In vivo effects of TGF-β1 in lung surfactant regulation, lung meachanics amd structure

Transforming growth factor beta 1 (TGF-β1) is a signalling protein with a wide range of biological activities. TGF-β1 is thought to have a pivotal role in fibrogenesis, where TGF-β1 induces myofibroblast migration and increases extracellular matrix synthesis, including collagen. Moreover, it has been described that TGF-β1 is a negative modulator of the regulation of surfactant associated proteins A (SP-A), B (SP-B) and C (SP-C) in vitro. Pulmonary surfactant is a lipid-protein complex that lowers surface tension at the respiratory air-liquid interface, stabilizing the lungs against physical forces tending to collapse alveoli. SP-B and SP-C deficiency has been found in patients suffering from lung diseases and related to potential mechanical stress of the lung epithelium. We have characterized lung surfactant protein composition 1 and 2 weeks after adenoviral mediated gene transfer of active TGF-β1 into lungs. Gene expression of surfactant proteins is down-regulated pointing at deficient transcriptional regulation that might include a deficient activity of TTF-1, during TGF-β1 overexpression. Deficiency on SP-B and SP-C at early stages correlates with high surface tension under dynamic cycling of isolated surfactant in Captive Bubble Surfactometry (CBS). In addition, high surface tension correlates with decreased quasistatic lung compliance and increased collapsibility of distal airspaces. Stereological data demonstrate a correlation between septal wall thickness and quasistatic compliance 2 weeks after gen-transfer. At the ultrastructural level thickening of septal walls, could be attributed to an increase in interstitial cells, formation of dense alveolar oedema and increase in profiles of epithelial type II (AEII) cells. The latter could be also attributed to Epithelial to Mesenchymal Transition (EMT), indicated by down-regulation of epithelial markers associated to up-regulation of mesenchymal molecular markers. We can conclude that in vivo TGF-β1 is a strong negative regulator of surfactant metabolism, originating a mechanical stress that may contribute to EMT at following stages.