Intratracheal instillation of keratinocyte growth factor decreases hyperoxia-induced mortality in rats.

Abstract

Alveolar type II cell proliferation occurs after many forms of lung injury and is thought to play a critical role in alveolar epithelial repair. Keratinocyte growth factor/fibroblast growth factor 7 (KGF) has been shown to promote alveolar type II cell growth in primary culture and alveolar epithelial hyperplasia in vivo. In this study, we used immunohistochemical analysis to determine the intrapulmonary distribution and cellular localization of recombinant human KGF (rhKGF) instilled into the trachea of rats. 6 h after administration, immunoreactive KGF was observed within the lung parenchyma and along alveolar epithelial cell membranes. By 18-24 h, KGF was detected intracellularly in alveolar epithelial cells and intraalveolar macrophages. Immunoreactive KGF was not demonstrable 48 h after delivery or in lung sections from PBS-treated animals. Intratracheal instillation of 5 mg/kg rhKGF stimulated a marked, timedependent increase in the alveolar type II cell specific labeling index to a maximum level of 33±3% 48 h after rhKGF administration compared with 1.3+0.3% after PBS instillation. In addition, this increase in type II cell proliferation in vivo was documented by flow cytometric analysis of isolated type II cells which revealed a nearly fivefold increase in the proportion of cells traversing through the S and G2/ M phases of the cell cycle. To test the hypothesis that KGFs effects on type II cells in vivo might affect the response to lung injury, rats were treated with rhKGF and exposed to hyperoxia. Animals that received 1 or 5 mg/kg rhKGF exhibited dramatically reduced mortality (P < 0.001, for both doses). Survival for animals treated with 0.1 mg/kg rhKGF was not significantly different from either untreated rats or animals treated with heat-denatured rhKGF. The lungs of rhKGF-treated animals that survived hyperoxia exposure had minimal hemorrhage and no exudate within the intraalveolar space. These experiments established that intratracheal administration of rhKGF stimulated alveolar type II cell proliferation in vivo and reduced hyperoxia-

Biomimetic Delivery of Keratinocyte Growth Factor upon Cellular Demand for Accelerated Wound Healing in Vitro and in Vivo

“…In contrast, the number of cells in control samples decreased throughout time likely due to cell death. In agreement with previous studies, [15][16][17][18][19][20][21] these results suggest that in addition to promoting proliferation, KGF, P-KGF, and PL-P-KGF may also promote cell survival.…”

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

“…We were particularly interested in KGF because of work from our group as well as other investigators who have reported that KGF can reduce lung injury in small animal models of pulmonary edema. Recombinant KGF pretreatment reduced mortality following intra-tracheal instillation of hydrochloric acid (37), bleomycin (38), hyperoxia (39) and Pseudomonas aeruginosa (40). In models of acute permeability edema such as ␣-naphthylthiourea (41), P. aeruginosa (40) or ventilator-induced lung injury (42), KGF reduced lung edema and bronchoalveolar lavage protein levels.…”

Mitogenic stimulation accelerates influenza-induced mortality by increasing susceptibility of alveolar type II cells to infection

“…1 repair, and protect the lung from a variety of infectious and noninfectious insults (25)(26)(27)(28)(29)(30)(31). Our initial hypothesis in this study was that KGF administration would increase pulmonary collectin levels in the airspace and enhance the survival of mice challenged with IAV.…”