inhaled corticosteroids in asthma—star wars
TRANSCRIPT
Journal of Asthma, 33(1), 1-3 (1996)
EDITORIAL
Inhaled Corticosteroids in Asthma-Star Wars
Martin I. Sachs, Ph.D., D.O. Mayo Medical School
Mayo Clinic and Foundation Rochester, Minnesota 55905
Asthma has evolved as a condition. It was once described “as a paroxysmal dyspnea of a peculmr character, generally periodic with healthy respirationbetweenattacks” (1). As wenear the end of the 20th century, asthma has been eluci- dated to be a sophisticated, immunologically complex, inflammatory airway disease.
The language of immunology applied to un- derstanding asthma includes a myriad of cyto- kines, IL-5, IL-9, IL-13, GM-CSF, and so forth, that execute cellular communication in a galaxy of immunological cells. The asthma galaxy ap- pears to be controlled by the now well-de- scribed TH2 lymphocyte capable of directing and activating other members of the cellular galaxy by production of the above-mentioned cytokines (2). It is surely no coincidence that the major cytokines involved in the inflammatory disease asthma are encoded on the long arm of chromosome 5: namely, IL-4, IL-13, IL-5, GM- CSF, IL-6, IL-9, and IL-12, as well as interferon regulatory factor I, the b-adrenergic, and corti- costeroid receptors (3). Thus asthma has evolved into a genetically controlled atopic con- dition. For the purpose of this discussion atopy may therefore be defined as a genetically con- trolled TH2-cell-directed, cytokine-communi- cated, eosinophil-mediated tissue disease. Bron- choalveolar lavage data inpatients withasthma
have demonstrated the predominance of T lym- phocytes to be of the TH2 type (4).
Understanding atopy as a TH2-directed in- flammatory disease allows for the understand- ing of the central role played in the inflamma- tory process within the lower airway by the Darth Vader of asthma, the eosinophil. It is well documented that IL-5 and GM-CSF are largely responsible for the formation, activation, and migration of eosinophils into bronchial tissue (5,6). Furthermore, when eosinophils are cul- tured with the appropriate cytokines IL-3, IL-5, or GM-CSF, their survival in vitro can be pro- longed, a dramatic example of interruptingpro- grammed cell death, or apoptosis (7,8). Eosino- phils are now suspected to be responsible for many of the pathological features of asthma. Toxic eosinophil granule proteins such as major basic protein have been implicated in airway reactivity, vascular leak syndromes, destruc- tion, and sloughing of the epithelium and other inflammatory changes that arepathopneumon- ic of asthma (6,9). While eosinophils appear to flow aimlessly through the vasculature, a com- plex network of chemoattractors, selectins, cy- tokines, and integrins allows these cells to ad- here to vascular endothelium and extravasate into bronchial tissue (5), the result being the presence in the targeted mucosa and sub-
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mucosa of the bronchial wall of an eosinophil whose death sentence has been prolonged (de- layed apoptosis) and whose toxic proteins are capable of causing the end-effect of inflamma- tion in asthma. It is also clear that eosinophils contain the glucocorticoid receptor and are im- portant targets of glucocorticoid action (10). It is therefore not surprising that glucocorticoids have been demonstrated both in vivo and in vitro to be effective players in inhibiting the activity of theeosinophil (llJ2). In culture, ste- roids have been demonstrated to diminish eosino- phi1 generation, survival, and function (11). In vitro glucocorticoid therapy results in a reduc- tion in the number of eosinophils in the circula- tion of the airways inpatients with asthma (12).
From the cyberspace language of cell and molecular immunology we return to the reality of asthma on planet Earth in the 1990s. Inhaled corticosteroids have been elevated to front-line agents in the treatment of chronic asthma (13,14). In this issue Robinson and Geddes care- fully dissect the benefits, risks, and peculiarities of inhaled corticosteroids (15). This carefully written review with extensive bibliography ad- dresses the following controversial issues:
1.
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Are inhaled corticosteroids disease modi- fiers? Which delivery systems are truly most ef- fective? What is the dose-response curve of various inhaled corticosteroids and how does this affect proper dosing of these drugs? Do budesonide and fluticasone really offer an advantage in increased topical activity and decreased systemic effects? Are inhaled corticosteroids really safe or is it the rule of caveat emptor (let the buyer beware)?
