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-agonist therapy
Cardiovascular Research Institute and Departments of Medicine, Anesthesia, and Physiology, University of California, San Francisco, California 94143-0130
Although keratinocyte growth factor (KGF)
protects against experimental acute lung injury, the mechanisms for the
protective effect are incompletely understood. Therefore, the
time-dependent effects of KGF on alveolar epithelial fluid transport
were studied in rats 48-240 h after intratracheal administration
of KGF (5 mg/kg). There was a marked proliferative response to KGF,
measured both by in vivo bromodeoxyuridine staining and by staining
with an antibody to a type II cell antigen. In controls, alveolar
liquid clearance (ALC) was 23 ± 3%/h. After KGF
pretreatment, ALC was significantly increased to 30 ± 2%/h at 48 h, to 39 ± 2%/h at 72 h, and to 36 ± 3%/h at 120 h compared
with controls (P < 0.05). By 240 h,
ALC had returned to near-control levels (26 ± 2%/h). The increase
in ALC was explained primarily by the proliferation of alveolar type II
cells, since there was a good correlation between the number of
alveolar type II cells and the increase in ALC
(r = 0.92, P = 0.02). The fraction of ALC
inhibited by amiloride was similar in control rats (33%) as in 72-h
KGF-pretreated rats (38%), indicating that there was probably no major
change in the apical pathways for Na uptake in the KGF-pretreated rats at this time point. However, more rapid ALC at 120 h, compared with 48 h after KGF treatment, may be explained by greater maturation of
-epithelial Na channel, since its expression was greater at 120 than
at 48 h, whereas the number of type II cells was the same at these two
time points. 
-Adrenergic stimulation with terbutaline 72 h after KGF
pretreatment further increased ALC to 50 ± 7%/h (P < 0.5). In summary, KGF induced a sustained increase
over 120 h in the fluid transport capacity of the alveolar epithelium. This impressive upregulation in fluid transport was further enhanced with -adrenergic agonist therapy, thus providing evidence that two
different treatments can simultaneously increase the fluid transport
capacity of the alveolar epithelium.
keratinocyte growth factor; pulmonary edema; acute lung injury; lung fluid balance; lung fluid clearance
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