Chest ACCP Member Benefits
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Guest Access | Sign In via User Name/Password
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by White, S. R.
Right arrow Articles by Dorscheid, D. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by White, S. R.
Right arrow Articles by Dorscheid, D. R.
(Chest. 2002;122:278S-284S.)
© 2002 American College of Chest Physicians

Corticosteroid-Induced Apoptosis of Airway Epithelium*

A Potential Mechanism for Chronic Airway Epithelial Damage in Asthma

Steven R. White, MD and Delbert R. Dorscheid, MD, PhD, FCCP

* From the Section of Pulmonary and Critical Care Medicine (Dr. White), Department of Medicine, University of Chicago, Chicago, IL; and the iCAPTURE Center (Dr. Dorscheid), University of British Columbia, Vancouver, BC, Canada.

Correspondence to: Steven R. White, MD, Section of Pulmonary and Critical Care Medicine, The University of Chicago, 5841 S Maryland Ave, MC6076, Chicago, IL 60637; e-mail: swhite{at}medicine.bsd.uchicago.edu


   Abstract
TOP
 Abstract
Introduction
 The Airway Epithelium Undergoes...
 CSs Elicit Apoptosis of...
 Conclusion
 References
 
Damage to the airway epithelium is one prominent feature of chronic asthma. Mucosal damage includes gap openings, partial denudation, and loss of ciliated cells. Apoptosis of the airway epithelium is increasingly recognized as a potential mechanism by which damage may occur. Corticosteroids (CSs) induce apoptosis in inflammatory cells, which in part explains their ability to suppress airway inflammation. However, CS therapy does not necessarily reverse epithelial damage. We examined whether CS therapy actually could induce airway epithelial apoptosis using culture models of primary airway epithelial cells and cell lines. The administration of CSs in low-micromolar concentrations induces apoptosis that involves the disruption of mitochondrial polarity, the activation of caspases, and the involvement of Bcl-2. Clear differences exist between CS-induced apoptosis in the cultured epithelium vs cultured hematopoietic cells in regard to time course and resistance to apoptosis. Our data suggest that the use of CSs, in concentrations that could be attained in vivo with the inhalation of potent preparations or with systemic administration, may be one factor in the airways remodeling and epithelial damage that is seen in many patients with chronic, persistent asthma.

Key Words: airway epithelium • asthma • apoptosis • corticosteroids • remodeling


   Introduction
TOP
 Abstract
 Introduction
The Airway Epithelium Undergoes...
 CSs Elicit Apoptosis of...
 Conclusion
 References
 
The airway epithelium is a target of inflammatory and physical stimuli in the patient with asthma. Injury to the epithelium is a common finding the in patients with asthma, even when the clinical state is mild.1 2 Epithelial damage correlates with airway hyperreactivity in asthmatic patients,3 is seen in about half of subjects with mild asthma and in almost all subjects with persistent asthma,4 and may be seen in patients with newly diagnosed asthma.5 This suggests that occult inflammation has already initiated the process of mucosal damage and remodeling. Asthmatic subjects shed fourfold as many epithelial cells as do healthy subjects after bronchial washing.6 Many of these are ciliated epithelial cells, which are shed preferentially.7 8 The epithelial layer disruption that has been described in bronchial biopsy specimens obtained during fiberoptic bronchoscopy has been attributed in part to biopsy artifacts.9 However, the increased expression of CD44 cells in the areas of damage10 and epithelial growth factor receptor expression (c-erbB-1)11 as markers of repair,12 along with extensive denudation of the epithelium that is seen in patients with severe and fatal asthma,13 indicates that epithelial damage does occur in vivo. While asthma is an inflammatory disorder of the airways, inflammation alone is insufficient to explain both the chronic nature of the disease and its progression over time. Inflammation must occur in an airway that is susceptible to damage. Epithelial damage, along with other changes such as smooth muscle hypertrophy, basement membrane thickening, and submucosal fibrosis, are cardinal features of chronic airway remodeling, which is the culmination of this combination of inflammation plus structural changes in patients with long-standing, persistent asthma.

