| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Asthma, Allergy, and Immunological Disease Research Center, Section of Pulmonary and Critical Care Medicine, Department of Medicine, and the Committees on Clinical Pharmacology, Cell Physiology, and Comparative Medicine and Pathology, Division of the Biological Sciences, The University of Chicago, Chicago, Illinois 60637; and Zentrum für Pneumologie und Thoraxchirurgie, Krankenhaus Grosshansdorf, LVA Hamburg, D-22927 Grosshansdorf, Germany
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Mitchell, R. W., K. F. Rabe, H. Magnussen, and A. R. Leff.
Passive sensitization of human airways induces myogenic contractile responses in vitro. J. Appl.
Physiol. 83(4): 1276-1281, 1997.
We assessed
effects of passive sensitization on human bronchial smooth muscle (BSM)
response to mechanical stretching in vitro. Bronchial rings were sham
(control) or passively sensitized overnight by using sera from donors
demonstrating sensitivity to Dermatophagoides farinae and having immunoglobulin E (IgE)
concentrations of 2,600 ± 200 U/ml. Tissues were fixed
isometrically to force transducers to measure responses to electrical
field stimulation (EFS) and quick stretch (QS). The myogenic response
to QS was normalized to the maximal response to EFS (%EFS). The
myogenic response of sensitized BSM was 47.9 ± 10.9 %EFS to a QS
of ~6.5% optimal length (Lo);
sham-sensitized tissues had a myogenic response of 13.5 ± 6.4 %EFS
(P = 0.012 vs. passively sensitized).
A QS of ~13% Lo in sensitized
BSM caused a response of 82.8 ± 20.9 %EFS; sham-sensitized tissues
developed a response of 38.2 ± 17.3 %EFS
(P = 0.004). BSM incubated with serum
from nonallergic donors did not demonstrate increased QS response (4.6 ± 1.4 %EFS, P = not significant
vs. tissue exposed to atopic sera). However, tissues incubated in sera
from nonatopic donors supplemented with hapten-specific chimeric IgE
(JW8) demonstrated augmented myogenic response to QS of ~6.5% Lo (21.9 ± 6.2 %EFS, P = 0.027 vs. nonatopic
sera alone). We demonstrate that passive sensitization of human BSM
preparations causes induction and augmentation of myogenic contractions
to QS; this hyperresponsiveness corresponds to the IgE concentration in
sensitizing sera.
airway smooth muscle; bronchial smooth muscle; quick stretch; electrical field stimulation; serum immunoglobulin E
INTRODUCTION THE MECHANISM(S) BY WHICH human airways become
hyperreactive to endogenous mediators of anaphylaxis in asthma remains
elusive. However, increased responsiveness of airway smooth muscle
(ASM) causes augmented narrowing of the conducting airways (9) and increased airway resistance (1). Using bronchoscopically placed extracellular electrodes, Akasaka et al. (1) demonstrated that asthmatic subjects have increased phasic electrical activity in their
bronchi compared with normal individuals. These data suggested that ASM
may change from a normally quiescent, multiunit type to a more
spontaneously active, single-unit type of smooth muscle with atopy;
this change alone could account for the increased responsiveness of
asthmatic subjects to a variety of stimuli (5, 6).
Our laboratory has shown previously that immune-sensitized guinea pigs
demonstrate increased ASM spontaneous tone compared with
sham-sensitized animals (10). This increased,
prostanoid-derived spontaneous tone was associated with increased
responsiveness to muscarinic agonists and decreased responsiveness to
We tested the hypothesis that passive sensitization of human bronchi
augments spontaneous mechanical activity. We assessed the effect of
quick stretch (QS) on myogenic responsiveness of passively sensitized
and sham-sensitized human bronchial smooth muscle (BSM). We also
assessed the effect of immunoglobulin E (IgE) concentrations in human
serum on responsiveness of BSM preparations to electrical field
stimulation (EFS) and QS. We show in vitro for the first time that
passive immune sensitization, by using both endogenous and
exogenous IgE, induces and augments myogenic contractile activity of
the smooth muscle from seventh-generation human airways. We also
demonstrate that increased serum IgE concentration corresponds to the
induction and augmentation of this myogenic hyperresponsiveness.
