EM Minshall, DY Leung, RJ Martin, YL Song, L Cameron, P Ernst and Q Hamid
Meakins-Christie Laboratories, McGill University, Montreal, Quebec, Canada.

The histopathology of bronchial asthma is associated with structural changes within the airways, including subepithelial fibrosis, as well as chronic eosinophilic inflammation. The mechanisms responsible for this tissue remodeling, and in particular the role of inflammatory cells, remain to be established. Transforming growth factor-beta (TGF- beta) is a potent profibrotic cytokine which may contribute to the thickening of the reticular lamina by the deposition of collagen fibers. To investigate the molecular mechanisms underlying these structural changes, we have investigated the expression of TGF-beta1 mRNA and immunoreactivity within the bronchial mucosa of mild to severe asthmatic individuals and normal control subjects using the techniques of in situ hybridization and immunocytochemistry. As eosinophils are prominent within the asthmatic airway and are known to synthesize pro- inflammatory cytokines, the presence of TGF-beta1 mRNA and immunoreactive protein in eosinophils was also examined. Asthmatic individuals exhibited a greater expression of TGF-beta1 mRNA and immunoreactivity in the airways submucosa than normal control subjects (P < 0.05), and these increases were directly related to the severity of the disorder. The extent of airways fibrosis, as detected histochemically, was also increased in asthmatics compared with normal control subjects (P < 0.005). In asthmatic subjects, the presence of subepithelial fibrosis was associated with the severity of the disease and correlated with the decline in forced expiratory volume in 1 s (r2 = 0.78; P < 0.05). Within the asthmatic airways, EG2-positive eosinophils represented the major source of TGF-beta1 mRNA and immunoreactivity. These results provide evidence that TGF-beta1 may play a role in the fibrotic changes occurring within asthmatic airways and that activated eosinophils are a major source of this cytokine.

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				S. Phipps, S. Ying, A. Wangoo, Y.-E. Ong, F. Levi-Schaffer, and A. B. Kay The Relationship Between Allergen-Induced Tissue Eosinophilia and Markers of Repair and Remodeling in Human Atopic Skin J. Immunol., October 15, 2002; 169(8): 4604 - 4612. [Abstract] [Full Text] [PDF]

				S. E. Wenzel, J. B. Trudeau, S. Barnes, X. Zhou, M. Cundall, J. Y. Westcott, K. McCord, and H. W. Chu TGF-{beta} and IL-13 Synergistically Increase Eotaxin-1 Production in Human Airway Fibroblasts J. Immunol., October 15, 2002; 169(8): 4613 - 4619. [Abstract] [Full Text] [PDF]

				F.-Q. Wen, T. Kohyama, X. Liu, Y. K. Zhu, H. Wang, H. J. Kim, T. Kobayashi, S. Abe, J. R. Spurzem, and S. I. Rennard Interleukin-4- and Interleukin-13-Enhanced Transforming Growth Factor-beta 2 Production in Cultured Human Bronchial Epithelial Cells Is Attenuated by Interferon-gamma Am. J. Respir. Cell Mol. Biol., April 1, 2002; 26(4): 484 - 490. [Abstract] [Full Text] [PDF]

				M. T. Hopfenspirger and D. K. Agrawal Airway Hyperresponsiveness, Late Allergic Response, and Eosinophilia Are Reversed with Mycobacterial Antigens in Ovalbumin-Presensitized Mice J. Immunol., March 1, 2002; 168(5): 2516 - 2522. [Abstract] [Full Text] [PDF]

				A. T. HASTIE, W. K. KRAFT, K. B. NYCE, J. G. ZANGRILLI, A. I. MUSANI, J. E. FISH, and S. P. PETERS Asthmatic Epithelial Cell Proliferation and Stimulation of Collagen Production . Human Asthmatic Epithelial Cells Stimulate Collagen Type III Production by Human Lung Myofibroblasts after Segmental Allergen Challenge Am. J. Respir. Crit. Care Med., January 15, 2002; 165(2): 266 - 272. [Abstract] [Full Text] [PDF]

				A. Kamachi, Y. Nasuhara, M. Nishimura, T. Takahashi, Y. Homma, Y. Ohtsuka, and M. Munakata Dissociation between airway responsiveness to methacholine and responsiveness to antigen Eur. Respir. J., January 1, 2002; 19(1): 76 - 83. [Abstract] [Full Text] [PDF]

				P. K. JEFFERY Remodeling in Asthma and Chronic Obstructive Lung Disease Am. J. Respir. Crit. Care Med., November 15, 2001; 164(10): S28 - 38. [Abstract] [Full Text] [PDF]

				C. G. Lee, R. J. Homer, Z. Zhu, S. Lanone, X. Wang, V. Koteliansky, J. M. Shipley, P. Gotwals, P. Noble, Q. Chen, et al. Interleukin-13 Induces Tissue Fibrosis by Selectively Stimulating and Activating Transforming Growth Factor {beta}1 J. Exp. Med., September 17, 2001; 194(6): 809 - 822. [Abstract] [Full Text] [PDF]

				A. ten BRINKE, A. H. ZWINDERMAN, P. J. STERK, K. F. RABE, and E. H. BEL Factors Associated with Persistent Airflow Limitation in Severe Asthma Am. J. Respir. Crit. Care Med., September 1, 2001; 164(5): 744 - 748. [Abstract] [Full Text] [PDF]

