Studies On The Signal Transduction Of TGFβ₁ In Radiation Pulmonary Injury

Objective: Much attention has been paid to the abnormalities of signal transduction underlying diseases. The signal transduction mechanism of radiation pulmonary injury (RPI) remains unknown. TGF@1 is a master switch and therapeutic target of RPI. Smad pathway is the key and specific signal transducer downstream TGFpi. Therefore the studies on the signal transduction of TGFpi in RPI might get a new insight into the pathogenesis of this disease and help to find new potential therapeutic measures.Materials and methods: Y ray, TGFp@1 SB203580 or WP631 were used to treat Wistarrats or RLFs in the experiments in vivo and in vitro. The changes of the Smad pathway,pulmonary histopathology and cellular biological behaviors were determined by immunoblotting, immunohistochemistry, coimmunoprecipitation, EMSA, RT-PCR, pathological methods, MTT and FACS.Results: (1) After irradiation, the pathological changes of lung undergone interstitial pneumonia, cells proliferation and local fibrosis. (2) The localization of Smad3, 4 and 1 proteins were in the cytoplasma of macrophages, alveolar epithelium and fibroblasts, and their expressional level became higher from Iw to 3m. Moreover, Smad3 and 4 translocated to nucleus on 1d and 3m. (3) The expressions of PAI-1, a -SMA and PCNA, which were products of the target genes of TGF @ or the symbols of its effect, were increased with the development of RPI. (4) Y ray irradiation could stimulate the proliferation, transformation, type I collagen and PAI-1 expressions of RLFs. At the same time, the formation and nucleus translocation of Smad3-4 complex were enhanced. TGF@1 could further augment the expressions of type I collagen and PAI-1 in irradiated RLFs and enhance the formation and nucleus translocation of the complex of Smad3-4. Moreover, both Y ray and TGFpi could facilitate the activation oftranscription factors Smad3-4, SP1 and AP1. (5) After irradiated by Y ray and stimulated by TGFpi, RLFs which have been pretreated with SB203580 or WP631 expressed less type I collagen and P-Smad3, and also the activation of transcription factors Smad3-4, SP1 and AP1 in RLFs were inhibited.Conclusions: (1) TGFp-Smad signal pathway is activated in the course of RPI, which indicated that Smad signal pathway play an important role in the pathogenesis of RPI, it might be a key pathway of TGFp-mediated RPI. (2) v ray can facilitate the activation of TGFp-Smad signal pathway in RLFs, and that the activation of this pathway play a role in the proliferation, transformation and type I collagen expressions of irradiated RLFs. TGF@1 can enhance the effects of y ray and stimulate the activation of Smad pathway further. (3) By blocking the signal transduction of TGFp-Smad pathway, SB203580 and WP631 can abrogate the proliferation and type 1 collagen expressions of RLFs caused by TGF@1 and/or v ray. So these two inhibitors might ameliorate RPI.