METHODS
-adrenergic-receptor agonists (10). After ablation of spontaneous
tone in these animals, either through cyclooxygenase inhibition or
removal of the epithelium, tissues from sensitized and sham-sensitized
guinea pigs demonstrated similar muscarinic and -adrenergic receptor
responsiveness (10). In a dog model of allergic bronchospasm,
spontaneous mechanical activity of the ASM also was demonstrated (8);
canine tracheal smooth muscle from nonsensitized animals has been shown
normally to be quiescent (6). Spontaneous activity, stretch-induced myogenic contractions, and increased phasic electrical activity also
could be induced in this tissue in the presence of the potassium channel blocker tetraethylammonium (6). This compound also has been
demonstrated to increase the number of nexuses in canine ASM (2); these
low-impedance cell-cell connections are associated more with
single-unit types of smooth muscle (14).
-adrenoceptor agonists,
corticosteroids, or anticholinergic drugs. None of the patients had a
history of atopy or respiratory allergies. Immediately after they were
surgically excised, lung sections were placed in ice-cold
Krebs-Henseleit (KH) solution of the following composition (in mM): 115 NaCl, 25 NaHCO3, 1.38 NaH2PO4,
2.5 KCl, 2.46 MgCl2 · 7H2O,
1.91 CaCl2, and 11.2 dextrose.
Sixth- to seventh-generation (~2-3 mm inside diameter) airways
were dissected from lung parenchyma and blood vessels immediately after
lung resection. Airway segments, 1.5 cm in longitudinal length, were
excised and cut into 1- to 2-mm sections. Care was taken to ensure that
all sections were made in 90° transverse plane with epithelium
intact. Contiguous bronchial rings prepared as described above were
passively sensitized or sham sensitized.
11 U/ml
(control serum), or 3) incubated in
a 1:9 dilution of serum from the same nonatopic individuals supplemented with a hapten-specific chimeric IgE, JW8 (16). The
concentration of JW8 was selected to approximate the concentrations of
total IgE in the sera from atopic donors (~2,600 U/ml). Bronchial rings were sensitized overnight with serum from several atopic donors
with serum IgE concentrations varying from 505 to >3,000 U/ml (mean = 2,600 ± 200 U/ml). Sensitizing serum was not pooled; each passively
sensitized tissue within cohorts received serum from a single atopic
donor, and no donor serum was used more than once. All atopic donors
demonstrated discrete sensitivity to Dermatophagoides farinae over other common sensitizing allergens.
Bronchial rings were put into 15-ml Falcon tubes containing 10% serum
and were rotated overnight at room temperature. Control tissues were
similarly incubated in buffer alone or with control serum, or with
control serum supplemented with JW8. Approximately 18 h later, tissues
were fixed isometrically in 10-ml organ baths containing gassed KH at
37°C. Sensitization was confirmed by challenging the bronchial
rings (see below) to D. farinae
antigen (15) or to the hapten 4-hydroxy-3-iodo-5-nitrophenylacetic
acid-bovine serum albumin (NIP-BSA) (16).
Equilibration and experimental protocol.
After isometric fixation (noncompliant stainless steel hooks) in the
organ bath and tethering to the force transducers, bronchial rings were
allowed to equilibrate passively for 90 min. Resting tone then was
adjusted to ~500 mg for each tissue (2). Control and sensitized
bronchial rings were then contracted by EFS through platinum wire
electrodes aligned on either side of the preparations, and optimal
electrical parameters (30 V, 40-Hz direct current, 10-s duration) and
length (Lo)
were determined for maximal contractile response to EFS for
parasympathetic neural activation;
Lo was determined
by a limited length-tension study during the equilibration period
(8-10).
All tissues were fixed isometrically in the organ bath by two hooks.
