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J Thorac Cardiovasc Surg 2009;137:1499-1507
© 2009 The American Association for Thoracic Surgery

Evolving Technology

Keratinocyte growth factor accelerates compensatory growth in the remaining lung after trilobectomy in rats

Keitaro Matsumoto, MDa,b, Takeshi Nagayasu, MDa, Yoshitaka Hishikawa, MDb, Tsutomu Tagawa, MDa, Takatomo Yamayoshi, MDa, Takafumi Abo, MDa, Shuichi Tobinaga, MDa, Katsuro Furukawa, MDa, Takehiko Koji, PhDb,*

a Division of Surgical Oncology, Department of Translational Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
b Department of Histology and Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

Received for publication March 2, 2008; revisions received October 27, 2008; accepted for publication November 22, 2008.

* Address for reprints: Takehiko Koji, PhD, Department of Histology and Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, Sakamoto 1-12-4, Nagasaki 852-8523, Japan. (Email: tkoji{at}nagasaki-u.ac.jp).

Objective: In rats pulmonary resection is followed by lung compensatory growth. However, the molecular mechanism underlying lung compensatory growth remains unclear. Keratinocyte growth factor is expressed in lung tissue and is considered a possible mitogen for lung epithelial cells. The objectives of this study were to define the role of keratinocyte growth factor and its receptor in rat lung compensatory growth after trilobectomy and the effect of exogenous keratinocyte growth factor gene transfection.

Methods: Adult Lewis rats were used. Right trilobectomy was performed in the operation group and sham thoracotomy in the sham group. In the operation group, keratinocyte growth factor–FLAG or FLAG expression vector was transfected directly into the lung by means of electroporation. Expression of keratinocyte growth factor and its receptor and alveolar cell proliferation index based on proliferating cell nuclear antigen levels were measured in the right lung at day 14 after the operation.

Results: Proliferating cell nuclear antigen, keratinocyte growth factor, and keratinocyte growth factor receptor expression in lung epithelial cells was significantly increased at day 4 after trilobectomy. Transfection of keratinocyte growth factor–FLAG expression vector resulted in further significant enhancement of proliferating cell nuclear antigen at day 4 after trilobectomy; however, the transfection of FLAG expression vector did not alter the enhancement of proliferating cell nuclear antigen. Exogenous expression of keratinocyte growth factor in the remaining lung by means of electroporation significantly augmented epithelial proliferation and decreased the average airspace distance (mean linear intercept).

Conclusion: Our results implicate keratinocyte growth factor in the induction of alveolar epithelial cell proliferation for compensatory lung growth and indicate that overexpression of keratinocyte growth factor in the remaining lung by means of electroporation significantly augmented lung epithelial proliferation.

Abbreviations and Acronyms BrdU = bromodeoxyuridine; HGF = hepatocyte growth factor; hKGF = human keratinocyte growth factor; HRP = horseradish peroxidase; KGF = keratinocyte growth factor; KGFR = keratinocyte growth factor receptor; PCR = polymerase chain reaction; SP-A = surfactant protein-A






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