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Mechanisms of Lung Development

Contribution to Adult Lung Disease and Relevance to Chronic Obstructive Pulmonary Disease

¹ Developmental Biology and Regenerative Medicine Program, Children's Hospital Los Angeles, University of Southern California, Los Angeles, California; ² Pulmonary Center, Department of Medicine, and ³ Department of Pathology, Boston University School of Medicine, Boston, Massachusetts

Correspondence and requests for reprints should be addressed to Wellington V. Cardoso, M.D., Ph.D., Pulmonary Center, Boston University School of Medicine, 72 East Concord Street, R-304 Boston, MA 02118. E-mail: wcardoso{at}bu.edu

ABSTRACT

Chronic obstructive pulmonary disease (COPD) results in major remodeling of the distal airspaces and changes in the differentiation profile of the airway epithelium. The cellular and molecular mechanisms involved in initiation and progression of this disease are little understood. Although environmental factors, including cigarette smoke, have been directly implicated in the pathogenesis of COPD, genetic risk factors also appear to play a fundamental role in the individual's susceptibility to this disease. Lung development depends on precise coordination of signals, such as fibroblast growth factors (Fgf), Sonic Hedgehog (Shh), retinoic acid, Notch, and Tgf β. Dramatic changes in the pattern of branching and differentiation of the lung epithelium results from disruption of these signals in genetically altered mice. Recent studies, including whole-genome expression and genome-wide association analyses, suggest that some molecular regulators originally described in developmental processes may be altered in patients with COPD. Whether disturbances in the molecular and cellular events mediated by these genes during development participate in the initiation or exacerbation of COPD, needs further investigation. The role of selected pathways, including Sonic hedgehog, Notch, retinoid, and Tgf β in the developing lung and the potential association with COPD are discussed.

Key Words: lung development • COPD • emphysema • morphogenesis • lung differentiation