One stainless steel hook was fastened to the bottom of the organ bath;
the other hook was fastened to a force transducer mounted on a threaded
rod to allow for the adjustment of resting tone and to elicit QS. A
calibrated thumbscrew enabled the accurate measurement of the angular
rotation of the threaded rod. The pitch of the screw was 1.0 mm;
therefore, a 90° rotation elicited a stretch of 0.25 mm and a
180° rotation elicited a stretch of 0.50 mm on the bronchial rings.
In preliminary studies, it was determined (at chart speeds of 25 mm/s)
that rotation of the thumbscrew (up to 360°) could be elicited
consistently in <200 ms, thus allowing for a rapid QS of the
bronchial ring preparations.
After a resting tone of 500 mg and maximal responsiveness to EFS were
established, control and sensitized bronchial rings were allowed to
equilibrate for 30 min. A QS of 0.25 or 0.50 mm was then elicited
randomly as described above for each tissue. Chart speed was set at 25 mm/min, and myogenic responses were measured for 2 min, during which
time contractile force induced by the QS began to wane. Bronchi were
allowed to recover for 10 min between stretches. These QS were ~6.5
and 13.0% of bronchial ring diameter, respectively. Myogenic responses
to QS were measured as a transient contraction above baseline after the
QS and normalized to the maximal response of each tissue to EFS
(%EFS). The myogenic contraction induced by QS (mg) was compared with
the maximal EFS response (mg).
Analysis of data.
All data were expressed as means ± SE. Where paired comparisons
were made, data were analyzed for statistical significance by paired
two-tailed Student's t-test. Where
data from more than two experimental groups were analyzed, a difference
among the groups was first determined by a one-way analysis of
variance. When a difference among groups was detected by an analysis of variance, statistical significance was assessed by Fisher's test for
multiple comparisons. Statistical significance was claimed whenever
P < 0.05.
RESULTS
Myogenic contractile response of control serum-incubated human bronchial rings with QS. From seven additional patients, bronchial rings passively sensitized by using sera from atopic donors demonstrated myogenic contractile responses (14 of 14 tissues) to QS of 0.25 mm (37.5 ± 6.5 %EFS) (Fig. 3). By contrast, bronchial rings from these same patients that were sham sensitized overnight in sera from nonatopic donors (IgE concentrations
11 U/ml) had no appreciable QS
response (4.6 ± 1.4 %EFS, 8 of 14 tissues;
P < 0.0001 vs. passively sensitized
bronchial rings). Tissue exposed to sera containing 11 U/ml IgE
demonstrated similar responsiveness to tissues incubated overnight in
KH buffer alone (P = NS; see above).
To test the hypothesis that the IgE concentration in the serum
corresponds to the hyperresponsiveness to QS observed in these
bronchial ring preparations, we assessed the effect of addition of a
hapten-specific chimeric IgE, JW8, to sera from nonatopic donors (11
U/ml IgE) on myogenic responsiveness. An augmented QS response (21.9 ± 6.2 %EFS; P = 0.027 vs.
sham-sensitized control, P = 0.046 vs.
passively sensitized bronchial rings) was elicited from bronchial rings (14 of 14 tissues) incubated with nonatopic sera plus exogenous IgE
(JW8).
In contrast to the QS response, passive sensitization did not affect parasympathetic contraction caused by EFS (Fig. 4). Maximal response to EFS was similar in tissues incubated with sera from nonatopic (449 ± 65 mg) and atopic donors (412 ± 77 mg) and in tissues incubated in sera containing JW8 (473 ± 74 mg) (P = NS for all comparisons). The QS was not significantly different among sham-sensitized (6.1 ± 0.3 %Lo), passively sensitized (6.4 ± 0.3 %Lo), or JW8-exposed (6.7 ± 0.3 %Lo) bronchial rings (P = NS for all comparisons).
All passively sensitized tissues demonstrated a significant Schultz-Dale contraction (497 ± 126 mg; Fig. 5) to D. farinae (30 U/ml); sham-sensitized tissues did not contract in response to the antigen. Tissues incubated in sera from nonatopic donors supplemented with JW8 all demonstrated contractile response (576 ± 94 mg) to the specific hapten NIP-BSA (10 µg/ml).