				P.J. Barnes Cytokine modulators as novel therapies for airway disease Eur. Respir. J., July 2, 2001; 18(34_suppl): 67S - 77s. [Abstract] [Full Text] [PDF]

				S. M. Ensminger, B. M. Spriewald, H. V. Sorensen, O. Witzke, E. G. Flashman, A. Bushell, P. J. Morris, M. L. Rose, A. Rahemtulla, and K. J. Wood Critical Role for IL-4 in the Development of Transplant Arteriosclerosis in the Absence of CD40-CD154 Costimulation J. Immunol., July 1, 2001; 167(1): 532 - 541. [Abstract] [Full Text] [PDF]

				A. Coutts, G. Chen, N. Stephens, S. Hirst, D. Douglas, T. Eichholtz, and N. Khalil Release of biologically active TGF-{beta} from airway smooth muscle cells induces autocrine synthesis of collagen Am J Physiol Lung Cell Mol Physiol, May 1, 2001; 280(5): L999 - L1008. [Abstract] [Full Text] [PDF]

				J.C. Kips, K.G. Tournoy, and R.A. Pauwels New anti-asthma therapies: suppression of the effect of interleukin (IL)-4 and IL-5 Eur. Respir. J., March 1, 2001; 17(3): 499 - 506. [Abstract] [Full Text] [PDF]

				C. L. S. George, H. Jin, C. L. Wohlford-Lenane, M. E. O'Neill, J. C. Phipps, P. O'Shaughnessy, J. N. Kline, P. S. Thorne, and D. A. Schwartz Endotoxin responsiveness and subchronic grain dust-induced airway disease Am J Physiol Lung Cell Mol Physiol, February 1, 2001; 280(2): L203 - L213. [Abstract] [Full Text] [PDF]

				S. Wenzel Proceedings of the ATS Workshop on Refractory Asthma . Current Understanding, Recommendations, and Unanswered Questions Am. J. Respir. Crit. Care Med., December 1, 2000; 162(6): 2341 - 2351. [Full Text]

				J. Wang, R. J. Homer, Q. Chen, and J. A. Elias Endogenous and Exogenous IL-6 Inhibit Aeroallergen-Induced Th2 Inflammation J. Immunol., October 1, 2000; 165(7): 4051 - 4061. [Abstract] [Full Text] [PDF]

				S. T. HOLGATE, P. LACKIE, S. WILSON, W. ROCHE, and D. DAVIES Bronchial Epithelium as a Key Regulator of Airway Allergen Sensitization and Remodeling in Asthma Am. J. Respir. Crit. Care Med., September 1, 2000; 162(3): S113 - 117. [Full Text] [PDF]

				S. M. PUDDICOMBE, R. POLOSA, A. RICHTER, M. T. KRISHNA, P. H. HOWARTH, S. T. HOLGATE, and D. E. DAVIES Involvement of the epidermal growth factor receptor in epithelial repair in asthma FASEB J, July 1, 2000; 14(10): 1362 - 1374. [Abstract] [Full Text]

				S. Ali, J. Kaur, and K. D. Patel Intercellular Cell Adhesion Molecule-1, Vascular Cell Adhesion Molecule-1, and Regulated on Activation Normal T Cell Expressed and Secreted Are Expressed by Human Breast Carcinoma Cells and Support Eosinophil Adhesion and Activation Am. J. Pathol., July 1, 2000; 157(1): 313 - 321. [Abstract] [Full Text] [PDF]

				R. O. Sanchez Mejia, B. K. Lam, and J. P. Arm Matrix-Associated Transforming Growth Factor-beta 1 Primes Mouse Bone Marrow-Derived Mast Cells for Increased High-Affinity Fc Receptor for Immunoglobulin E-Dependent Eicosanoid Biosynthesis Am. J. Respir. Cell Mol. Biol., May 1, 2000; 22(5): 557 - 565. [Abstract] [Full Text]

				J. BOUSQUET, P. K. JEFFERY, W. W. BUSSE, M. JOHNSON, and A. M. VIGNOLA Asthma . From Bronchoconstriction to Airways Inflammation and Remodeling Am. J. Respir. Crit. Care Med., May 1, 2000; 161(5): 1720 - 1745. [Full Text]

				A. Oriente, N. S. Fedarko, S. E. Pacocha, S.-K. Huang, L. M. Lichtenstein, and D. M. Essayan Interleukin-13 Modulates Collagen Homeostasis in Human Skin and Keloid Fibroblasts J. Pharmacol. Exp. Ther., March 1, 2000; 292(3): 988 - 994. [Abstract] [Full Text]

				P. Cohen, R. Rajah, J. Rosenbloom, and D. J. Herrick IGFBP-3 mediates TGF-beta 1-induced cell growth in human airway smooth muscle cells Am J Physiol Lung Cell Mol Physiol, March 1, 2000; 278(3): L545 - L551. [Abstract] [Full Text] [PDF]

				K. Sato, H. Kawasaki, H. Nagayama, M. Enomoto, C. Morimoto, K. Tadokoro, T. Juji, and T. A. Takahashi TGF-{beta}1 Reciprocally Controls Chemotaxis of Human Peripheral Blood Monocyte-Derived Dendritic Cells Via Chemokine Receptors J. Immunol., March 1, 2000; 164(5): 2285 - 2295. [Abstract] [Full Text] [PDF]