugs as well as in
some pathophysiological situations. Such modifications induce, at
a fixed [Ca2+]i value, either an increase (referred to
as sensitization) or a decrease (desensitization) of the
contraction force. The molecular mechanisms underlying this
modulation are not yet fully elucidated. Nevertheless, recent
studies have identified sites of regulation of the actomyosin
interaction in smooth muscle. ...
... for the complete abstract, please enquire http://www.healthy.net/library/search/medline.htm
Ref (3): Roux E., Guibert C., Crevel H., Savineau J.P., Marthan R. Human and rat airway smooth muscle responsiveness after ozone exposure in vitro. American Journal of Physiology (Lung Cell and Molecular Physiology 15), 1996, 271 : L631-L636. (partial abstract from http://www.healthy.net/library/search/medline.htm )
Author : Roux E; Guibert C; Crevel H; Savineau JP; Marthan R
Address : Laboratoire de Physiologie Cellulaire Respiratoire,
Université Bordeaux 2, France.
Source : Am J Physiol, 271(4 Pt 1):L631-6 1996 Oct
Abstract : We
previously reported that NO2 and acrolein administered ex vivo to
the lung altered the subsequent responsiveness of airway smooth
muscle. The aim of this study was to determine the dose-response
relationship for O3 in both human isolated bronchi and rat
tracheae and to investigate the mechanisms underlying O3-induced
airway responsiveness. Exposure to 1 ppm O3 for 15 min
significantly increased the maximal response to carbachol of rat
tracheal rings to 149.6 +/- 5.4% of the reference response to
acetylcholine (ACh) compared with that of unexposed rings (131.3
+/- 2.4%, n = 6, P < 0.05). The change in maximal airway
responsiveness to carbachol, when plotted against the product of
exposure concentration and exposure time to O3, a surrogate for
the dose, formed a bell-shaped curve. The peak of this
dose-response curve was shifted to the right for human bronchi
(50 ppm x min, n = 5) compared with that of rat tracheae (15 ppm
x min, n = 6). In the rat trachea, responses to KCl were not
altered by O3, whereas those to 5-hydroxytryptamine hydrochloride
(5-HT) were significantly increased. Finally, in the absence of
external Ca2+, O3 exposure still potentiated the
maximal response to carbachol from 73.6 +/- 13.9 to 137.0 +/-
6.0% and that to 5-HT from 21.5 +/- 5.5 to 38.7 +/- 2.2% of the
reference ACh response....
... for the complete abstract, please enquire http://www.healthy.net/library/search/medline.htm
Ref (4): Marthan R., Roux E., Savineau J.P. Human bronchial smooth muscle responsiveness after exposure in vitro to oxidizing pollutants. Cell Biology and Toxicology, 1996, 12 : 245-249. (partial abstract from http://www.healthy.net/library/search/medline.htm )
Author : Marthan R; Roux E; Savineau JP
Address : Laboratoire de Physiologie Cellulaire Respiratoire,
Université Bordeaux 2, France.
Source : Cell Biol Toxicol, 12(4-6):245-9 1996 Dec
Abstract : The aims
of this work were (1) to determine the dose-response relationship
between ex vivo exposure to oxidizing pollutants such as nitrogen
dioxide (NO2), the aldehyde acrolein, and ozone (O3), and the
reactivity to agonists in isolated human bronchial smooth muscle;
and (2) to investigate the alterations in the cellular mechanisms
of human airway smooth muscle contraction induced by such
exposures. Experiments were performed in isolated human bronchi
obtained at thoracotomy. Isometric contraction in response to a
variety of agonists was compared between pollutant-exposed
preparations and paired controls. Short exposures to NO2,
acrolein, or O3 altered the subsequent airway smooth muscle
responsiveness in a dose-dependent manner. The cellular
mechanisms producing the airway hyperresponsiveness observed in
vitro are shared by the three pollutants and include alterations
in airway smooth muscle excitation-contraction coupling as well
as indirect effects on neutral endopeptidase activity.
... for the complete abstract, please enquire http://www.healthy.net/library/search/medline.htm
Ref (5): Ben-Jebria, A., R. Marthan, M. Rossetti, and J.P. Savineau. 1993. Effect of passive sensitization on the mechanical activity of human isolated bronchial smooth muscle induced by substance P, neurokinin A and VIP. British Journal of Pharmacology. 109:131-136.. (partial abstract from http://www.healthy.net/library/search/medline.htm )
Author : Ben-Jebria A; Marthan R; Rossetti M; Savineau JP
Address : Laboratoire de Physiologie, Faculté de Médecine
Victor Pachon, Université de Bordeaux II, France.