DISCUSSION
The purpose of this study was to assess the effect of passive immune sensitization on intrinsic contractile activity of the smooth muscle of conducting airways. We found that ~50% of seventh-generation human bronchial ring preparations demonstrate modest contractile response to a QS of ~6.5% of Lo; with sensitization, all bronchi tested elicited a myogenic contractile response to this QS that was greater in magnitude than responses induced for sham-sensitized tissues (Figs. 1, 2, 3). We also found that the induced myogenic contractile response depended on the magnitude of the QS; a QS of ~13% of Lo caused a greater intrinsic contraction, and sensitized bronchi demonstrated significantly greater myogenic response than sham-sensitized ring preparations (Fig. 2).
To test the hypothesis that a serum component other than IgE was
responsible for the tissue hyperresponsiveness to QS, we assessed
responses of bronchial rings from three separate groups: 1) passively sensitized, using sera
from atopic donors, 2) sham sensitized, using sera from nonatopic donors with serum IgE levels 11
U/ml, and 3) passively sensitized,
using sera from these same nonatopic donors but supplemented with a
hapten-specific chimeric IgE (JW8). We found that the presence of serum
alone did not augment subsequent myogenic responses compared with
tissues incubated overnight in buffer only. However, tissues incubated
with either sera from atopic donors or sera from nonatopic donors
supplemented with JW8 demonstrated augmented myogenic contractile
response to QS (Fig. 3). These data suggest the presence of increased
IgE is necessary for the induction and augmentation of myogenic
contractile response to QS in human bronchial rings in vitro.
Previous studies have demonstrated increased electrical activity in airways of asthmatic subjects compared with nonasthmatic volunteers (1). Increased electrical activity (spontaneous action potentials) of ASM has been demonstrated to be consonant with the induction of myogenic contractions in response to QS in canine airway tissues (5, 6). We have shown previously in a canine model of allergic bronchospasm that the normally quiescent tracheal smooth muscle demonstrates spontaneous contractile activity (8). Microelectrode studies of BSM strips from the same canine model demonstrated significant spontaneous electrical activity of the sarcolemma of the smooth muscle myocyte compared with tissues from sham-sensitized animals (12), which normally show no action potentials (6, 12). These studies suggested alterations in excitation, induced by immune sensitization, may cause the hyperresponsiveness observed in asthmatic individuals and in a canine model of allergic bronchospasm (5, 6, 8, 12).
We have also demonstrated previously augmentation of intrinsic contractile activity of passively sensitized human bronchi (9). Sensitized tissues contracted with greater velocity and shortened to a greater extent than paired control bronchial rings. The previous study suggested alterations in contraction coupling may also contribute to the ASM hyperresponsiveness observed with passive immune sensitization. Jiang et al. (4) have demonstrated a twofold increase in actomyosin adenosinetriphosphatase activity in the immune-sensitized canine model of allergic bronchospasm. This increased parameter of contraction coupling could be attributed to a 30% increase in myosin light chain kinase content and activity found in sensitized tissues (4).
The above-mentioned previous studies suggest that the increased myogenic response observed on QS of human bronchi that we observed may be due to increased contraction coupling, perhaps through an alteration in membrane excitability with passive sensitization by IgE. The increased sensitivity of the smooth muscle to mechanical stretch could be a consequence of an alteration in potassium channel activity (6). Alternatively, the attachment of the Fc fragment of IgE to mast cell or smooth muscle membranes may alter calcium flux through voltage-dependent channels, with a concomitant change in membrane potential (13).
It is important to specify some limitations of our findings. Our data are limited to passively sensitized bronchial rings from patients undergoing lung resection for carcinoma. The effect of long-term tobacco consumption on either the general or myogenic responsiveness of BSM in humans is not known. However, we used contiguous tissue preparations from the same individuals in these studies, and comparisons of data were made between and among bronchial rings from similar airways. Using contiguous rings also ensured similar airway dimensions so that a QS of 0.25 or 0.50 mm was not significantly different between groups of tissues.
