Effects Of TGF-β1, TβRⅠand TβRⅡ On Type Ⅰ, Ⅲ, Ⅳ, And Ⅴ Collagen Deposition In Bleomycin-induced Pulmonary Fibrosis

Interstitial lung fibrosis attracts more and more attentions in recent years due to increasing occurrence, known little about pathogenesis and poor therapy. This disorder is characterized by an inflammation of alveolar walls/spaces, terminal bronchioles and connective tissue around them at early lesion, with destruction of alveolar wall and deposition of extracellular matrix, resulting in loss of lung function. Most of the patients die from respiratory failure from progressive pulmonary fibrosis. In the spectrum of pulmonary fibrotic diseases, majority is idiopathic pulmonary fibrosis, which is the proto -type of the former diseases. Its etiology is unclear, with an average duration of about 4 years and a prognosis similar to lung cancer. Current therapeutic agents, if there is any effect on improving lung function, are limited by severe side effects. It is still a challenge in respiratory society looking for an efficient therapy for the disorder.Bleomyin, an anti - neoplastic agent, is well known to induce- dose - dependent lung injury and pulmonary fibrosis in both humans and animals. Bleomycin induced pulmonary fibrosis in rodent models has been investigated in many studies and the pathophysiologic findings resemble those in human pulmonary fibrosis.TGF - βS (transforming growth factor βs ) , considered as one of the most important cytokines involving in fibrosis, regulate cell growth and extraccellular matrix accumulation by autocrine/paracrine pathways. TGF - βs may stimulate the synthesis and accumulation of extracellular matrix, including upregulation of transcript, translation and post translation process, stimulating the production of matrix protein and also decrease matrix degradation via inhibiting proteases andinducing their inhibitors. Meanwhile, TGF - βS can induce production of various cytokines such as PDGF (platelet derived growth factor) and FGF (fibro-blast growth factor) , exert effects on proliferation of fibroblasts and collagen synthesis with them together. There are 3 isoforms of TGF - βS in mammals, namely, TGF - β1, TGF - β2 and TGF - β3, with almost identical biological functions. There has been extensive study on TGF - β1, which is believed to play a pivotal role in liver cirrhosis, glomerulonephritis and skin scar formation.TGF - βS exerts a variety of biological effects through binding to specific receptors after being activated in vivo. There are three types of receptors, TpRI, TpRII and TpRHI. TpRI and TpRII which containing serine/threonine kinase domains are more important for signal transduction. Once TGF - βS bind to TpRII, it results in the recruitment of TpRI to form a heteromeric complex as TpRII-TGF - βs -TpRI. Activated TpRII transphosphorylates the kinase of TpRI, which then propagates the signal to downstream intracellular substrates, Smads. Then the signal transduction into nucleus is finished. TpRHI is responsible for presenting TGF - βS to TpRII to regulate TGF - βS binding its receptors.Excessive extracellular matrix deposition directly leads to pulmonary ventilation and gas exchange disorders in pulmonary fibrosis. Collagen is the major protein found in the extracellular matrix. There are four types of collagen mainly locating in lung tissues, that is, type I, III, IV, and V collagen. In vitro, investigations indicate that TGF - pi promotes the synthesis of types I, III, IV and V collagen in alveolar epithelium, vascular smooth muscle cell and fibro-blast. There has been few studies focusing on the effects of TGF - pi cooperation with its receptors on pulmonary fibrogenesis and massive localization of collagen in pulmonary interstitium.Male Wistar rats were used in the present study. Bleomycin at doses of 0.5img/kg body weight was reconstituted in sterile 75 mM NaCL solution were instilled intratracheally into rats. Control animals received the same amounting sterile 75 mM NaCl. Five rats from both groups were sacrificed at days 1,3,7, 14, and 28 post bleomycin administration. Lungs tissues, free of blood, werefixed in fo...