Physiology Program, Harvard School of Public Health, Boston, Massachusetts 02115
THE ROLE OF AIRWAY SMOOTH MUSCLE in
asthma has been appreciated for some time. In 1859, Salter
(12) wrote: "the phenomena of asthma - the
distressing sensation and the demand for extraordinary respiratory
efforts immediately depend upon a spastic contraction of the
fibre cells of organic or unstriped muscle." Airway
obstruction caused by excessive airway smooth muscle contraction is one
of the hallmarks of asthma, and its importance is emphasized by
the fact that drugs designed either to prevent or to reverse the
bronchoconstriction of asthma are the cornerstone of asthma therapy.
Asthma is also an inflammatory disease characterized by increased
numbers of eosinophils and activated CD4+ T cells in the
airways, especially T cells expressing Th2 type cytokines including
interleukin (IL)-4, IL-5, IL-9, and IL-13. A growing body of data
supports a role for these cytokines in the pathogenesis of asthma. Not
only is there increased expression of these cytokines in
bronchoalveolar lavage fluid and bronchial biopsies from asthmatics but
the actions of these cytokines are consistent with the features of
allergic asthma: IL-4 and IL-13 promote IgE synthesis, IL-5
promotes eosinophil emigration and survival, and IL-9 promotes mucous
hypersecretion, another common feature of asthma. The genes for each of
these cytokines are located on chromosome 5q in a region that has been
linked to asthma (11). Furthermore, a role for each of
these cytokines in airway hyperresponsiveness has been suggested from
work in animal models. For example, administration of exogenous IL-13
to nonimmunized mice or overexpression of IL-13 in mice results in
eosinophil migration into the airways, mucus hypersecretion, and
increased airway responsiveness, whereas neutralization of endogenous
IL-13 in allergen-sensitized and -challenged mice results in
attenuation of these asthma phenotypes (15, 16).
While it is clear that there is a link between the airway
inflammation and the airway smooth muscle contraction of asthma, the
mechanistic basis for this link remains undefined. Furthermore, until
recently the role of the airway smooth muscle cell in this relationship
was assumed to be as a passive downstream target of spasmogens derived
from the inflammatory process. However, a series of publications within
the last few years suggests that airway smooth muscle cells are also
important sources of cytokines and chemokines. Furthermore, the cells
respond to these cytokines by 1) expressing adhesion
molecules that permit cell-cell interactions between smooth muscle
cells, eosinophils, and T cells; 2) producing additional
cytokines and chemokines; 3) increasing their contractile responses to bronchoconstricting agonists and decreasing their relaxant
responses to Until now, the cytokines produced by airway smooth muscle
appeared to be restricted to chemokines such as IL-8, eotaxin, RANTES, granulocyte-macrophage colony-stimulating factor, monocyte
chemoattractant protein (MCP)-1, MCP-2, and MCP-3, and acute phase
cytokines such as IL-1 Although the ability of airway smooth muscle to produce Th2 cytokines
is perhaps surprising, the authors (4) used a number of
different techniques to confirm the synthesis of IL-13 and IL-5 by the
HASM cells. In addition to the functional data, the authors also used
RT-PCR to show a time-related increase in IL-13 mRNA following
incubation of HASM cells with asthmatic serum and a time-related
increase in IL-5 mRNA following administration of IL-13. The primers
used resulted in a product that spanned introns, so there is no
question of the results being caused by contamination of the RNA with
genomic DNA. The authors also used flow cytometry to demonstrate the
intracellular expression of IL-13 protein in cells treated with
asthmatic serum and ELISA to confirm the release of IL-5 from cells
treated with IL-13.