Our experimental design also considered predominantly the relationship between airway responsiveness and atopy as marked by serum IgE concentrations. It is nonetheless possible that other serum factors could be responsible for the induction of hyperresponsiveness and that these occurred in concert with induction of increased IgE concentrations in sera from atopic donors. However, sera from nonatopic donors that were supplemented with JW8 induced greater responses to QS of human bronchi compared with tissues incubated with sera containing low IgE concentrations (Fig. 3). Therefore, it appears that addition of IgE alone is sufficient to induce this response and the specific contractile response to antigen (either D. farinae or NIP-BSA; Fig. 5).
We did not observe nonspecific augmentation to EFS in these bronchial rings (Fig. 4), whereas Ichinose et al. (3) demonstrated that incubation of human airways with IgE increased cholinergic neurotransmission in vitro. However, Ichinose and colleagues elicited EFS responses by using frequencies between 1 and 8 Hz on bronchial strips compared with 40 Hz on bronchial rings in the present study. It is possible that a frequency of 40 Hz is supramaximal for both sham- and passively sensitized tissues and that all tissues respond similarly to high-frequency EFS. In contrast to our studies, Watson et al. (16) have demonstrated in human tissues that IgE (JW8) is not sufficient to induce nonspecific contractile hyperresponsiveness to histamine. They concluded that nonspecific histamine hyperresponsiveness may be independent of IgE or may require IgE in the presence of some other factor(s) present in sensitizing serum (16). A separation between specific and nonspecific hyperresponsiveness also has been demonstrated in an IgE-deficient mouse model (7). Both wild-type and IgE-deficient mice were sensitized to specific allergens, and, whereas IgE-deficient mice did not produce IgE in response to antigen challenge, both wild-type and IgE-deficient strains demonstrated bronchial hyperreactivity and eosinophilia. These data further suggest that IgE may not be necessary for nonspecific airway hyperresponsiveness. It is important to note that, in our study, JW8 did induce a myogenic response that was significantly different from that in sham-sensitized, control bronchial rings; however, the myogenic response to QS induced by sera from atopic individuals was significantly greater than that induced by JW8 (Fig. 3). This significantly greater response could be because of additional serum factors (16).
We demonstrate in vitro for the first time that sensitization induces and augments myogenic contractile activity of the smooth muscle from human seventh-generation airways. We also demonstrate that the presence of serum alone does not affect myogenic contractile responses but that the presence of significant concentrations of IgE (either endogenous or exogenously added) induces passive sensitization of human bronchial rings in vitro. Myogenic responses were induced and augmented in the presence of either IgE-rich sera from atopic donors or in the presence of JW8, a hapten-specific chimeric IgE mixed with sera from nonatopic individuals. Tissues incubated in sera from nonatopic donors or in the absence of serum (KH buffer alone) demonstrated similar, minimal response to QS. Our data suggest that allergic bronchospasm in vivo may be manifested, in part, through augmentation of myogenic responsiveness of the smooth muscle from intrapulmonary, conducting airways.
ACKNOWLEDGEMENTS
The authors thank Nikki Watson for assistance in completing the studies, the surgical staff of Krankenhaus Grosshansdorf for cooperation, and the members of the Clinical Laboratory for performing the total and specific IgE analysis. The donation of JW8 and NIP-BSA by Dr. C Heusser (Novartis, Basel, Switzerland) is gratefully acknowledged.
FOOTNOTES
Address for reprint requests: A. R. Leff, Section of Pulmonary and Critical Care Medicine, MC 6076, The Univ. of Chicago, 5841 S. Maryland Ave., Chicago IL 60637.
Received 15 April 1997; accepted in final form 17 June 1997.
