Keratinocyte growth factor therapy in murine oleic acid-induced acute lung injury

1 Department of Gene Therapy, National Heart and Lung Institute, and 2 Anaesthetics and Intensive Care, Chelsea and Westminster Hospital, and 3 Electron Microscopy Unit, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London; and 4 Gene Medicine Research Group, Nuffi...

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Published in:	American journal of physiology. Lung cellular and molecular physiology 2005-06, Vol.288 (6), p.L1179-L1192
Main Authors:	Ulrich, K, Stern, M, Goddard, M. E, Williams, J, Zhu, J, Dewar, A, Painter, H. A, Jeffery, P. K, Gill, D. R, Hyde, S. C, Geddes, D. M, Takata, M, Alton, E. W. F. W
Format:	Article
Language:	eng
Subjects:	Acute Disease Animals Cell Differentiation Cell Proliferation Fibroblast Growth Factor 7 Fibroblast Growth Factors - therapeutic use Humans Keratinocytes - metabolism Lung Diseases - chemically induced Lung Diseases - prevention & control Lung Injury Male Mice Mice, Inbred BALB C Oleic Acid - toxicity Pulmonary Alveoli - cytology Pulmonary Alveoli - drug effects Pulmonary Surfactant-Associated Protein B - metabolism Recombinant Proteins - therapeutic use
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Summary:	1 Department of Gene Therapy, National Heart and Lung Institute, and 2 Anaesthetics and Intensive Care, Chelsea and Westminster Hospital, and 3 Electron Microscopy Unit, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London; and 4 Gene Medicine Research Group, Nuffield Department of Clinical Laboratory Sciences, University of Oxford, United Kingdom Submitted 1 December 2004 ; accepted in final form 24 January 2005 Alveolar type II (ATII) cell proliferation and differentiation are important mechanisms in repair following injury to the alveolar epithelium. KGF is a potent ATII cell mitogen, which has been demonstrated to be protective in a number of animal models of lung injury. We have assessed the effect of recombinant human KGF (rhKGF) and liposome-mediated KGF gene delivery in vivo and evaluated the potential of KGF as a therapy for acute lung injury in mice. rhKGF was administered intratracheally in male BALB/c mice to assess dose response and time course of proliferation. SP-B immunohistochemistry demonstrated significant increases in ATII cell numbers at all rhKGF doses compared with control animals and peaked 2 days following administration of 10 mg/kg rhKGF. Protein therapy in general is very expensive, and gene therapy has been suggested as a cheaper alternative for many protein replacement therapies. We evaluated the effect of topical and systemic liposome-mediated KGF-gene delivery on ATII cell proliferation. SP-B immunohistochemistry showed only modest increases in ATII cell numbers following gene delivery, and these approaches were therefore not believed to be capable of reaching therapeutic levels. The effect of rhKGF was evaluated in a murine model of OA-induced lung injury. This model was found to be associated with significant alveolar damage leading to severe impairment of gas exchange and lung compliance. Pretreatment with rhKGF 2 days before intravenous OA challenge resulted in significant improvements in P O 2 , P CO 2 , and lung compliance. This study suggests the feasibility of KGF as a therapy for acute lung injury. acute respiratory distress syndrome; alveolar epithelial damage; oleic acid; gene therapy Address for reprint requests and other correspondence: Prof. E. W. F. W. Alton, Dept. of Gene Therapy, National Heart and Lung Institute, Manresa Road, London SW3 6LR, United Kingdom (E-mail: e.alton{at}ic.ac.uk )
ISSN:	1040-0605 1522-1504