Keratinocyte growth factor ameliorates radiation- and bleomycin-induced lung injury and mortality.
Keratinocyte growth factor (KGF) is a growth factor for type II pneumocytes. Type II pneumocyte hyperplasia, a common reaction to lung injury, has been postulated to play an important role in lung repair. The potential protective effect of KGF was therefore studied in rat models of radiation- and bleomycin-induced lung injury. Intratracheal instillation of KGF (5 mg/kg) 72 and 48 hours before 18 Gy of bilateral thoracic irradiation did not significantly improve survival, although histology showed less pneumonitis and fibrosis in KGF-pretreated as compared with control-irradiated rats. Intratracheal pretreatment with KGF in rats receiving intratracheal bleomycin (2.5 U) improved survival at 3 weeks to 100% (20/20 rats) from 40% (8/20 rats) in controls. All KGF-pretreated rats receiving bleomycin were well at 3 weeks and without histological evidence of pulmonary fibrosis whereas the 8 surviving control rats exhibited severe respiratory distress. Finally, in the most lethal challenge to the lung, rats pretreated with intratracheal KGF or saline were challenged with a combination of bleomycin (1.5 U) and bilateral thoracic irradiation (18 Gy). KGF-pretreated rats did not begin to die or show signs of respiratory distress until 7 weeks, whereas all saline-pretreated control rats receiving radiation and bleomycin died within approximately 4 weeks with severe respiratory distress and weight loss. In conclusion, radiation- and bleomycin-induced pulmonary injury and respiratory death are ameliorated by KGF pretreatment, suggesting a protective role for KGF-induced type II pneumocyte proliferation in lung injury.
Yi
E S
ES
Department of Pathology, School of Medicine, University of California at San Diego, USA.
Williams
S T
ST
Lee
H
H
Malicki
D M
DM
Chin
E M
EM
Yin
S
S
Tarpley
J
J
Ulich
T R
TR
D000818:Animals; D001761:Bleomycin; D001973:Bromodeoxyuridine / Q000378:metabolism; D051526:Fibroblast Growth Factor 10; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D006133:Growth Substances / Q000008:administration & dosage / Q000627:therapeutic use*; D007442:Intubation, Intratracheal; D008168:Lung / Q000187:drug effects / Q000473:pathology* / Q000528:radiation effects; D008171:Lung Diseases / Q000139:chemically induced / Q000401:mortality / Q000628:therapy*; D008297:Male; D011833:Radiation Injuries, Experimental / Q000401:mortality / Q000473:pathology* / Q000628:therapy*; D051381:Rats; D011917:Rats, Inbred Lew
C496455:Fgf7 protein, rat; D051526:Fibroblast Growth Factor 10; D006133:Growth Substances; D001761:Bleomycin; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D001973:Bromodeoxyuridine