Alveolar epithelial fluid transport can be simultaneously upregulated by both KGF and beta-agonist therapy

Although keratinocyte growth factor (KGF) protects against experimental acu te lung injury, the mechanisms for the protective effect are incompletely u nderstood. Therefore, the time-dependent effects of KGF on alveolar epithel ial fluid transport were studied in rats 48-240 h after intratracheal admin istration of KGF (5 mg/kg). There was a marked proliferative response to KG F, measured both by in vivo bromodeoxyuridine staining and by staining with an antibody to a type II cell antigen. In controls, alveolar liquid cleara nce (ALC) was 23 +/- 3%/h. After KGF pretreatment, ALC was significantly in creased 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 n ear-control levels (26 +/- 2%/h). The increase in ALC was explained primari ly by the proliferation of alveolar type II cells, since there was a good c orrelation 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 s imilar in control rats (33%) as in 72-h KGF-pretreated rats (38%), indicati ng that there was probably no major change in the apical pathways for Na up take in the KG;F-pretreated rats at this time point. However, more rapid AL C at 120 h, compared with 48 h after KGF treatment, may be explained by gre ater maturation of alpha-epithelial Na channel, since its expression was gr eater at 120 than at 48 h, whereas the number of type II cells was the same at these two time points. beta-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 transpor t capacity of the alveolar epithelium. This impressive upregulation in flui d transport was further enhanced with beta-adrenergic agonist therapy, thus providing evidence that two different treatments can simultaneously increa se the fluid transport capacity of the alveolar epithelium.