Keratinocyte growth factor and the transcription factors C/EBPα, C/EBPδ, and SREBP-1c regulate fatty acid synthesis in alveolar type II cells

The Journal of Clinical Investigation | July 2003 | Volume 112 | Number 2 Introduction Pulmonary surfactant lowers the surface tension at the air/liquid interface in the lung and prevents alveolar instability, small airway closure, and alveolar flooding. Surfactant is composed predominantly of phospholipids, especially phosphatidylcholine and phosphatidylglycerol, and the surfactant proteins (SP-A, SP-B, SP-C, and SP-D). The phospholipid that is most responsible for the low surface tension is dipalmitoylphosphatidylcholine. Although the pathways for fatty acid and phospholipid synthesis in type II cells have been defined previously through metabolic labeling experiments, relatively little is known about the regulation of these pathways (1–5). Understanding the regulation of lipid synthesis is important for the development of new therapeutic strategies to increase endogenous surfactant production. Surfactant deficiency or dysfunction is thought to be important in respiratory deficiency of the newborn, acute lung injury/acute respiratory distress syndrome, diffuse pulmonary fibrosis, and diseases of small airways such as asthma and bronchiolitis. Although treatment with exogenous surfactant is highly effective in respiratory distress syndrome of the newborn and partially effective in acute lung injury/acute respiratory distress syndrome, this form of therapy is expensive, requires intubation, and is not practical in milder forms of disease. If it were possible to stimulate the production of endogenous surfactant, this therapy would likely be beneficial in a variety of diffuse parenchymal diseases or diseases of small airways. A means of stimulating the production of surfactant phospholipids in the mature lung is not known. A major problem for studies on the regulation of lipogenesis in adult type II cells has been the requirement of a culture system that maintains or induces type II cell differentiation. We have recently developed a system that permits differentiation in vitro (6). Rat alveolar cells are plated on a matrix of type I collagen and Matrigel, and the cells are cultured with rat serum and keratinocyte growth factor (KGF, FGF-7). In this system, type II cells maintain relatively high levels of Keratinocyte growth factor and the transcription factors C/EBPα, C/EBPδ, and SREBP-1c regulate fatty acid synthesis in alveolar type II cells