Overexpression of transforming growth factor- 1 in fetal monkey lung results in prenatal pulmonary fibrosis

Abstract

Altered transforming growth factor (TGF)-b expression levels have been linked to a variety of human respiratory diseases, including bronchopulmonary dysplasia and pulmonary fibrosis. However, a causative role for aberrant TGF-b in neonatal lung diseases has not been defined in primates.Exogenous and transient TGF-b1 overexpression in fetal monkey lung was achieved by transabdominal ultrasound-guided fetal intrapulmonary injection of adenoviral vector expressing TGF-b1 at the second or third trimester of pregnancy. The lungs were then harvested near term, and fixed for histology and immunohistochemistry.Lung hypoplasia was observed where TGF-b1 was overexpressed during the second trimester. The most clearly marked phenotype consisted of severe pulmonary and pleural fibrosis, which was independent of the gestational time point when TGF-b1 was overexpressed. Increased cell proliferation, particularly in a-smooth muscle actin-positive myofibroblasts, was detected within the fibrotic foci. But epithelium to mesenchyme transdifferentiation was not detected. Massive collagen fibres were deposited on the inner and outer sides of the pleural membrane, with an intact elastin layer in the middle. This induced fibrotic pathology persisted even after adenoviralmediated TGF-b1 overexpression was no longer evident.Therefore, overexpression of TGF-b1 within developing fetal monkey lung results in severe and progressive fibrosis in lung parenchyma and pleural membrane, in addition to pulmonary hypoplasia.

Increased TGF-β: a drawback of tracheal occlusion in human and experimental congenital diaphragmatic hernia?

“…Correlations between changes in TGF-␤ expression, downstream targets and hysteresivity in the current study do not imply causality, but potentially suggest that upregulated TGF-␤ after TO might favor extracellular matrix remodeling. This assumption is supported by the observation of pulmonary fibrosis rather than hypoplasia in fetal monkeys subject to TGF-␤1 overexpression during the saccular stage (54).…”

Prenatal inflammation exacerbates hyperoxia-induced functional and structural changes in adult mice

“…In addition to its role in matrix remodeling and fibrosis, TGF-␤ plays a key role in alveolar development and maintenance of alveolar structure (1). Developmental overexpression of TGF-␤ results in impaired alveolarization and Smad-dependent interstitial fibrosis in monkeys (51) and rats (20,21). Increases in IL-1␤, TGF-␤, and collagen I mRNA levels were persistent after birth in hyperoxia-exposed mice.…”

Glucocorticoids Recruit Tgfbr3 and Smad1 to Shift Transforming Growth Factor-β Signaling from the Tgfbr1/Smad2/3 Axis to the Acvrl1/Smad1 Axis in Lung Fibroblasts

“…In lung fibrosis, the pro-fibrotic activities of TGF-␤ drive the production of the fibrotic mediator connective tissue growth factor and plasminogen activator inhibitor-1 (encoded by the SERPINE1 gene in humans) by lung fibroblasts and promote fibroblast to pathological myofibroblast differentiation (16). TGF-␤ also drives aberrant production of extracellular matrix molecules such pro-collagen, which limit alveolar repair and proper alveolar development in diseases such as chronic obstructive pulmonary disease (17)(18)(19), lung fibrosis (17,20), acute respiratory distress syndrome (21), and bronchopulmonary dysplasia (22,23). In general, matrix production relies on TGF-␤ signaling by the type I TGF-␤ receptor Tgfbr1 (also called , in complex with the type II receptor (Tgfbr2), which together recruit the downstream signaling molecules Smad2 and Smad3 to transduce signals to the nucleus, regulating the expression of TGF-␤-responsive genes in the so-called "Tgfbr1/Smad2/3 axis" (24 -26).…”