Hepatocyte growth factor and keratinocyte growth factor in the pulmonary edema fluid of patients with acute lung injury - Biological and clinical significance

Hepatocyte growth factor (HCF) and keratinocyte growth factor (KCF) are among the most potent mitogens identified for alveolar type II epithelial cells and may have other important functions in repair of the alveolar epithelium in acute lung injury (ALI). However, neither growth factor has been identified in the distal air spaces or plasma of patients with ALI. The goals of this study were to determine: (I) whether HCF and KCF are present in pulmonary edema fluid from patients with ALI and control patients with hydrostatic pulmonary edema; (2) whether HGF and KCF are biologically active in pulmonary edema; and (3) whether HGF or KCF levels are associated with clinical outcome. Pulmonary edema and plasma samples were obtained within 48 h of onset of acute pulmonary edema requiring mechanical ventilation in 26 patients with ALI and 11 control patients with hydrostatic edema. HCF and KCF concentrations were measured with enzyme-linked immunosorbent assays (ELISAs). The median (25th to 75th percentiles) concentration of HCF in pulmonary edema fluid was 21.4 (8.3 to 41.3) ng/ml in ALI and 6.6 (4.8 to 11.4) ng/ml in hydrostatic edema fluid (p < 0.01). The HGF concentration was 7-fold higher in the edema fluid than in the plasma of patients with ALI. In contrast, KCF was detected in low concentrations in edema fluid of patients with ALI and hydrostatic pulmonary edema; the concentration of KCF did not differ in ALI edema (0.6 [0.3 to 2.1] ng/ml) and hydrostatic edema fluid (0.2 [0.0 to 2.6] ng/ml) (p = NS). HGF and KGF were partly purified from four edema-fluid samples by heparin-Sepharose chromatography. Partly purified edema fluids were potent stimuli of DNA synthesis in cultured rat type II alveolar cells; addition of neutralizing antibodies to HCF and KCF attenuated this increase in DNA synthesis by 66% and 53%, respectively. Interestingly, higher edema-fluid levels of HCF were associated with higher mortality in patients with ALI. These novel results show that HCF and KCF are active in the alveolar space early in ALI, probably mediating early events in lung repair, and that increased levels of HCF in edema fluid may have prognostic value early in ALI.