Understanding the regulation of surfactant gene expression.

Among a number of biochemical and morphological criteria, alveolar type-II epithelial cells are defined by the synthesis of surfactant proteins. These molecules are implicated in numerous human diseases such as neonatal respiratory distress syndrome [1] and possibly acute respiratory distress syndrome (ARDS) [2], where a better understanding could lead to new therapeutic modalities via a targeted induction of surfactant synthesis. The synthesis of surfactant proteins (SPs) is under the control of a variety of potential developmental and hormonal regulators, however, two transcription factors, thyroid transcription factor (TTF)-1 and hepatocyte nuclear factor (HNF)-3, have a crucial role in mediating the expression of SPs [3]. The promoter region of the SP-B gene has been studied extensively [4]. In the human SP-B gene, a region located at the immediate 59 flanking region of the basal promoter TATA box between 80–110 contains two cis-acting elements for TTF-1 and HNF-3 binding [4]. These two elements are important for the specificity and activation of SPs gene expression in the lung. SP-B is a 79-amino acid peptide critical to postnatal respiratory adaptation. SP-B is the only surfactant-associated protein required for postnatal lung function and survival. Complete deficiency of SP-B in mice and humans results in lethal neonatal respiratory distress syndrome and is char-acterised by a virtual absence of lung compliance, highly disorganised lamellar bodies, and greatly diminished levels of SP-C mature peptide [5]. Its expression is developmentally regulated. Although the expression of SP-B is known to be dependent, at least in part, on TTF-1 and HNF-3, other factors such as SP1 and SP3 are also required for its expression. TTF-1 can also regulate SPA and SP-C expression in mammals. Besides TTF-1, human upstream stimulatory factor-1, nuclear factor (NF)-1, and GT-box binding protein also play roles in regulating SPA and/or SP-C expression [3]. TTF-1 also known as Nkx2.1, is a homeodomain-containing transcription factor which plays a role in regulating genes expressed within the thyroid, lung and brain, including thyro-globulin, thyroid peroxidase, Clara cell secretory protein (CCSP), type-I pneumocyte-specific T1 gene and the SPs [6]. Additional studies, including gene-targeting experiments, have clearly shown that expression of TTF-1 is essential for morphogenesis of the thyroid, lung and ventral forebrain, as TTF-1 knockout mice lack these organs. There are three primary domain structures in TTF-1: an N-terminal transactivation domain, a deoxyribonucleic acid (DNA)-binding homeodomain in the middle, and a C-terminal activation domain [7]. The N-terminal domain was shown to bear the …