REFERENCES
| 1. | Akasaka, K., K. Kono, Y. Ono, S. Mue, M. Kumagai, and T. Tse. A new electrode for electromyographic study of bronchial smooth muscle. Tohoku J. Exp. Med. 117: 49-56, 1975[Medline]. |
| 2. | Finney, M. J. B., J.-A. Karlsson, and C. G. A. Persson. Effect of bronchoconstrictors and bronchodilators on a novel human small airway preparation. Br. J. Pharmacol. 85: 29-36, 1985. [Medline] |
| 3. | Ichinose, M., M. Miura, M. Tomaki, T. Oyake, N. Kageyama, Y. Ikarashi, Y. Maruyama, and K. Shirato. Incubation with IgE increases cholinergic neurotransmission in human airways in vitro. Am. J. Respir. Crit. Care Med. 154: 1272-1276, 1996[Abstract]. |
| 4. | Jiang, H., A. J. Halayko, X. Liu, and N. L. Stephens. Ragweed sensitization-induced increase of myosin light chain kinase content in canine airway smooth muscle. Am. J. Respir. Cell Mol. Biol. 7: 567-573, 1992. |
| 5. |
Kannan, M. S.,
L. P. Jager,
E. E. Daniel,
and
R. E. Garfield.
Effects of 4-aminopyridine and tetraethylammonium chloride on the electrical activity and cable properties of canine tracheal smooth muscle.
J. Pharmacol. Exp. Ther.
227:
706-715,
1983 |
| 6. | Kroeger, E. A., and N. L. Stephens. Effect of tetraethylammonium on tonic airway smooth muscle: initiation of phasic electrical activity. Am. J. Physiol. 228: 633-636, 1975. |
| 7. |
Melhap, P. D.,
M. van de Rijn,
A. B. Goldberg,
J. P. Brewer,
V. P. Kurup,
T. R. Martin,
and
H. C. Oettgen.
Allergen-induced bronchial hyperreactivity and eosinophilic inflammation occur in the absence of IgE in a mouse model of asthma.
Proc. Natl. Acad. Sci. USA
94:
1344-1349,
1997 |
| 8. |
Mitchell, R. W.,
E. A. Kroeger,
W. Kepron,
and
N. L. Stephens.
Local parasympathetic mechanisms for ragweed-sensitized canine trachealis hyperresponsiveness.
J. Pharmacol. Exp. Ther.
243:
907-914,
1987 |
| 9. | Mitchell, R. W., E. Rühlmann, H. Magnussen, A. R. Leff, and K. F. Rabe. Passive sensitization of human bronchi augments smooth muscle shortening velocity and capacity. Am. J. Physiol. 242 (Lung Cell. Mol. Physiol. 11): L218-L222, 1994. |
| 10. | Ndukwu, I. M., J. Solway, K. Arbetter, K. Uzendoski, A. R. Leff, and R. W. Mitchell. Immune sensitization augments epithelium-dependent spontaneous tone in guinea pig trachealis. Am. J. Physiol. 241 (Lung Cell. Mol. Physiol. 10): L485-L492, 1994. |
| 11. | Rabe, K. F., B. Morton, G. Dent, R. A. Coleman, and H. Magnussen. Increased responsiveness to histamine, anti-IgE and allergen after passive sensitization of human airways in vitro (Abstract). Eur. Respir. J. 6: 481s, 1993. |
| 12. | Sigurdsson, S., R. Jabr, A. Miller, N. L. Stephens, and W. C. Cole. Whole-cell and single channel K+ currents in isolated canine bronchial smooth muscle cells (Abstract). Biophys. J. 61: A251, 1992. |
| 13. |
Souhrada, M.,
and
J. F. Souhrada.
Immunologically induced alterations of airway smooth muscle cell membrane.
