Prevention of bleomycin-induced lung injury in rats by keratinocyte growth factor.
Intratracheal instillation of bleomycin produces pulmonary fibrosis in rats. Alveolar type II cell proliferation is thought to minimize the fibrotic response after lung injury. Because keratinocyte growth factor (KGF) stimulates type II cell proliferation in the rat, we designed experiments to evaluate whether intratracheal KGF before or after intratracheal bleomycin would prevent pulmonary fibrosis. Intratracheal bleomycin without KGF resulted in moderate to severe lung injury and subsequent fibrosis. Conversely, intratracheal KGF pretreatment at 48 or 72 hr before bleomycin resulted in minimal to no visible lung injury. Rats pretreated with phosphate buffered saline before bleomycin had significantly more neutrophils and protein in bronchoalveolar lavage fluid at 4 and 6 days and higher hydroxyproline levels after bleomycin as compared to KGF-pretreated rats. Pretreatment with KGF at 48 hr protected against bleomycin-induced alterations in pulmonary physiology and increased surfactant protein C-positive (SP-C)-positive cells and SP-A, SP-B, SP-C, and SP-D mRNA levels after bleomycin instillation when compared to saline pretreated rats on day 1 or day 7. KGF posttreatment protocols did not prevent bleomycin lung injury and fibrosis. We conclude that KGF pretreatment attenuates bleomycin lung injury and increases type II cell proliferation and surfactant protein gene expression after bleomycin instillation in the rat.
Deterding
R R
RR
Department of Pediatrics, University of Colorado, Children's Hospital, Denver, USA.
Havill
A M
AM
Yano
T
T
Middleton
S C
SC
Jacoby
C R
CR
Shannon
J M
JM
Simonet
W S
WS
Mason
R J
RJ
D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D001761:Bleomycin / Q000633:toxicity*; D004336:Drug Antagonism; D051526:Fibroblast Growth Factor 10; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D006133:Growth Substances / Q000008:administration & dosage*; D006909:Hydroxyproline / Q000032:analysis; D008168:Lung / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D009929:Organ Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D012129:Respiratory Function Tests
D000900:Anti-Bacterial Agents; C496455:Fgf7 protein, rat; D051526:Fibroblast Growth Factor 10; D006133:Growth Substances; D001761:Bleomycin; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D006909:Hydroxyproline