Corticosteroids (CSs) elicit apoptosis in inflammatory cells such as eosinophils14 and T lymphocytes,15 and suppress the production and release of both inflammatory eicosanoids and cytokines.16 This in part explains the potent antiinflammatory effects of CSs in asthma patients.17 However, CS therapy does not necessarily reverse the epithelial damage seen in patients with asthma. While CS therapy clearly suppresses inflammation16 18 and the release of epithelial cell-derived inflammatory mediators,19 subjects with severe asthma receiving regular inhaled CS therapy still have substantial epithelial destruction at all levels.20 Epithelial cells are seen in the BAL fluid of asthmatic patients with varying severities of the disease, regardless of CS therapy history.21 Adequate treatment with CSs may not completely prevent airway inflammation, and some patients may continue to have asthma symptoms and a long-term decline in lung function despite their use.22 Since epithelial restitution occurs quickly after a single insult,23 the mechanism by which epithelial denudation persists after repeated injury, particularly an injury that has been treated with CSs, suggests several possibilities, as follows: (1) the incomplete suppression of inflammation may allow continued damage to the mucosa; (2) suppressing inflammation does not suppress an underlying defect in the epithelial-mesenchymal unit that permits disordered repair to continue; and (3) CS therapy itself has effects that facilitate or continue the process of disordered repair.

Our laboratory has focused on the last possibility, that CSs may damage the airway epithelium. CSs have long been associated with the suppression of inflammatory cells, and this is mediated in part by apoptosis. CSs elicit rapid, synchronous apoptosis in lymphocytes24 that is mediated by the glucocorticoid receptor (GR).25 An activation-deficient mutant, the GR is capable of inducing apoptosis in lymphocytes, suggesting that the primary effect of the GR in mediating apoptosis is via transcriptional repression rather than through activation.26 27 In contrast, the effect of CSs on epithelial cells derived from various tissues is variable. CSs impair keratinocyte repair after injury28 but also protect mammary gland epithelial cells from apoptotic stimuli29 30 and inhibit apoptosis induced by Fas ligation in alveolar epithelial cells.31 In cultured corneal keratinocytes, low concentrations (ie, approximately 10-8 mol/L) of dexamethasone, a potent CS, elicit increased proliferation, whereas higher concentrations (ie, approximately 10-6 mol/L) increased apoptosis.32 It is not clear from these studies what the predicted effect of CSs would be on the airway epithelium.


   The Airway Epithelium Undergoes Apoptosis When Stimulated To Do So
TOP
 Abstract
 Introduction
 The Airway Epithelium Undergoes...
CSs Elicit Apoptosis of...
 Conclusion
 References
 
The airway epithelium has death receptors and can undergo apoptosis when these receptors are stimulated. We have demonstrated the expression of the death receptor Fas and its ligand, FasL, in 1HAEo- cells, primary human bronchial epithelial cell in culture, and airway tissue sections from healthy human subjects.33 In additional experiments, we have demonstrated that airway epithelial cells in culture undergo apoptosis on the cross-ligation of Fas. This occurs in <= 24 h, can approximate 30% of all cells, and can be blocked with an appropriate antibody against Fas. While both Fas and FasL are expressed in subjects with fatal asthma and severe, nonfatal asthma, there are no significant differences in either group compared to those with nonasthmatic subjects. This suggests that mechanisms other than Fas ligation may be different in subjects with asthma and may be activated during allergen challenge or environmental insult. In support of this idea, house dust mite cysteine proteinases can induce airway epithelial cell apoptosis.34 Oxidant-induced apoptosis may be substantially greater in epithelial cells collected from asthmatic subjects compared to cells collected from healthy subjects (DE Davies, PhD; University of Southampton, UK; personal communication). This suggests the presence of at least quantitative, and perhaps qualitative, differences between the normal and asthmatic epithelium.

The asthmatic airway epithelium also may be apoptotic, although the examination of this may depend, in part, on the disease state and its duration. We have recently reviewed a series of subjects who died of asthma and subjects with severe asthma who died of other causes. Terminal deoxyuridine nick-end labeling (TUNEL) staining of the airway epithelium demonstrates the presence of a substantial proportion of apoptotic cells compared to the presence of very few such cells in the epithelium of nonasthmatic subjects (Fig 1 ). In contrast, one recent article35 suggested that in patients with mild asthma few apoptotic epithelial cells can be demonstrated to be present, regardless of the CS treatment. These divergent data suggest that, at least in some asthmatic patients, the ongoing damage to the epithelium may be due to an apoptotic loss of cells. The contribution of CSs may be to reduce inflammation, which may reduce damage. Conversely, CSs might induce damage and contribute to the genesis of long-term airway damage.



