Inhibition of obliterative bronchiolitis by platelet-derived growth factor receptor protein-tyrosine kinase inhibitor

Inhibition of Obliterative Bronchiolitis by Platelet-Derived Growth Factor Receptor Protein-Tyrosine Kinase Inhibitor E. Kallio, P. Koskinen, E. Buchdunger, and K. Lemstro¨m

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BLITERATIVE BRONCHIOLITIS (OB), characterized by airway wall inflammation and proliferation and migration of mesenchymal cells, leading to gradual occlusion of the airway lumen, is a major complication, having a negative effect on long-term results of lung transplantation.1 Platelet-derived growth factor (PDGF) has been suggested to have a role in OB.2 In this study, we investigated PDGF in the development of OB, and the effect of a protein-tyrosine kinase (PTK) inhibitor selective for PDGF-R, CGP53716,3 on OB. METHODS Tracheal transplantations were performed as described4 from DA to WF rats and syngeneic controls from DA to DA rats. Nontreated allografts and syngeneic grafts were removed at 3, 10, and 30 days for immunohistochemistry and RT-PCR. Allografts were treated with CGP53716 or vehicle alone, or in combination with CsA (Table 1).

RESULTS AND DISCUSSION

Significant upregulation of allograft PDGF-AA and -Ra expression was observed at 3 and 10 days after transplantation, compared with syngeneic grafts. The effect of

CGP53716 is shown in Table 1. In conclusion, this study suggests a regulatory role for PDGF, especially for PDGF-AA and -Ra, in the development of OB. This study also demonstrates that inhibition of PDGF-R with PTK inhibitor significantly reduces myofibroproliferation and airway occlusion, suggesting a novel therapeutic strategy for the prevention of OB. REFERENCES 1. Hosenpud JD, Bennett LE, Berkeley M, et al: J Heart Lung Transplant 16:691, 1997 2. Hertz MI, Henke CA, Nakhleh RE, et al: Proc Natl Acad Sci 89:10385, 1992 3. Buchdunger E, Zimmermann J, Mett H, et al: Proc Natl Acad Sci 92:2558, 1995 4. Koskinen PK, Kallio EA, Krebs R, et al: Am J Resp Crit Care Med 155:303, 1997 From the Transplantation Laboratory, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland (E.K., P.K., K.L.); and Novartis Pharma Inc, Basel, Switzerland (E.B.). Address reprint requests to Dr Erkki Kallio, Transplantation Laboratory, University of Helsinki and Helsinki University Central Hospital, PO Box 21, FIN-00014 Helsinki, Finland.

Table 1. Effect of CGP53716 on Airway Occlusion, Myofibroproliferation, and Airway Wall Inflammatory Cell Proliferation (Mean 6 SEM) Time After Tx

10 days

30 days

Group

Airway Occlusion

Myofibroproliferation*

Airway Wall Cell Proliferation†

Vehicle CG53716 Vehicle 1 CsA CGP53716 1 CsA Vehicle CG53716 Vehicle 1 CsA CGP53716 1 CsA

18 6 5 8 6 2‡ 661 762 86 6 5 43 6 6\ 85 6 6 37 6 6\

88 6 25 20 6 5§ 62 6 17 30 6 10 10 6 2 661 31 6 9 9 6 3\

408 6 87 401 6 43 388 6 91 214 6 22 29 6 4 32 6 3 38 6 7 46 6 9

Allografts were treated with CGP53716 (50 mg/kg, IP), an equal amount of vehicle, CGP53716 in combination with a suboptimal dose of CsA (1 mg/kg, sc), or vehicle in combination with CsA. Grafts were removed at 10 and 30 days. CGP53716 significantly inhibited airway occlusion at 10 and 30 days after transplant ion. In addition, myofibroproliferation was significantly inhibited, whereas airway wall inflammatory cell proliferation, or number or activation level of graft-infiltrating macrophages or T cells were not affected, indicating that the effect of CGP53716 on the development of OB is not immunosuppressive, but rather due to inhibition of PDGF induced mesenchymal cell proliferation. *Percent of luminal occlusion. †BrdU1 cells/cross-section. ‡ P , .05, §P , .01, \P , .01 CGP53716 vs vehicle and CGP53716 1 CsA vs vehicle 1 CsA (ANOVA).

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Transplantation Proceedings, 31, 187 (1999)