Inhibition of TGF-β Signaling and Decreased Apoptosis in IUGR-Associated Lung Disease in RatsReport as inadecuate

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Intrauterine growth restriction is associated with impaired lung function in adulthood. It is unknown whether such impairment of lung function is linked to the transforming growth factor TGF-β system in the lung. Therefore, we investigated the effects of IUGR on lung function, expression of extracellular matrix ECM components and TGF-β signaling in rats. IUGR was induced in rats by isocaloric protein restriction during gestation. Lung function was assessed with direct plethysmography at postnatal day P 70. Pulmonary activity of the TGF-β system was determined at P1 and P70. TGF-β signaling was blocked in vitro using adenovirus-delivered Smad7. At P70, respiratory airway compliance was significantly impaired after IUGR. These changes were accompanied by decreased expression of TGF-β1 at P1 and P70 and a consistently dampened phosphorylation of Smad2 and Smad3. Furthermore, the mRNA expression levels of inhibitors of TGF-β signaling Smad7 and Smurf2 were reduced, and the expression of TGF-β-regulated ECM components e.g. collagen I was decreased in the lungs of IUGR animals at P1; whereas elastin and tenascin N expression was significantly upregulated. In vitro inhibition of TGF-β signaling in NIH-3T3, MLE 12 and endothelial cells by adenovirus-delivered Smad7 demonstrated a direct effect on the expression of ECM components. Taken together, these data demonstrate a significant impact of IUGR on lung development and function and suggest that attenuated TGF-β signaling may contribute to the pathological processes of IUGR-associated lung disease.

Author: Miguel Angel Alejandre Alcázar , Rory E. Morty, Lisa Lendzian, Christina Vohlen, Iris Oestreicher, Christian Plank, Holm Schneid



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