View larger version (49K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 1.. Representative photomicrographs of asthmatic human airways to demonstrate apoptosis. Left, A: TUNEL staining using a peroxidase protocol of a central airway from a subject without asthma (original x200). Middle, B, right, C: TUNEL staining of a central airway of a subject with fatal asthma, with the airways counterstained with hematoxylin (originals x400). A substantial number of apoptotic epithelial cells (brown nuclei) in the asthmatic airway are seen, along with clear damage to the mucosa.

 

   CSs Elicit Apoptosis of the Airway Epithelium
TOP
 Abstract
 Introduction
 The Airway Epithelium Undergoes...
 CSs Elicit Apoptosis of...
Conclusion
 References
 
With this in mind, we recently initiated a study36 to examine CS-induced apoptosis in the airway epithelium. We originally hypothesized that CSs would protect the airway epithelium from apoptotic stimuli. This hypothesis fit the available data, which suggested that CS therapy would aid in the restitution of a damaged airway epithelium37 without eliciting damage itself.35 To our surprise, CS treatment induced apoptosis in central airway epithelial cells. In both primary human airway epithelial cells and in the central airway epithelial cell line 1HAEo-, treatment with dexamethasone, budesonide, triamcinolone, or beclomethasone elicited concentration-dependent and time-dependent apoptosis (Fig 2 ). Little necrosis was present after CS treatment, as demonstrated by a lack of lactate dehydrogenase activity in culture medium after 48 h. Apoptosis occurred with CS concentrations (ie, >= 1 µmol/L) that are at the high end of the range generally used to treat patients with asthma.



View larger version (31K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 2.. Left, A: apoptosis in primary human airway epithelial cells after CS treatment or after ligation of the Fas receptor, as demonstrated by TUNEL staining. Cells were treated with dexamethasone or 1 µg/mL CH11 Fas-ligating monoclonal antibody. Apoptosis increased through 24 h and at dexamethasone concentrations of >= 3 µmol/L (µM), and was equivalent to that seen with Fas ligation. * = p < 0.05 (vs control subjects); § = p < 0.02 (vs control subjects); {dagger} = p < 0.01 (vs control subjects); and ¶ = p < 0.005 (vs control subjects). Right, B: apoptosis in the 1HAEo- airway epithelial cell line after treatment with beclomethasone, triamcinolone, or budesonide for 24 h. Apoptosis was significant after treatment with >= 3 µmol/L each CS. Ctl = control; CH11 = CH11 Fas-ligating monoclonal antibody. Reprinted with permission from Dorscheid et al.36 .

 
Some consideration of the concentrations of glucocorticoids that are attainable in the airway will illustrate this point. CSs must dissolve in the periciliary layer of fluid atop the airway epithelium before entering cells and binding the GR. The average depth of the airway surface liquid (ASL) layer in the first 10 generations of human central airways generally is accepted as being approximately 5 to 25 µm,38 39 and the aggregate area of airways from the trachea to 1 mm diameter is approximately 1,000 cm2.40 The total volume in these airways calculates then as approximately 0.5 to 2.0 mL, which matches the estimated values.41 The inhalation of 400 µg CS, assuming 10 to 60% deposition in the airways,42 43 leads to a local concentration of approximately 4 to 120 µg/mL (10 to 400 µmol/L) at the central airways epithelium, which is at and above the level that was used in our experiments. Even assuming a relatively low deposition (eg, 10%) of a single dose of inhaled CS (eg, 200 µg) with a thicker ASL of approximately 60 µm (as measured in vivo44 ) into an average ASL volume (eg, 6 mL) leads to a potential point concentration atop the airway epithelium of 3 µg/mL, or approximately 10 µmol/L. The concentration range of CSs used in culture-based experiments thus approximates the peak concentrations that may be attained in vivo. An additional consideration is the potency of the inhaled CS. The trifluorinated glucocorticoids that are used in current asthma therapy have increased potency and lipid solubility compared to dexamethasone.45 For these reasons, CS treatment in these cell culture-based experiments may actually understate the potential in vivo effect of inhaled (or parental) CS therapy on the airway epithelium.

