| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS | REGISTER |
|
|
|
|
|||||||||||||
|
|
|||||||||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
ASTHMA |
) as a novel therapeutic target in symptomatic corticosteroid dependent asthma
1 Allergy and Inflammation Research, Division of Infection, Inflammation and Repair, School of Medicine, Southampton General Hospital, Southampton, UK
2 St Mary’s Hospital, Respiratory Medicine, Portsmouth, UK
3 Wyeth Laboratories, Taplow, Maidenhead, Berkshire, UK
Correspondence to:
Correspondence to:
Professor S T Holgate
Infection, Inflammation and Repair Division, F Level South Block (810), Southampton General Hospital, Southampton SO16 6YD, UK; sth{at}soton.ac.uk
Background: Tumour necrosis factor 
(TNF) is a major therapeutic target in a range of chronic inflammatory disorders characterised by a Th1 type immune response in which TNF is generated in excess. By contrast, asthma is regarded as a Th2 type disorder, especially when associated with atopy. However, as asthma becomes more severe and chronic, it adopts additional characteristics including corticosteroid refractoriness and involvement of neutrophils suggestive of an altered inflammatory profile towards a Th1 type response, incriminating cytokines such as TNF.
Methods: TNF levels in bronchoalveolar lavage (BAL) fluid of 26 healthy controls, 42 subjects with mild asthma and 20 with severe asthma were measured by immunoassay, and TNF gene expression was determined in endobronchial biopsy specimens from 14 patients with mild asthma and 14 with severe asthma. The cellular localisation of TNF was assessed by immunohistochemistry. An open label uncontrolled clinical study was then undertaken in 17 subjects with severe asthma to evaluate the effect of 12 weeks of treatment with the soluble TNF receptor-IgG1Fc fusion protein, etanercept.
Results: TNF levels in BAL fluid, TNF gene expression and TNF immunoreative cells were increased in subjects with severe corticosteroid dependent asthma. Etanercept treatment was associated with improvement in asthma symptoms, lung function, and bronchial hyperresponsiveness.
Conclusions: These findings may be of clinical significance in identifying TNF as a new therapeutic target in subjects with severe asthma. The effects of anti-TNF treatment now require confirmation in placebo controlled studies.
Abbreviations: BHR, bronchial hyperresponsiveness; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; PEF, peak expiratory flow; TNF, tumour necrosis factor
Keywords: asthma; tumour necrosis factor alpha (TNF); bronchial hyperresponsiveness; etanercept; corticosteroid
Related Article
Thorax 2005 60: 977.
This article has been cited by other articles:
|
|
 |
|
  M. A Berry and I. D Pavord Antagonism of tumour necrosis factor {alpha} in refractory asthma Thorax, July 1, 2008; 63(7): 571 - 572. [Full Text] [PDF]
|
|
|
|
|
|
J B Morjaria, A J Chauhan, K S Babu, R Polosa, D E Davies, and S T Holgate The role of a soluble TNF{alpha} receptor fusion protein (etanercept) in corticosteroid refractory asthma: a double blind, randomised, placebo controlled trial Thorax, July 1, 2008; 63(7): 584 - 591. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. A. Hanania Targeting Airway Inflammation in Asthma: Current and Future Therapies Chest, April 1, 2008; 133(4): 989 - 998. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Reuter, A. Heinz, M. Sieren, R. Wiewrodt, E. W. Gelfand, M. Stassen, R. Buhl, and C. Taube Mast cell-derived tumour necrosis factor is essential for allergic airway disease Eur. Respir. J., April 1, 2008; 31(4): 773 - 782. