Abstract
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.
Highlights
The term fetal programming reflects the assumption that a temporary environmental influence during intrauterine development may lead to permanent alterations of physiological processes later in life [1], [2], [3]
These data demonstrate a significant impact of intrauterine growth restriction (IUGR) on lung development and function and suggest that attenuated transforming growth factor (TGF)-b signaling may contribute to the pathological processes of IUGR-associated lung disease
Dynamic lung compliance is a dimension for the lung scaffold and extracellular matrix (ECM), and the pulmonary ability to distend in response to pressure
Summary
The term fetal programming reflects the assumption that a temporary environmental influence during intrauterine development may lead to permanent alterations of physiological processes later in life [1], [2], [3]. Intrauterine undernourishment can represent such an environmental factor, leading to intrauterine growth restriction (IUGR) and, in most cases, to low birth weight (LBW). Disturbed intrauterine growth may induce changes in lung structure, which predispose lungs to later disease. Intrauterine protein restriction has been shown to be a reliable animal model of IUGR [13], [14], and several animal studies addressing structural changes of the pulmonary system have demonstrated reduced lung function following IUGR [15], [16], [17]
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