Use of Transgenic Mouse Models to Understand the Origins of Familial Pulmonary Fibrosis

Abstract

Pulmonary fibrosis is an unremitting degenerative lung disease that has an associated high mortality. The major pathological features include the growth of fibroblasts, emergence of myofibroblasts and their production of extracellular matrix that distorts the peripheral lung tissue and impairs respiratory function. Efforts to pharmacologically reduce inflammation, inhibit fibroblast growth, or matrix synthesis have not been successful in ameliorating disease. Genetic mutations associated with rare hereditary forms of interstitial lung disease (ILD) and idiopathic pulmonary fibrosis (IPF) link definitive causes to this enigmatic group of diseases. The generation of mouse models with similar genetic lesions or deficiencies is providing insight into the mechanisms that lead to fibrosis. Mutations that alter components of pulmonary surfactant or surfactant homeostasis have been associated with specific forms of ILD and/or IPF. This small but growing collection of IPF related surfactant dysfunction mutations implicate respiratory epithelial cell injury as an early event in the molecular pathogenesis and progression of fibrosis. Determining the mechanisms for genetically defined examples of IPF should be informative for investigating the larger segment of IPF where the underlying cause remains obscure.

Surfactant Protein-C in the Maintenance of Lung Integrity and Function

“…Cloned segments of the SP-C gene promoter have been used as probes of alveolar epithelial cell development and to identify transcription factors that determine cell specific expression. These SP-C promoter elements are widely used to alter lung development and model lung disease in transgenic mice [9]. Defects of SP-C expression underlie some forms of human lung disease and mutated or deficient SP-C cause interstitial lung disease (ILD) and idiopathic pulmonary fibrosis (IPF).…”