Multiple apoptotic signals link to a signaling cascade of caspase proteases. These proteases are constitutively expressed as inactive zymogens that are cleaved when activated. Two distinct pathways exist for caspase activation, as follows: type I, in which caspases are activated early after death receptor stimulation46 47 ; and type II, in which increased mitochondrial permeability and loss of mitochondrial membrane polarity are required prior to caspase activation.48 We examined whether CS-induced apoptosis in airway epithelial cells would be associated with a disruption in mitochondrial polarity. To do this, we loaded epithelial cells with the vital fluorescent lipophilic cation 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolcarbocyanine iodide, and then treated cells with 3 µmol/L dexamethasone for up to 24 h. Cells demonstrated loss of mitochondrial polarity as early as 1 h and significant disruption within 4 h (Fig 3 ). In mitochondrial-facilitated apoptosis, caspase cascade activation is triggered by the formation of a multimeric Apaf-1/cytochrome c complex to recruit and activate pro-caspase-9 with subsequent effector caspase activation.49 Airway epithelial cells treated with dexamethasone released a significant amount of cytochrome c from the mitochondria into the cell cytosol, aiding the subsequent cleavage and activation of caspase 9 (Fig 3 ).



View larger version (62K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 3.. Top, A: demonstration of mitochondrial membrane potential after the CS treatment of 1HAEo- airway epithelial cells. Cells were treated with control medium or 3 µmol/L dexamethasone (Dex) for 4 h. Cells then were loaded with 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolcarbocyanine iodide, and mitochondrial membrane potential was assessed by fluorescent microscopy. The preservation of polarity, demonstrated by aggregated (red) dye, was lost with permeability transition as demonstrated by the dye in monomeric form (green) in cells treated with dexamethasone. Bottom, B: cleavage of pro-caspase-9 in 1HAEo- airway epithelial cells after CS treatment, as demonstrated by Western blot. Cells were treated with 3 µmol/L dexamethasone for 0 to 12 h. Protein lysates were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, were transferred onto nitrocellulose, and were probed for caspase-9 using an antibody that recognized both the pro-form and the active fragments. Cleavage products became apparent within 6 h of treatment (arrows). Reprinted with permission from Dorscheid et al.36 .

 
Mitochondria-facilitated apoptosis is regulated by several proteins, including Bcl-2 and Bcl-xL.50 51 We generated airway epithelial cell lines that stably overexpressed each of these regulators and treated these cells with 10 µmol/L dexamethasone for 24 h. The overexpression of either Bcl-2 or Bcl-xL prevented apoptotic cell death compared to cells transfected with an empty vector (Fig 4 ).



View larger version (17K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 4.. Apoptosis after CS treatment in 1HAEo- airway epithelial cells stably overexpressing Bcl-2 or Bcl-xL by TUNEL staining. Each transfected cell line was treated with 10 µmol/L dexamethasone, budesonide, beclomethasone, or triamcinolone for 24 h and was processed for TUNEL staining. * = p = 0.05 (vs empty vector transfected cells within each group); § = p = 0.03 (vs empty vector transfected cells within each group); {dagger} = p = 0.01 (vs empty vector transfected cells within each group); and ¶ = p < 0.002 (vs empty vector transfected cells within each group). Bud = budesonide; Bec = beclomethasone; Tri = triamcinolone; EV = empty vector. See legend of Figure 3 for abbreviations not used in text. Reprinted with permission from Dorscheid et al.36 .

 

   Conclusion
TOP
 Abstract
 Introduction
 The Airway Epithelium Undergoes...
 CSs Elicit Apoptosis of...
 Conclusion
References
 
In summary, damage to the airway epithelium is an important pathologic event in patients with asthma, although demonstrating it by the currently available methods can be problematic. In addition to any derangements that may occur in the communication between the epithelium and underlying mesenchymal cells, and any damage that may be caused by inflammatory mediators and cells, we suggest that CSs may elicit apoptosis of the epithelium. Apoptosis is elicited in a concentration range similar to that attainable in vivo, is associated with the disruption of mitochondrial polarity and the activation of both caspase-9 and caspase-3, and can be blocked by overexpressing the apoptotic regulators Bcl-2 and Bcl-xL. Yet clear differences exist between CS-induced apoptosis in the cultured epithelium vs cultured hematopoietic cells. In the latter, apoptosis is rapid (ie, <= 12 h) and nearly complete (ie, > 70% of cells),52 whereas in the former, apoptosis is slower and accounts for approximately 10 to 15% of cells. While the magnitude is substantially lower, the effects of the long-term administration of CSs on cells that have a low proliferation index in vivo53 may become significant over time.