There are, however, some important caveats to be addressed before
we fully embrace the concept of the smooth muscle cell as an important
source of Th2 cytokines in the asthmatic. First, the human cells used
in these studies were derived from culture. It has been well
established that there are important phenotypic changes that occur in
smooth muscle cells in culture, including changes in the level of
expression of contractile proteins (14). It is not known
whether culture also induces changes in the capacity of HASM cells to
produce cytokines. Therefore, it will be important to confirm the
expression of IL-5 and IL-13 in airway smooth muscle either by
immunohistochemical techniques or by in situ hybridization in biopsies
that contain smooth muscle or in tissue sections derived from
asthmatics. Second, the airway smooth muscle cells used in these
studies were derived from only two donors. There are fairly common
polymorphisms in both the IL-13 gene itself and the IL-4R The results of this and other studies clearly suggest that we can
no longer consider the smooth muscle cell to be a passive player
in the asthmatic syndrome. Rather, the smooth muscle cell is gradually
regaining its place at the center of a dynamic asthmatic response, not only because of its role in the bronchospasm of asthma
but also because of its apparent capacity to initiate and amplify
inflammatory cascades, including Th2 cytokine cascades.
ARTICLE
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ARTICLE
REFERENCES
-agonists; and 4) proliferating (1, 3,
6, 9, 13).
(reviewed in Ref. 2). The
sources of the Th2 cytokines produced in the asthmatic airway was
thought to be limited to cells of hematopoietic origin. However, in the
study by Grunstein et al., one of the current articles in focus (Ref.
4, see p. L520 in this issue), it is now suggested
that airway smooth muscle cells also have the capacity to synthesize
IL-13 and IL-5. The authors (4) show that IgE immune
complexes administered to rabbit airway smooth muscle in vitro increase
contractile responses to acetylcholine and decrease relaxant responses
to isoproterenol, presumably through effects on low affinity IgE
(Fc
RII) receptors that are expressed on the airway smooth muscle
itself, as previously reported by these authors (5). The
authors also show that antibodies to the IL-4 receptor-
(IL-4R
),
which is required for responses to IL-13, abrogate these changes in
responsiveness. In addition, they show that both IL-13 and IL-5
expression are induced when serum from asthmatics with high IgE titres
is administered to human airway smooth muscle (HASM) cells in culture.
Furthermore, exogenous IL-13 induces IL-5 expression in these cultured
cells and also causes changes in the contractility of rabbit airway smooth muscle similar to those induced by the IgE immune complexes. Moreover, these effects of IL-13 on airway smooth muscle contractility are abolished by an IL-5 receptor antibody. The authors
(4) interpret their data as indicating that IgE induces
IL-13 in airway smooth muscle, which then induces IL-5, and that the
effects of IL-5 subsequently mediate the effects on airway smooth
muscle contractility. Data from our lab showing that IL-13 also causes decreased
-adrenergic responsiveness (8) and increased
contractile responses to leukotrienes (unpublished observations) in
HASM cells support these observations.
that are
required for IL-13 signal transduction (7, 10), but the
genotypes of the cells used in this study have not been described.
Hence, it will also be important to confirm these results on cells or
tissues derived from a larger number of donors to show that the results
obtained here are not restricted to cells of a particular or possibly
rare genotype. Finally, although the authors (4) were able
to confirm the expression of IL-13 and IL-5 by HASM cells, the
amount produced appears to be fairly small. However, where autocrine
effects are concerned, what matters is the concentration in the
microenvironment of the airway smooth muscle cell, and it is
clear from the functional data in the rabbit trachea that there is
sufficient IL-13 and IL-5 produced to affect contractile responses
since the effects of IgE immune complexes are abolished by IL-4 or IL-5
receptor antibodies. Whether the effects that are induced in airway
smooth muscle by autologously produced IL-13 and/or IL-5 are large or
small compared with the effects produced by IL-13 and IL-5 derived from
T cells or other sources remains to be determined.
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FOOTNOTES |
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Address for reprint requests and other correspondence: S. Shore, Physiology Program, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115 (E-mail: sshore{at}hsph.harvard.edu).
10.1152/ajplung.00450.2001
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REFERENCES |
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1.
Amrani, Y,
Martinet N,
and
Bronner C.
Potentiation by tumour necrosis factor- of calcium signals induced by bradykinin and carbachol in human tracheal smooth muscle cells.
Br J Pharmacol
114:
4-5,
1995[Abstract].
2.
Chung, KF.
Airway smooth muscle cells: contributing to and regulating airway mucosal inflammation?
Eur Respir J
15:
961-968,
2000
3.
