Keratinocyte growth factor increases transalveolar sodium reabsorption in normal and injured rat lungs.

Abstract

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.

Keratinocyte growth factor improves alterations of lung permeability and bronchial epithelium in allergic rats

“…The protective effect of KGF is multifactorial. The current authors have shown, in a-naphthylthiourea-induced lung injury, a potentiation of alveolar fluid clearance through sodium-potassium-adenosine triphosphatase stimulation [14]. In Pseudomonas aeruginosa pneumonia, KGF restored lung liquid clearance related to an improvement of the endothelial barrier [15].…”

“…KGF has been demonstrated to be a potent mitogen of alveolar epithelial type II cells in the lung, and also of bronchial epithelial cells in vitro and in vivo [10,11,29]. The protective effect of KGF has been demonstrated in different situations, including the prevention of cell loss but also the repair of the epithelium after injury [14][15][16][17].…”

“…Either KGF (recombinant human KGF 1 mg?kg -1 in 1 mL PBS; Amgen, Thousand Oaks, CA, USA) or an equal volume of isotonic saline was injected; the animal was then allowed to recover. An effective dose was established in models of lung injury [14,15].…”

Allogeneic human mesenchymal stem cells for treatment of E. coli endotoxin-induced acute lung injury in the ex vivo perfused human lung

“…5B). Because previous studies demonstrated that KGF increased ␣ENaC expression at the mRNA level (35,36), we tested the effect of MSCs on both trafficking of ENaC subunits to the apical surface using biotinylation and on total cellular protein levels in the cultured alveolar type II cells injured with cytomix. Cytomix reduced both the total cellular level and the apical membrane expression of ␣ENaC by 41% and 50%, respectively, at 24 h in primary cultures of human alveolar epithelial type II cells.…”

Mechanical Ventilation Down-Regulates Surfactant Protein A and Keratinocyte Growth Factor Expression in Premature Rabbits

“…In adult respiratory distress syndrome animal models, the administration of KGF before injurious ventilation has been shown to protect the lung (6,7). In addition to its role as an epithelial cell mitogen, KGF also has been shown to increase the expression of surfactant proteins and improve alveolar fluid clearance (8,9).…”