Our data suggest that the use of CSs may be one factor in the airways remodeling and epithelial damage that are seen in many patients with chronic, persistent asthma. This may seem provocative but should be placed within the context of the asthma state in the airways. Data that may seem irreconcilable may in fact have a common theme. CS therapy in modest concentrations is useful in suppressing inflammation, and the absence of inflammation may allow a damaged epithelium to recover. In contrast, CS in higher concentrations may elicit damage that is independent of that caused by inflammatory mediators. This suggests that while CSs are and should remain the mainstay of controller therapy for asthma, combination therapy with other agents, such as long-acting ß-adrenergic agonists or leukotriene receptor antagonists, may be preferable in attaining asthma control compared to the use of high concentrations of CSs. The long-term implications of therapy-induced airway damage will require further investigation.


   Acknowledgements
 
I thank Kimm Hamann, PhD, Marcus Peter, PhD, and Charles Rudin, MD, at the University of Chicago for their advice. I thank Bertha Marroquin and Kimberly Wojcik for their many years of technical assistance.


   Footnotes
 
This research was supported by grants HL-60531 and HL-63300 from the National Heart, Lung, and Blood Institute, and by grant CIHR 43898 from the Canadian Institute of Health Research.

Abbreviations: ASL = airway surface liquid; CS = corticosteroid; GR = glucocorticoid receptor; TUNEL = terminal deoxynucleotidyl transferase mediated dUTP


   References
TOP
 Abstract
 Introduction
 The Airway Epithelium Undergoes...
 CSs Elicit Apoptosis of...
 Conclusion
 References
 

