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Lung Development and Adult Lung Diseases^*

^* From the Developmental Biology Program, Saban Research Institute, Childrens Hospital Los Angeles, Keck School of Medicine and School of Dentistry, University of Southern California, Los Angeles, CA.

Correspondence to: David Warburton, DSc, MD, Developmental Biology Program, Saban Research Institute, Children’s Hospital Los Angeles, 4650 Sunset Blvd MS35, Los Angeles, CA 90027; e-mail: DWarburton{at}chla.usc.edu

Abstract

Adult respiratory diseases are caused by many factors, including genetic-environmental interaction. Genetic abnormalities can impact early fetal lung development, postnatal lung maturation, as well as adult lung injury and repair. Studies suggest that abnormally developed lung structure and function may contribute as a susceptibility factor for several adult lung diseases. This review focuses on the relationship between lung development and pathogenesis of several lung diseases including COPD, cystic fibrosis (CF), and asthma. COPD with emphysema has been considered to be an accelerated involutional disease of aging smokers. However, since only a proportion (approximately 15%) of smokers get COPD with emphysema, clearly genetic susceptibility must play a significant part in determining both the age of onset and the rapidity of decline in lung function. In mice, interference with key genes either by null mutation, hypomorphism, or gain or loss of function results in phenotypes comprising either neonatal lethal respiratory distress if the structural effect is severe, or reduced alveolarization and/or early onset emphysema if the effect is milder. Reported susceptibility candidate genes are therefore discussed in some detail, including elastin, lysyl oxidase, fibrillin, the transforming growth factor-ß-Smad3 pathway, as well as extracellular matrix proteases. In the case of CF, the Cftr gene has been shown to regulate fetal lung epithelial cell differentiation and maturation. Subtle abnormalities of lung structure and function are found in clinically asymptomatic CF infants. Finally, airway remodeling due to chronic inflammation is important in infants who later acquire asthma.

Key Words: adult lung disease • asthma • COPD • cystic fibrosis • genetic susceptibility • lung development