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Airway smooth muscle: new tricks for an old dog

Stephanie Shore

Physiology Program, Harvard School of Public Health, Boston, Massachusetts 02115


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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 beta -agonists; and 4) proliferating (1, 3, 6, 9, 13).

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-1beta (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 (Fcepsilon 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-alpha (IL-4Ralpha ), 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 beta -adrenergic responsiveness (8) and increased contractile responses to leukotrienes (unpublished observations) in HASM cells support these observations.

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-4Ralpha 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.

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.


    FOOTNOTES

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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Am J Physiol Lung Cell Mol Physiol 282(3):L518-L519
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