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Uddin, G. Seumois, L. C. Lau, P. Rytila, D. E. Davies, and R. Djukanovic Enhancement of neutrophil function by the bronchial epithelium stimulated by epidermal growth factor Eur. Respir. J., April 1, 2008; 31(4): 714 - 724. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Matsuda, S. Fukuda, K. Matsumoto, and H. Saito Th1/Th2 Cytokines Reciprocally Regulate In Vitro Pulmonary Angiogenesis via CXC Chemokine Synthesis Am. J. Respir. Cell Mol. Biol., February 1, 2008; 38(2): 168 - 175. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. K. Oyoshi, P. Bryce, S. Goya, M. Pichavant, D. T. Umetsu, H. C. Oettgen, and E. N. Tsitsikov TNF Receptor-Associated Factor 1 Expressed in Resident Lung Cells Is Required for the Development of Allergic Lung Inflammation J. Immunol., February 1, 2008; 180(3): 1878 - 1885. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. C. Sieck, T. A. White, M. A. Thompson, C. M. Pabelick, M. E. Wylam, and Y. S. Prakash Regulation of store-operated Ca2+ entry by CD38 in human airway smooth muscle Am J Physiol Lung Cell Mol Physiol, February 1, 2008; 294(2): L378 - L385. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. M. Erin, G. R. Jenkins, O. M. Kon, A. S. Zacharasiewicz, G. C. Nicholson, H. Neighbour, R. C. Tennant, A. J. Tan, B. R. Leaker, A. Bush, et al. Optimized Dialysis and Protease Inhibition of Sputum Dithiothreitol Supernatants Am. J. Respir. Crit. Care Med., January 15, 2008; 177(2): 132 - 141. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Jude, M. E. Wylam, T. F. Walseth, and M. S. Kannan Calcium Signaling in Airway Smooth Muscle Proceedings of the ATS, January 1, 2008; 5(1): 15 - 22. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. H. Walters, D. W. Reid, D. P. Johns, and C. Ward Nonpharmacological and pharmacological interventions to prevent or reduce airway remodelling Eur. Respir. J., September 1, 2007; 30(3): 574 - 588. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Ma, K. T. HayGlass, A. B. Becker, Y. Fan, X. Yang, S. Basu, G. Srinivasan, F. E. R. Simons, A. J. Halayko, and Z. Peng Novel Recombinant Interleukin-13 Peptide-based Vaccine Reduces Airway Allergic Inflammatory Responses in Mice Am. J. Respir. Crit. Care Med., September 1, 2007; 176(5): 439 - 445. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Turato, S. Baraldo, R. Zuin, and M. Saetta The laws of attraction: chemokines, neutrophils and eosinophils in severe exacerbations of asthma Thorax, June 1, 2007; 62(6): 465 - 466. [Full Text] [PDF]
|
|
|
|
|
|
P. Bradding Mast cell regulation of airway smooth muscle function in asthma Eur. Respir. J., May 1, 2007; 29(5): 827 - 830. [Full Text] [PDF]
|
|
|
|
|
|
W. C. Moore and S. P. Peters Update in Asthma 2006 Am. J. Respir. Crit. Care Med., April 1, 2007; 175(7): 649 - 654. [Full Text] [PDF]
|
|
|
|
 |
|
 K. L. McCann and F. Imani Transforming Growth Factor {beta} Enhances Respiratory Syncytial Virus Replication and Tumor Necrosis Factor Alpha Induction in Human Epithelial Cells J. Virol., March 15, 2007; 81(6): 2880 - 2886. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Amrani TNF-{alpha} and Calcium Signaling in Airway Smooth Muscle Cells: A Never-Ending Story with Promising Therapeutic Relevance Am. J. Respir. Cell Mol. Biol., March 1, 2007; 36(3): 387 - 388. [Full Text] [PDF]
|
|
|
|
|
|
E. M. Erin, O. M. Kon, P. J. Barnes, and T. T. Hansel Study of Infliximab Treatment in Asthma Am. J. Respir. Crit. Care Med., January 15, 2007; 175(2): 196a - 197. [Full Text] [PDF]
