Genes and transcriptional programs regulating alveolar homeostasis

Abstract

Abstract: Lung formation and homeostasis are regulated by transcriptional programs that are precisely influenced by signaling among various cell types. Alveolar formation and function are dependent upon transcription factors and programs directed by TTF‐1, Foxa family members, Stat‐3, β‐catenin, and others. These nuclear factors determine the behavior of cells during lung morphogenesis, and are used later in development to maintain alveolar homeostasis and pulmonary integrity. Gene mutations (deletion studies) in the mouse, have been used to discern the roles and to identify the target genes of these critical nuclear transcription factors. TTF‐1, Foxa2, and β‐catenin play distinct and overlapping roles during the formation of the mammalian lung, and are required at precise developmental periods for commitment of endodermal cell lineages, sacculation, and alveolarization, and for maintenance of lung function and homeostasis in the postnatal period. These master regulatory genes are required for the expression of surfactant proteins, lipids and host defense molecules. Mutations in their target genes (e.g. ABCA3 transporter, SP‐C and SP‐B genes) cause acute and chronic pulmonary diseases in newborns and in older individuals. Mutations in these genes cause interstitial lung disease and acute respiratory failure. In a like manner, disruption of signaling via granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) blocks the expression of PU.1, a member of the Ets transcription factor family of proteins that is required for the regulation of alveolar macrophage differentiation and function. Impairment of GM‐CSF signaling results in accumulation of pulmonary surfactant in the alveolar spaces and underlies the human disorder, pulmonary alveolar proteinosis. It is hoped that the elucidation of mechanisms by which transcription regulates lung function and homeostasis will provide insight into the pathogenesis of chronic and acute pulmonary diseases in humans.