  1. Laitenen, LA, Heino, M, Laitenen, A, et al (1985) Damage of the airway epithelium and bronchial reactivity in patients with asthma. Am Rev Respir Dis 131,599-606
  2. Beasley, R, Roche, WR, Robets, JA, et al Cellular events in the bronchi in mild asthma and after bronchial provocation. Am Rev Respir Dis 1989;139,806-817
  3. Jeffery, PK, Wardlaw, AJ, Nelson, FC, et al Bronchial biopsies in asthma: an ultrastructural, quantitative study and correlation with hyperreactivity. Am Rev Respir Dis 1989;140,1745-1753
  4. Vignola, AM, Chanez, P, Campbell, AM, et al Airway inflammation in mild intermittent and in persistent asthma. Am J Respir Crit Care Med 1998;157,403-409
  5. Laitinen, LA, Laitinen, A, Haahtela, T Airway mucosal inflammation even in patients with newly diagnosed asthma. Am Rev Respir Dis 1993;147,697-704
  6. Demoly, P, Simony-LaFontaine, J, Chanez, P, et al Cell proliferation in the bronchial mucosa of asthmatics and chronic bronchitis. Am J Respir Crit Care Med 1994;150,214-217
  7. Montefort, S, Djukanovic, R, Holgate, ST, et al Ciliated cell damage in the bronchial epithelium of asthmatics and non-asthmatics. Clin Exp Allergy 1993;23,185-189
  8. Montefort, S, Roberts, JA, Beasley, R, et al The site of disruption of the bronchial epithelium in asthmatic and non-asthmatic subjects. Thorax 1992;47,499-503
  9. Ordonez, C, Ferrando, R, Hyde, DM, et al Epithelial desquamation in asthma: artifact or pathology? Am J Respir Crit Care Med 2000;162,2324-2329
  10. Lackie, PM, Baker, JE, Ganthert, U, Holgate, ST Expression of CD44 isoforms is increased in the airway epithelium of asthmatic subjects. Am J Respir Cell Mol Biol 1997;16,14-22
  11. Puddicombe, SM, Polosa, R, Richter, A, et al The involvement of the epidermal growth factor receptor in epithelial repair in asthma. FASEB J 2000;14,1362-1374
  12. Davies, DE, Polosa, R, Puddicombe, SM, et al The epidermal growth factor receptor and its ligand family: their potential role in repair and remodeling in asthma. Allergy 1999;54,771-783
  13. Bousquet, J, Jeffery, PK, Busse, WW, et al Asthma from bronchoconstriction to airways inflammation and remodeling. Am J Respir Crit Care Med 2000;161,1720-1745
  14. Meagher, LC, Cousin, JM, Seckl, JR, et al Opposing effects of glucocorticoids on the rate of apoptosis in neutrophilic and eosinophilic granulocytes. J Immunol 1996;156,4422-4428
  15. Compton, MM, Cidlowski, JA Rapid in vivo effects of glucocorticoids on the integrity of rat lymphocyte genomic deoxyribonucleic acid. Endocrinology 1986;118,38-45
  16. Barnes, PJ, Pedersen, S Efficacy and safety of inhaled corticosteroids in asthma. Am Rev Respir Dis 1993;148,S1-S26
  17. Djukanovic, R, Homeyard, S, Gratziou, C, et al The effect of treatment with oral corticosteroids on asthma symptoms and airway inflammation. Am J Respir Crit Care Med 1997;155,826-832
  18. Barnes, PJ Current issues for establishing inhaled corticosteroids as the antiinflammatory agents of choice in asthma. J Allergy Clin Immunol 1999;101,S427-S433
  19. Wang, JH, Devalia, JL, Sapsford, RJ, et al Effect of corticosteroids on release of RANTES and sICAM-1 from cultured human bronchial epithelial cells, induced by TNF-alpha. Eur Respir J 1997;10,834-840
  20. Laitinen, LA, Laitinen, A Remodeling of asthmatic airways by glucocorticosteroids. J Allergy Clin Immunol 1996;97,153-158
  21. Foresi, A, Bertorelli, G, Pesci, A, et al Inflammatory markers in bronchoalveolar lavage and in bronchial biopsy in asthma during remission. Chest 1990;98,528-535
  22. Lange, P, Parner, J, Vestbo, J, et al A 15-year follow-up study of ventilatory function in adults with asthma. N Engl J Med 1999;339,1194-1200
  23. Erjefalt, JS, Persson, CG Airway epithelial repair: breathtakingly quick and multipotentially pathogenic. Thorax 1997;52,1010-1012
  24. Compton, MM, Cidlowski, JA Rapid in vivo effects of glucocorticoids on the integrity of rat lymphocyte genomic deoxyribonucleic acid. Endocrinology 1986;118,38-45
  25. King, LB, Vacchio, MS, Dixon, K, et al A targeted glucocorticoid receptor antisense transgene increases thymocyte apoptosis and alters thymocyte development. Immunity 1995;3,647-656
  26. Helmberg, A, Auphan, N, Caelles, C, et al Glucocorticoid-induced apoptosis of human leukemic cells is caused by the repressive function of the glucocorticoid receptor. EMBO J 1995;14,452-460
  27. Rogatsky, I, Hittelman, AB, Pearce, D, et al Distinct glucocorticoid receptor transcriptional regulatory surfaces mediate the cytotoxic and cytostatic effects of glucocorticoids. Mol Cell Biol 1999;19,5036-5049