Source : Br J Pharmacol, 109(1):131-6 1993 May
Abstract : 1. The
effect of passive sensitization on the mechanical activity of
human isolated bronchial smooth muscle induced by the following
neuropeptides substance P (SP), neurokinin A (NKA) and vasoactive
intestinal peptide (VIP) was studied both in the absence and in
the presence of the neutral endopeptidase (NEP) inhibitor,
phosphoramidon. 2. Cumulative concentration-response curves
(CCRC) to these neuropeptides were constructed in human passively
sensitized isolated bronchial rings and compared to those in
paired controls. Passively sensitized human isolated bronchial
rings were tissues incubated overnight in serum from asthmatic
patients atopic to Dermatophagoides pteronyssinus and paired
controls were tissues originating from the same lung specimens
but incubated overnight in serum from healthy donors. 3. In the
absence of phosphoramidon, passive sensitization significantly
increased the amplitude of the contractile responses to SP and
NKA including that to the maximal concentration given from 50 +/-
5% to 76 +/- 6% (n = 5, P < 0.05) and from 70 +/- 7% to 101
+/- 6% (n = 5, P < 0.05) of the maximal response to
acetylcholine, respectively. Passive sensitization significantly
shifted to the left the CCRC for both tachykinins as measured by
the geometric means dose-ratios which were 8.5 (95% confidence
limits (CL): 3.1-13.9) and 7.3 (95% CL: 4.2-10.3) for SP and NKA,
respectively....
... for the complete abstract, please enquire http://www.healthy.net/library/search/medline.htm
Ref (6): Villanove X., Marthan R., Tunon de Lara M., Johnson P., Savineau J.P., McKay K., Alouan L., Armour, C., Black J. Sensitization decreases relaxation in human isolated airways. American Review of Respiratory Disease, 1993, 148 : 107-112. (partial abstract from http://www.healthy.net/library/search/medline.htm )
Author : Villanove X; Marthan R; Tunon de Lara JM; Johnson PR;
Savineau JP; McKay KO; Alouan LA; Armour CL; Black JL
Address : Laboratoire de Physiologie, Université de Bordeaux II,
France.
Source : Am Rev Respir Dis, 148(1):107-12 1993 Jul
Abstract :
Passively sensitized human isolated airways provide an
opportunity to study some aspects of bronchial
hyperresponsiveness in vitro. Since it has been suggested that
excessive airway narrowing could be due to impaired relaxation,
we examined the effect of a variety of agents producing
relaxation via different mechanisms, i.e., verapamil and
lemakalim (a calcium channel antagonist and a potassium channel
opener, respectively) and isoproterenol, forskolin, and dibutyryl
cAMP (modulators of the beta-adrenoceptor signal transduction
pathway). Human bronchial rings, obtained at thoracotomy, were
passively sensitized by incubation in serum from atopic asthmatic
patients, and control rings were incubated in serum from
nonatopic subjects. We also studied bronchial rings from five
spontaneously sensitized human lung specimens. Responses to the
relaxant compounds were measured isometrically. Passive
sensitization significantly decreased the efficacy of verapamil
in maximally contracted tissues from 60 +/- 10 to 45 +/- 7% of
the maximal carbachol response (n = 6, p < 0.05) and that of
lemakalim from 51 +/- 16 to 38
+/- 14% (n = 7, p < 0.05) in tissues at baseline tone....
... for the complete abstract, please enquire http://www.healthy.net/library/search/medline.htm
Ref (7): Tunon de Lara J. M., Okayama Y., Savineau J.P., Marthan R. IgE-induced sensitization of human isolated bronchi and lung mast cells. European Respiratory Journal, 1995, 8 : 1861-1865. (partial abstract from http://www.healthy.net/library/search/medline.htm )
Author : Tunon de Lara JM; Okayama Y; Savineau JP; Marthan R
Address : Laboratoire de Physiologie, Université de Bordeaux II,
France.
Source : Eur Respir J, 8(11):1861-5 1995 Nov
Abstract : Passive
sensitization of human isolated lung with serum from atopic
asthmatic patients provides an opportunity to study the link
between airway hyper-responsiveness and the allergic process. To
directly demonstrate the role of immunoglobulin E (IgE) in the
effect of the atopic serum, we have compared the effect of
passively sensitizing both human bronchi and isolated lung mast
cells with either serum from atopic asthmatic patients or human
monoclonal IgE. Peripheral bronchi ( < 5 mm in internal
diameter) were dissected out from human lung obtained at
thoractomy and isometric contraction was studied in response to a
variety of immunological stimuli according to the sensitization
protocol. Mast cells were also isolated from human lung and
histamine release was measured under similar experimental
conditions. A contractile response was elicited by either the
specific antigen or anti-IgE (0.6-600 ng.mL-1) but not
anti-immunoglobulin G (IgG) 0.2-20 micrograms.mL-1) in airways
sensitized with atopic serum (total IgE concentration of
approximately 1,000 international units (IU).mL-1). The maximal
contractile response to anti-IgE was 75 +/- 22% of the response
to 1 mM acetylcholine....
... for the complete abstract, please enquire http://www.healthy.net/library/search/medline.htm
Ref (8): Berger P., Walls A.P., Marthan R., Tunon de Lara J.M. IgE-induced passive sensitization of human isolated bronchi: an immunohistochemical study. American Journal of Respiratory and Critical Care Medicine, 1998 (in press). (partial abstract from http://www.healthy.net/library/search/medline.htm )
in press
... for the complete abstract, please enquire http://www.healthy.net/library/search/medline.htm
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