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1 Department of Gene Therapy, National Heart and Lung Institute, Imperial College London, London, United Kingdom
* To whom correspondence should be addressed. E-mail: e.alton{at}imperial.ac.uk.
AT II cell proliferation and differentiation are important mechanisms in repair following injury to the alveolar epithelium. KGF is a potent AT II 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 (1, 5, 10 and 15 mg/kg) and time course (1-7 days) of proliferation. SP-B immunohistochemistry demonstrated significant (p<0.001) increases in AT II cell numbers at all rhKGF doses compared to control animals, and peaked two 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 AT II cell proliferation. SP-B immunohistochemistry showed only modest increases in AT II cell numbers following gene delivery, and these approaches were therefore not believed to be capable of reaching therapeutic levels. The effect of rhKGF (10 mg/kg) 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. Pre-treatment with rhKGF two days prior to intravenous OA challenge resulted in significant (p<0.05) improvements in pO2, pCO2 and lung compliance. In summary, this study suggests the feasibility of KGF as a therapy for acute lung injury.
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