Science
225:
723-725,
1984 |
| 14. | Stephens, N. L., and H. Jiang. Basic physiology of airway smooth muscle. In: The Lung: Scientific Foundations, edited by R. G. Crystal, and J. B. West. New York: Raven, 1991, p. 1087-1115. |
| 15. | Tunon de Lara, J. M., Y. Okayama, J.-P. Savineau, and R. Marthan. IgE-induced passive sensitization of human isolated bronchi and lung mast cells. Eur. Respir. J. 8: 1861-1865, 1995[Abstract]. |
| 16. | Watson, N., K. Bodtke, R. A. Coleman, G. Dent, B. E. Morton, E. Rühlmann, H. Magnussen, and K. F. Rabe. Role of IgE in hyperresponsiveness induced by passive sensitization of human airways. Am. J. Respir. Crit. Care Med. 155: 839-844, 1997[Abstract]. |
This article has been cited by other articles:
|
|
 |
|
  M. Baroffio, E. Crimi, and V. Brusasco Review: Airway smooth muscle as a model for new investigative drugs in asthma Therapeutic Advances in Respiratory Disease, June 1, 2008; 2(3): 129 - 139. [Abstract] [PDF]
|
|
|
|
 |
|
 R. W. Mitchell, M. L. Dowell, J. Solway, and O. J. Lakser Force Fluctuation induced Relengthening of Acetylcholine-contracted Airway Smooth Muscle Proceedings of the ATS, January 1, 2008; 5(1): 68 - 72. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. S. An, T. R. Bai, J. H. T. Bates, J. L. Black, R. H. Brown, V. Brusasco, P. Chitano, L. Deng, M. Dowell, D. H. Eidelman, et al. Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma Eur. Respir. J., May 1, 2007; 29(5): 834 - 860. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. D. Mentzelopoulos, C. Roussos, and S. G. Zakynthinos Prone position improves expiratory airway mechanics in severe chronic bronchitis Eur. Respir. J., February 1, 2005; 25(2): 259 - 268. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Brusasco and R. Pellegrino Invited Review: Complexity of factors modulating airway narrowing in vivo: relevance to assessment of airway hyperresponsiveness J Appl Physiol, September 1, 2003; 95(3): 1305 - 1313. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Fernandes, R. W. Mitchell, O. Lakser, M. Dowell, A. G. Stewart, and J. Solway Invited Review: Do inflammatory mediators influence the contribution of airway smooth muscle contraction to airway hyperresponsiveness in asthma? J Appl Physiol, August 1, 2003; 95(2): 844 - 853. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Crimi, R. Pellegrino, M. Milanese, and V. Brusasco Deep breaths, methacholine, and airway narrowing in healthy and mild asthmatic subjects J Appl Physiol, October 1, 2002; 93(4): 1384 - 1390. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. SOLWAY What Makes the Airways Contract Abnormally? Is It Inflammation? Am. J. Respir. Crit. Care Med., March 1, 2000; 161(3): S164 - 167. [Full Text] [PDF]
|
|
|
|
|
|
J. L. BLACK and P. R. A. JOHNSON What Determines Asthma Phenotype? Is It the Interaction between Allergy and the Smooth Muscle? Am. J. Respir. Crit. Care Med., March 1, 2000; 161(3): S207 - 210. [Full Text] [PDF]
|
|
|
|
|
|
E. ROUX, J.-M. HYVELIN, J.-P. SAVINEAU, and R. MARTHAN Human Isolated Airway Contraction . Interaction between Air Pollutants and Passive Sensitization Am. J. Respir. Crit. Care Med., August 1, 1999; 160(2): 439 - 445. [Abstract] [Full Text]
|
|
|
|
|
|
H. W. Mitchell, D. J. Turner, P. R. Gray, and P. K. McFawn Compliance and stability of the bronchial wall in a model of allergen-induced lung inflammation J Appl Physiol, March 1, 1999; 86(3): 932 - 937. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. SONG, E. CRIMI, M. MILANESE, J. DUAN, K. REHDER, and V. BRUSASCO Anti-inflammatory Agents and Allergen-induced beta 2-Receptor Dysfunction in Isolated Human Bronchi Am. J. Respir. Crit. Care Med., December 1, 1998; 158(6): 1809 - 1814. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. F. RABE Mechanisms of Immune Sensitization of Human Bronchus Am. J. Respir. Crit. Care Med., November 1, 1998; 158(2007): S161 - S170. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