|
|
|
|
|
|
S. Wenzel and S. T. Holgate The Mouse Trap: It Still Yields Few Answers in Asthma Am. J. Respir. Crit. Care Med., December 1, 2006; 174(11): 1173 - 1176. [Full Text] [PDF]
|
|
|
|
 |
|
 I. Hunter and G. F. Nixon Spatial Compartmentalization of Tumor Necrosis Factor (TNF) Receptor 1-dependent Signaling Pathways in Human Airway Smooth Muscle Cells: LIPID RAFTS ARE ESSENTIAL FOR TNF-{alpha}-MEDIATED ACTIVATION OF RhoA BUT DISPENSABLE FOR THE ACTIVATION OF THE NF-{kappa}B AND MAPK PATHWAYS J. Biol. Chem., November 10, 2006; 281(45): 34705 - 34715. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. M. Erin, B. R. Leaker, G. C. Nicholson, A. J. Tan, L. M. Green, H. Neighbour, A. S. Zacharasiewicz, J. Turner, E. S. Barnathan, O. M. Kon, et al. The Effects of a Monoclonal Antibody Directed against Tumor Necrosis Factor-{alpha} in Asthma Am. J. Respir. Crit. Care Med., October 1, 2006; 174(7): 753 - 762. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. K. Trow Clinical Year in Review I: Diagnostic Imaging, Asthma, Lung Transplantation, and Interventional Pulmonology Proceedings of the ATS, September 1, 2006; 3(7): 553 - 556. [Full Text] [PDF]
|
|
|
|
|
|
V. Laza-Stanca, L. A. Stanciu, S. D. Message, M. R. Edwards, J. E. Gern, and S. L. Johnston Rhinovirus Replication in Human Macrophages Induces NF-{kappa}B-Dependent Tumor Necrosis Factor Alpha Production. J. Virol., August 1, 2006; 80(16): 8248 - 8258. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. A. White, A. Xue, E. N. Chini, M. Thompson, G. C. Sieck, and M. E. Wylam Role of Transient Receptor Potential C3 in TNF-{alpha}-Enhanced Calcium Influx in Human Airway Myocytes Am. J. Respir. Cell Mol. Biol., August 1, 2006; 35(2): 243 - 251. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. O'Byrne Cytokines or their antagonists for the treatment of asthma. Chest, July 1, 2006; 130(1): 244 - 250. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C Oliveri, R Polosa, S T Holgate, P H Haworth, K S Babu, and H S Arshad Etanercept in chronic severe asthma * Authors' reply. Thorax, July 1, 2006; 61(7): 640 - 640. [Full Text] [PDF]
|
|
|
|
 |
|
 C. Oliveri, R. Polosa, M. A. Berry, and I. D. Pavord Tumor Necrosis Factor {alpha} in Refractory Asthma. N. Engl. J. Med., May 11, 2006; 354(19): 2074 - 2075. [Full Text] [PDF]
|
|
|
|
|
|
I. D. Pavord, S. S. Birring, M. Berry, R. H. Green, C. E. Brightling, and A. J. Wardlaw Multiple inflammatory hits and the pathogenesis of severe airway disease. Eur. Respir. J., May 1, 2006; 27(5): 884 - 888. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J L Heraghty and A J Henderson Highlights in asthma 2005. Arch. Dis. Child., May 1, 2006; 91(5): 422 - 425. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Feldmann and C. D. Pusey Is There a Role for TNF-{alpha} in Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis? Lessons from Other Chronic Inflammatory Diseases J. Am. Soc. Nephrol., May 1, 2006; 17(5): 1243 - 1252. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Berry, B. Hargadon, M. Shelley, D. Parker, D. E. Shaw, R. H. Green, P. Bradding, C. E. Brightling, A. J. Wardlaw, and I. D. Pavord Evidence of a Role of Tumor Necrosis Factor {alpha} in Refractory Asthma N. Engl. J. Med., February 16, 2006; 354(7): 697 - 708. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Barnes, J. C. Virchow, J. Sanchis, T. Welte, and S. Pedersen Asthma management: important issues Eur. Respir. Rev., December 1, 2005; 14(97): 147 - 151. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS | REGISTER |