This review, together with that published by Barnes (16), concretely deals with the biology and medical usefulness of inhaled corticoste- roids. These reviews do not address (and were not expected to) the following bothersome enig- mas concerning asthma therapy:
1. How can compliance with preventive medications be increased? Should these
2.
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medications be administered at schools and places of employment? How can medication be effectively deliv- ered to the population without a primary care physician? Should allergists and pul- monologists be using training programs to staff inner-city and rural clinics? Is the failure to use these effective preven- tive anti-inflammatory medications a fail- ure of asthma specialists to be able to edu- cate primary care physicians?
Ultimately, the effectiveness of inhaled cor- ticosteroids in the treatment of asthma will not only be a function of their topical potency and anti-inflammatory properties. It will be a reflec- tion of physicians’ ability to place these medi- cations in the hands and airways of millions of people with asthma.
REFERENCES
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Salter H H On Asthma: Its Pathologyand Treatment, 2nd ed. Churchill, London, 1868. Ricci M, Rossi 0, BertoN M, Matucci A. Th2-like cells in the apthogenesis of airway allergic inflammation. Clin E x p Allergy 23:36&369 (1993). Lawrence S, Watson M, Collins A, h u l l I, Beasley R, Begishvili 8, Lampe F, Holgate S, Morton NE: Tests for major genes in atopy and asthma. International Genetic Epidemiology Society, 1994 (abstract). Robinson DR, Hamid Q, Ying S, Tsicopoulos A, Bar- kans J, Bentley AM, Corrigan C, Durham s, Kay A B Evidence for a predominant ”Th2 type” bronche alveolar lavage T-lymphocyte population in atopic asthma. N Engl J Med 326:298-304 (1992). Schleimer W, Bochner BS The effects of glucocor- ticoids on human eosinophils. J Allergy Clin Zmmunol
Sur S, Adolphson CR, Gleich GJ: Eosinophils: Bio- chemical and cellular aspects. In Allergy: Principles and Practice, 4th ed. (Middleton E, Reed CE, Ellis EF, Adkinson NF Jr, Yunginger JW, Busse W, editors). CV Mosby, St. Louis, 1993,169-200. Cox G, Ohtoshi T, Vanceri C, et al: Promotion of eosinophil survival by human bronchial epithelial cells and its modulation by steroids. Am J Respir Cell Mol Biol4:525-531(1991). Hallsworth MP, Litchfield TM, Lee TH: Glucocorti- coids inhibit granulocytemacrophage colony-stimulat- ingfactorandinterleukin-5enhancedinvitrosurvivalof human eosinophils. Immunology 75382-385 (1992). Flavahan NA, Slifman NR, Gleich GJ, Vanhoutte P M Human eosinophil major basic protein causes hyper- reactivityofrespiratory smoothmuscle.Am ReuRespir Dis 138685688 (1988). Schleimer Rp: Glucocorticosteroids: Their mecha-
94(6 pt 2):129-140 (1994).
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nism of action and use in allergic diseases. In Allergy: Principles and Practice, 4th ed. (h4iddleton E, Reed CE, Ellis EF, Adkinson NF Jr, Yunginger JW, Busse W, editors). CV Mosby, St. Louis, 1993, B!XW2.5. Rolfe FG, Hughes jh4, Armour CL, Sewell W A Inhi- bition of interleukin-5 gene expression by dexameth- asone. Immunology 77494-499 (1992). Djukanovic R, Wilson JW, Britten Kh4, et al: Effect of an inhaled corticosteroid on airway inflammation and symptoms in asthma. Am Rev Respir Dis 145 669-674 (1992). National Heart, Lung, and Blood Institute: Guide- lines for the diagnosis and management of asthma. j Allergy Clin Immunol88425534 (1991).
14. British Thoracic Society, British Paediatric Society, Research Unit of the Royal College of Physicians, Kings Fund Centre, National Asthma Campaign, Royal College of General Practitioners, the General Practitioners in Asthma Group, the British Asso- ciation of Accident and Emergency Medicine, and the British Paediatric Respiratory Group: Guidelines for the management of asthma. Thorax 48:sl-s24 (1993).
15. Robinson DS, Geddes DM Inhaled corticosteroids: Benefits and risks. ]Asthma 33:00-00 (1996).
16. Barnes PJ: Inhaled glucocorticoids for asthma. N Engl j Med 332(13):868874 (1995).
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