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Transforming Growth Factor-β Signaling across Ages

From Distorted Lung Development to Chronic Obstructive Pulmonary Disease

¹ Department of Medicine, University of Giessen Lung Center, University of Giessen, Giessen, Germany; and ² Comprehensive Pneumology Center, Ludwig Maximilians University, Asklepios Hospital, and Helmholtz Zentrum München, Institute of Lung Biology and Disease, Neuherberg/Munich, Germany

Correspondence and requests for reprints should be addressed to Oliver Eickelberg, M.D., Comprehensive Pneumology Center, Ludwig Maximilians University Munich and Helmholtz Zentrum München, Institute of Lung Biology and Disease (iLBD), Ingolstädter Landstraße 1, 85764 Neuherberg/Munich, Germany. E-mail: oliver.eickelberg{at}helmholtz-muenchen.de

ABSTRACT

The transforming growth factor (TGF)-β superfamily of secreted growth factors consists of more than 40 members, including the TGF-β isoforms themselves, bone morphogenetic proteins, and activins. Most of these factors have been shown to be essential for proper organ development, a process often recapitulated in chronic diseases. Importantly, TGF-β superfamily members are key regulators of extracellular matrix composition and alveolar epithelial cell and fibroblast function in the lung. Both during lung development and disease, TGF-βs therefore control lung homeostasis by providing the structural requirements and functional micromilieu needed for physiological epithelial cell function and proper gas exchange. Prolonged alterations of TGF-β signaling have been shown to result in structural changes in the lung that compromise gas exchange and lung function, as seen in arrested lung development, a feature of bronchopulmonary dysplasia, lung fibrosis, and chronic obstructive pulmonary disease. All these syndromes share a loss of functional alveolar structures, which ultimately leads to a decreased life expectancy. In this review, we cover our current understanding of the impact of TGF-β signaling on chronic lung disease. We focus on distorted TGF-β signaling in bronchopulmonary dysplasia and chronic obstructive pulmonary disease as prototype diseases of the premature and matured lung, respectively, which are both characterized by functional and structural loss of alveolar units.

Key Words: bronchopulmonary dysplasia • chronic obstructive pulmonary disease • emphysema • small airway disease • transforming growth factor-β