  28. Sidhu, GS, Singh, AK, Banaudha, KK, et al Arnebin-1 accelerates normal and hydrocortisone-induced impaired wound healing. J Invest Dermatol 1999;113,773-781
  29. Feng, Z, Marti, A, Jehn, B, et al Glucocorticoid and progesterone inhibit involution and programmed cell death in the mouse mammary gland. J Cell Biol 1995;131,1095-1103
  30. Harris, RA, Hiles, ID, Page, MJ, et al The induction of apoptosis in human mammary luminal epithelial cells by expression of activated c-neu and its abrogation by glucocorticoids. Br J Cancer 1995;72,386-392
  31. Wen, L-P, Madani, K, Fahrni, JA, et al Dexamethasone inhibits lung epithelial cell apoptosis induced by IFN-’67 and Fas. Am J Physiol 1997;273,L921-L929
  32. Bourcier, T, Borderie, V, Forgez, P, et al In vitro effects of dexamethasone on human corneal keratocytes. Invest Ophthalmol Vis Sci 1999;40,1061-1070
  33. Hamann, KJ, Dorscheid, DR, Ko, FD, et al Expression of Fas (CD95), and FasL (CD95 L) in human airway epithelium. Am J Respir Cell Mol Biol 1999;19,537-542
  34. Winton, HL, Wan, H, Cannell, MB, et al Class specific inhibition of house dust mite proteinases which cleave cell adhesion, induce cell death and which increase the permeability of lung epithelium. Br J Pharmacol 1999;124,1048-1059
  35. Vignola, AM, Chiappara, G, Siena, L, et al Proliferation and activation of bronchial epithelial cells in corticosteroid-dependent asthma. J Allergy Clin Immunol 2001;108,738-746
  36. Dorscheid, DR, Wojcik, KR, Sun, S, et al Apoptosis of airway epithelial cells induced by corticosteroids. Am J Respir Crit Care Med 2001;164,1939-1947
  37. Laitinen, LA, Laitinen, A Inhaled corticosteroid treatment and extracellular matrix in the airways in asthma. Int Arch Allergy Immunol 1995;107,215-216
  38. Wanner, A Clinical aspects of mucociliary transport. Am Rev Respir Dis 1977;116,73-125
  39. Widdicombe, J Airway and alveolar permeability and surface liquid thickness: theory. J Appl Physiol 1997;82,3-12
  40. Weibel, ER Morphometrics of the lung. Handbook of physiology: respiration. 1964,285-307 American Physiology Society Washington, DC.
  41. Anderson, SD, Daviskas, E, Smith, CM Exercise-induced asthma: a difference in opinion regarding the stimulus. Allergy Proc 1989;10,215-226
  42. Leach, CL, Davidson, PJ, Boudreau, RJ Improved airway targeting with the CFC-free HFA-beclomethasone metered-dose inhaler compared with CFC-beclomethasone. Eur Respir J 1999;12,1346-1353
  43. Saari, SM, Vidgren, MT, Koskinen, MO, et al Regional lung deposition and clearance of 99mTc-labeled beclomethasone-DLPC liposomes in mild and severe asthma. Chest 1999;113,1573-1579
  44. Jayaraman, S, Song, Y, Vetrivel, L, et al Noninvasive in vivo fluorescence measurement of airway-surface liquid depth, salt concentration, and pH. J Clin Invest 2001;107,317-324
  45. Stellato, C, Atsuta, J, Bickel, CA, et al An in vitro comparison of commonly used topical glucocorticoid preparations. J Allergy Clin Immunol 1999;104,623-629
  46. Muzio, M, Chinnaiyan, AR, Kischel, FC, et al FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex (DISC). Cell 1996;85,817-827
  47. Medema, JP, Scaffidi, C, Krammer, PH, et al Bcl-xL acts downstream of caspase-8 activation by the CD95 death-inducing signaling complex. J Biol Chem 1999;273,3388-3393
  48. Scaffidi, C, Fulda, S, Srinivasan, A, et al Two CD95 (APO-1/Fas) signaling pathways. EMBO J 1999;17,1675-1687
  49. Zou, H, Li, Y, Liu, X, et al An APAF-1-cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. J Biol Chem 1999;274,11549-11556
  50. Krajewski, S, Tanaka, S, Takayama, S, et al Investigation of the subcellular distribution of the bcl-2 oncoprotein: residence in the nuclear envelope, endoplasmic reticulum, and outer mitochondrial membranes. Cancer Res 1993;53,4701-4714
  51. Adams, JM, Cory, S The Bcl-2 protein family: arbiters of cell survival. Science 1999;281,1322-1326
  52. Jamieson, CAM, Yamamoto, KR Crosstalk pathway for inhibition of glucocorticoid-induced apoptosis by T cell receptor signaling. Proc Natl Acad Sci USA 2000;97,7319-7324
  53. Ayers, MM, Jeffery, PK Proliferation and differentiation in mammalian airway epithelium. Eur Respir J 1988;1,58-80




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by White, S. R.
Right arrow Articles by Dorscheid, D. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by White, S. R.
Right arrow Articles by Dorscheid, D. R.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS