This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Aris, R. M. Articles by Neuringer, I. P. Search for Related Content PubMed PubMed Citation Articles by Aris, R. M. Articles by Neuringer, I. P.

Growth Factor Upregulation during Obliterative Bronchiolitis in the Mouse Model

Divisions of Pulmonary and Critical Care Medicine, Department of Medicine and the Cystic Fibrosis Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

Correspondence and requests for reprints should be addressed to Robert Aris, M.D., CB# 7020, 420 Burnett-Womack Building, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7524. E-mail: aris{at}med.unc.edu

Obliterative bronchiolitis (OB), or chronic allograft rejection, is a major cause of morbidity and mortality after lung transplantation. The goal of these experiments was to determine whether several important growth factors were upregulated during OB in the mouse heterotopic trachea model. Isografts (BALB/c into BALB/c) and allografts (BALB/c into C57BL/6) were implanted in three sets of cyclosporine-treated animals and were harvested from 2 to 10 weeks. Ribonucleic acid was isolated using the cesium chloride-guanidine method and was reverse transcribed and semiquantitated with the polymerase chain reaction using specific primers for platelet-derived growth factor (PDGF)-A and PDGF-B chains, fibroblast growth factor (FGF) isoforms 1 and 2, transforming growth factor-ß, tumor necrosis factor- (TNF-), edothelin-1, (prepro) epidermal growth factor, insulin-like growth factor-1, and ß-actin as a control. Transforming growth factor-ß, TNF-, endothelin-1, and insulin-like growth factor-1 expression were increased 1.5-fold to 5.0-fold (p 0.04 for each) in the allografts compared with the isografts at Weeks 2 through 6. Significantly increased expression of FGF-1, FGF-2, and PDGF-B was noted in the allografts at 4 weeks (p < 0.05 for each), which reversed at 6 and 10 weeks. No differences were found with the PDGF-A chain. The isografts expressed more epidermal growth factor than allografts (p < 0.001). Treatment with a TNF-–soluble receptor (human TNFR:Fc) significantly reduced epithelial injury (p = 0.01) and lumenal obstruction (p = 0.037) in this model. We conclude that increased expression of a large number of growth factors occurs during OB in this model. Growth factor blockade (in particular with regard to TNF-) may be useful in ameliorating OB in this model.

Key Words: obliterative bronchiolitis • chronic rejection • lung • growth factors • mouse

This article has been cited by other articles:

				T. A. Goers, S. Ramachandran, A. Aloush, E. Trulock, G. A. Patterson, and T. Mohanakumar De Novo Production of K-{alpha}1 Tubulin-Specific Antibodies: Role in Chronic Lung Allograft Rejection J. Immunol., April 1, 2008; 180(7): 4487 - 4494. [Abstract] [Full Text] [PDF]

				L. P. Shornick, A. G. Wells, Y. Zhang, A. C. Patel, G. Huang, K. Takami, M. Sosa, N. A. Shukla, E. Agapov, and M. J. Holtzman Airway Epithelial versus Immune Cell Stat1 Function for Innate Defense against Respiratory Viral Infection J. Immunol., March 1, 2008; 180(5): 3319 - 3328. [Abstract] [Full Text] [PDF]

				H. Harada, V. N. Lama, L. N. Badri, T. Ohtsuka, D. Petrovic-Djergovic, H. Liao, Y. Yoshikawa, K. Iwanaga, C. L. Lau, and D. J. Pinsky Early growth response gene-1 promotes airway allograft rejection Am J Physiol Lung Cell Mol Physiol, July 1, 2007; 293(1): L124 - L130. [Abstract] [Full Text] [PDF]

				J. M. Tikkanen, M. Hollmen, A. I. Nykanen, J. Wood, P. K. Koskinen, and K. B. Lemstrom Role of Platelet-derived Growth Factor and Vascular Endothelial Growth Factor in Obliterative Airway Disease Am. J. Respir. Crit. Care Med., November 15, 2006; 174(10): 1145 - 1152. [Abstract] [Full Text] [PDF]

				B. S. Lu, A. D. Yu, X. Zhu, E. R. Garrity Jr, W. T. Vigneswaran, and S. M. Bhorade Sequential gene expression profiling in lung transplant recipients with chronic rejection. Chest, September 1, 2006; 130(3): 847 - 854. [Abstract] [Full Text] [PDF]

				S.-C. LAI Chinese herbal medicine yin-chen-extract as an adjunct to anthelmintic albendazole used against angiostrongylus cantonensis-induced eosinophilic meningitis or meningoencephalitis. Am J Trop Med Hyg, September 1, 2006; 75(3): 556 - 562. [Abstract] [Full Text] [PDF]

				L. P. Nicod Mechanisms of airway obliteration after lung transplantation. Proceedings of the ATS, July 1, 2006; 3(5): 444 - 449. [Abstract] [Full Text] [PDF]

				V. N. Lama, H. Harada, L. N. Badri, A. Flint, C. M. Hogaboam, A. McKenzie, F. J. Martinez, G. B. Toews, B. B. Moore, and D. J. Pinsky Obligatory Role for Interleukin-13 in Obstructive Lesion Development in Airway Allografts Am. J. Pathol., July 1, 2006; 169(1): 47 - 60. [Abstract] [Full Text] [PDF]

				M. G. Hartwig, J. Z. Appel, B. Li, C.-C. Hsieh, Y. H. Yoon, S. S. Lin, W. Irish, W. Parker, and R. D. Davis Chronic aspiration of gastric fluid accelerates pulmonary allograft dysfunction in a rat model of lung transplantation J. Thorac. Cardiovasc. Surg., January 1, 2006; 131(1): 209 - 217. [Abstract] [Full Text] [PDF]

				E. E. West, T. L. Lavoie, J. B. Orens, E. S. Chen, S. Q. Ye, F. D. Finkelman, J. G. N. Garcia, and J. F. McDyer Pluripotent Allospecific CD8+ Effector T Cells Traffic to Lung in Murine Obliterative Airway Disease Am. J. Respir. Cell Mol. Biol., January 1, 2006; 34(1): 108 - 118. [Abstract] [Full Text] [PDF]

				W Chalermskulrat, K P McKinnon, W J Brickey, I P Neuringer, R C Park, D G Sterka, B R Long, P McNeillie, R J Noelle, J P Ting, et al. Combined donor specific transfusion and anti-CD154 therapy achieves airway allograft tolerance Thorax, January 1, 2006; 61(1): 61 - 67. [Abstract] [Full Text] [PDF]

				J. J. Fullmer, L. L. Fan, M. K. Dishop, C. Rodgers, and R. Krance Successful Treatment of Bronchiolitis Obliterans in a Bone Marrow Transplant Patient With Tumor Necrosis Factor-{alpha} Blockade Pediatrics, September 1, 2005; 116(3): 767 - 770. [Abstract] [Full Text] [PDF]

				D. M. Richards, S. L. Dalheimer, B. D. Ehst, T. L. Vanasek, M. K. Jenkins, M. I. Hertz, and D. L. Mueller Indirect Minor Histocompatibility Antigen Presentation by Allograft Recipient Cells in the Draining Lymph Node Leads to the Activation and Clonal Expansion of CD4+ T Cells That Cause Obliterative Airways Disease J. Immunol., March 15, 2004; 172(6): 3469 - 3479. [Abstract] [Full Text] [PDF]

				D. M. Richards, S. L. Dalheimer, M. I. Hertz, and D. L. Mueller Trachea Allograft Class I Molecules Directly Activate and Retain CD8+ T Cells That Cause Obliterative Airways Disease J. Immunol., December 15, 2003; 171(12): 6919 - 6928. [Abstract] [Full Text] [PDF]

				A. Boehler and M. Estenne Post-transplant bronchiolitis obliterans Eur. Respir. J., December 1, 2003; 22(6): 1007 - 1018. [Abstract] [Full Text] [PDF]

				R. Song, M. Kubo, D. Morse, Z. Zhou, X. Zhang, J. H. Dauber, J. Fabisiak, S. M. Alber, S. C. Watkins, B. S. Zuckerbraun, et al. Carbon Monoxide Induces Cytoprotection in Rat Orthotopic Lung Transplantation via Anti-Inflammatory and Anti-Apoptotic Effects Am. J. Pathol., July 1, 2003; 163(1): 231 - 242. [Abstract] [Full Text] [PDF]

				W. Chalermskulrat, I. P. Neuringer, W. J. Brickey, N. J. Felix, S. H. Randell, J. P. Ting, and R. M. Aris Hierarchical Contributions of Allorecognition Pathways in Chronic Lung Rejection Am. J. Respir. Crit. Care Med., April 1, 2003; 167(7): 999 - 1007. [Abstract] [Full Text] [PDF]

				M. J. Tobin Chronic Obstructive Pulmonary Disease, Pollution, Pulmonary Vascular Disease, Transplantation, Pleural Disease, and Lung Cancer in AJRCCM 2002 Am. J. Respir. Crit. Care Med., February 1, 2003; 167(3): 356 - 370. [Full Text] [PDF]