Molecular Pathway Linked to Chronic Lung Diseases

Researchers have traced a molecular pathway that connects different populations of cells in the developing lung that if overexpressed plays a role in lung diseases of adults such as asthma and pulmonary hypertension.

Investigators from the University of Pennsylvania (Philadelphia, USA) used advanced genetic engineering techniques to create both gain-of-function (overexpression) and loss-of-function (null) mouse models in order to study the molecular interaction between lung epithelial cells and airway smooth muscle cells.

The investigators reported in the August 17, 2009, online edition of the Journal of Clinical Investigation that sections of the pathway were unique to each type of cell. The Wnt7b component was exclusively expressed in the lung epithelium where it was important for lung vascular smooth muscle integrity. The Pdgfr component was expressed by the developing airway smooth muscle cells, where it was involved in the direct transcriptional regulation of the ECM (extracellular matrix) protein tenascin C (Tnc).

Genetic loss-of-function studies showed that Wnt7b and beta-catenin were required for expression of Pdgfr-alpha and Pdgfr-beta and proliferation in pulmonary smooth muscle cell precursors. In contrast, gain-of-function studies showed that activation of Wnt signaling increased the expression of both Pdgfr-alpha and Pdgfr-beta as well as the proliferation of smooth muscle cell precursors.

The investigators reported that expression of the components of this molecular pathway was upregulated in a mouse model of asthma and in humans with pulmonary hypertension. Thus, they concluded that, "These data define a Wnt/Tnc/Pdgfr signaling axis that is critical for smooth muscle development and disease progression in the lung.”

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