Alveolar type II epithelial cells are critical for maintaining the gas exchange units of the lung. They produce pulmonary surfactant and restore the alveolar epithelium after injury. Keratinocyte growth factor (KGF) is a known mitogen for type II cells, stimulates type II cell differentiation in vitro, and protects the lung against a variety of injuries. In this proposal, we will examine the effects of KGF on two aspects of type II cell biology: phospholipid biosynthesis and the production of chemokines. KGF greatly stimulates overall phospholipid biosynthesis, and specifically increases synthesis of phosphatidylcholine, disaturated phosphatidylcholine, and phosphatidylglycerol. In the first Specific Aim, we will determine the mechanism by which KGF stimulates fatty acid synthesis in type II cells. Based on studies in adipose tissue and on our preliminary data, we believe the KGF stimulates fatty acid synthesis by activation of a coordinated group of transcription factors that includes C/EBPs, SREBP-lc, and PPARgamma. The effect of KGF on expression and activation of these transcription factors in cultured type II cells will be examined in detail. In the second Specific Aim, we will determine how KGF alters the enzymes involved in phosphatidylcholine and phosphatidylglycerol synthesis. KGF also activates a series of cytokines and growth factors that are probably important in the alveolar response to injury. In the third Specific Aim, we will examine the expression of a defined panel of chemokines produced in response to KGF and compare the effects of KGF to those elicited by other growth factors and cytokines. The data generated in vitro will then be evaluated in vivo. At the end of this proposal, we will have a much better understanding of the role of KGF in type II cell biology. These data will be especially important for the development of strategies for increasing endogenous surfactant production that can be used clinically.
Showing the most recent 10 out of 105 publications