Ghaffar, O,
Hamid Q,
Renzi PM,
Allakhverdi Z,
Molet S,
Hogg JC,
Shore SA,
Luster AD,
and
Lamkhioued B.
Constitutive and cytokine-stimulated expression of eotaxin by human airway smooth muscle cells.
Am J Respir Crit Care Med
159:
1933-1942,
1999
4.
Grunstein, MM,
Hakonarson H,
Leiter J,
Chen M,
Whelan R,
Grunstein JS,
and
Chuang S.
IL-13-dependent autocrine signaling mediates altered responsiveness of IgE-sensitized airway smooth muscle.
Am J Physiol Lung Cell Mol Physiol
282:
L520-L528,
2002
5.
Hakonarson, H,
and
Grunstein MM.
Autologously up-regulated Fc receptor expression and action in airway smooth muscle mediates its altered responsiveness in the atopic asthmatic sensitized state.
Proc Natl Acad Sci USA
95:
5257-5262,
1998
6.
Hirst, SJ.
Airway smooth muscle as a target in asthma.
Clin Exp Allergy
30, Suppl1:
54-59,
2000[ISI][Medline].
7.
Howard, TD,
Whittaker PA,
Zaiman AL,
Koppelman GH,
Xu J,
Hanley MT,
Meyers DA,
Postma DS,
and
Bleecker ER.
Identification and association of polymorphisms in the interleukin-13 gene with asthma and atopy in a Dutch population.
Am J Respir Cell Mol Biol
25:
377-384,
2001
8.
Laporte, JC,
Moore PE,
Baraldo S,
Jouvin MH,
Church TL,
Schwartzman IN,
Panettieri RA, Jr,
Kinet JP,
and
Shore SA.
Direct effects of interleukin-13 on signaling pathways for physiological responses in cultured human airway smooth muscle cells.
Am J Respir Crit Care Med
164:
141-148,
2001
9.
Lazaar, AL,
Albelda SM,
Pilewski JM,
Brennan B,
Pure E,
and
Panettieri RA, Jr.
T lymphocytes adhere to airway smooth muscle cells via integrins and CD44 and induce smooth muscle cell DNA synthesis.
J Exp Med
180:
807-816,
1994[Abstract].
10.
Ober, C,
Leavitt SA,
Tsalenko A,
Howard TD,
Hoki DM,
Daniel R,
Newman DL,
Wu X,
Parry R,
Lester LA,
Solway J,
Blumenthal M,
King RA,
Xu J,
Meyers DA,
Bleecker ER,
and
Cox NJ.
Variation in the interleukin 4 receptor- gene confers susceptibility to asthma and atopy in ethnically diverse populations.
Am J Hum Genet
66:
517-526,
2000[ISI][Medline].
11.
Palmer, LJ,
Daniels SE,
Rye PJ,
Gibson NA,
Tay GK,
Cookson WO,
Goldblatt J,
Burton PR,
and
LeSouef PN.
Linkage of chromosome 5q and 11q gene markers to asthma-associated quantitative traits in Australian children.
Am J Respir Crit Care Med
158:
1825-1830,
1998
12.
Salter, HH.
On Asthma: Its Pathology and Treatment. London: J. Churchill, 1859, p. 24.
13.
Shore, SA,
Laporte J,
Hall IP,
Hardy E,
and
Panettieri RA, Jr.
Effect of IL-1 on responses of cultured human airway smooth muscle cells to bronchodilator agonists.
Am J Respir Cell Mol Biol
16:
702-712,
1997[Abstract].
14.
Stephens, NL,
and
Halayko AJ.
Airway smooth muscle contractile, regulatory and cytoskeletal protein expression in health and disease.
Comp Biochem Physiol B Biochem Mol Biol
119:
415-424,
1998[ISI][Medline].
15.
Wills-Karp, M,
Luyimbazi J,
Xu X,
Schofield B,
Neben TY,
Karp CL,
and
Donaldson DD.
Interleukin-13: central mediator of allergic asthma.
Science
282:
2258-2261,
1998
16.
Zhu, Z,
Homer RJ,
Wang Z,
Chen Q,
Geba GP,
Wang J,
Zhang Y,
and
Elias JA.
Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production.
J Clin Invest
103:
779-788,
1999