Keratinocyte growth factor (KGF) prevents
alpha-naphthylthiourea (
ANTU)-induced permeability
edema ex vivo. To explore the mechanisms in this involved effect, we administered KGF (5 mg/kg, intratracheally) 48 h prior to
ANTU (50 mg/kg, intraperitoneally). Several groups were studied:
phosphate-buffered saline/
dimethylsulfoxide (PBS/
DMSO) (vehicles), PBS/
ANTU, and KGF/
ANTU. At 90 min after
ANTU injection the lungs were removed, ventilated, and perfused ex vivo for 180 min. Quantification of
fluorescein isothiocyanate (
FITC)-labeled
dextran in bronchoalveolar lavage fluid (BALF) was used to assess alveolar capillary barrier permeability. KGF attenuated
ANTU-induced
edema and blockade of
sodium transport, with
ouabain (10(-3) M) or
amiloride (10(-4) M) added ex vivo reversed this effect.
FITC-dextran was increased in the PBS/
ANTU group as compared with the PBS/
DMSO group, indicating permeability
edema. In the KGF/
ANTU group, there was concentration of BALF
FITC-dextran, consistent with permeability
edema and increased alveolar fluid export.
Albumin space measurements showed similar increases in permeability in the PBS/
ANTU and KGF/
ANTU groups. Extravascular lung water (measured with radiolabeled erythrocytes) was decreased in the KGF/
ANTU group. Following KGF pretreatment, uninjured lungs exported more intratracheal PBS than normal lungs following
terbutaline stimulation ex vivo. In conclusion, KGF, through type II alveolar pneumocyte
hyperplasia with increased
sodium-potassium-adenosine triphosphatase (Na,K-
ATPase) activity, attenuated
ANTU-induced
edema formation by potentiating alveolar fluid clearance.