Pulmonary and pleural fibrosis is one of pathological characterized by Mycobacterium tuberculosis (M. tb) infection in the lungs. When the lungs are infected with M. tb, the recruitment of immune cells and fibroblasts leads to granuloma formation and fibrotic scaring in interstitial lung tissue, which in turns causes irreversible loss of pulmonary function and pulmonary failure. Several studies indicated that the fibrotic factors, such as transforming growth factor- (TGF-), were increased in pleural effusion and serum of patient with tuberculosis. The expression of connective tissue growth factor (CTGF), a fibrotic factor, has been reported in lung fibrosis. However, the mechanism of M. tb-induced CTGF expression in human lung fibroblasts is still unclear. Fibrocytes are unique bone marrow-derived mesenchymal progenitor cells found in circulation. Fibrocytes have been shown to play an important role in wound healing following injury and in the generation of pulmonary fibrosis. Previous studies have shown that there is significant increase of circulating fibrocytes in patients with chronic obstructive asthma. However, the role of CTGF in the differentiation of pleural fibroblast and circulating fibrocyte to myofibroblast in patient with tuberculosis is still unknown. Our preliminary data for the first time found that M. tb time-dependently induced CTGF expression in human lung fibroblasts. M. tb-induced CTGF expression was inhibited by actinomycin D (a transcriptional inhibitor) and cycloheximide (a translational inhibitor), suggesting that M. tb-induced CTGF expression is through de novo synthesis. Moreover, we found that M. tb-induced CTGF expression was attenuated by curcumin (an AP-1 inhibitor) and PDTC (a NF-B inhibitor). Therefore, the Central Hypothesis is that M. tb can induce CTGF expression, which in turns cause differentiation of pleural fibroblast and circulating fibrocyte to myofibroblast, and ultimately induce pleural and pulmonary fibrosis. The overall objective of this project is to elucidate the role of CTGF in pulmonary fibrosis in patient with tuberculosis so that effective interventions can be developed to prevent pulmonary fibrosis in tuberculosis. The hypotheses and specific aims are described below: Specific Aim 1 (1st year): To study the role of interaction between transcription factors and coactivators in M. tb-induced CTGF expression in human lung fibroblasts Hypothesis 1: M. tb-induced CTGF expression in lung fibroblasts is regulated by cooperation with transcription factors and coactivators Specific Aim 2 (2nd year): To study the role of mRNA stability in M. tb-induced CTGF expression in human lung fibroblast Hypothesis 2: M. tb increases CTGF mRNA stability to mediate CTGF expression Specific Aim 3 (2nd year): To investigate the role of CTGF in M. tb-induced lung fibroblast differentiation to myofibroblast Hypothesis 3: CTGF mediates M. tb-induced lung fibroblast differentiation to myofibroblast Specific Aim 4 (3rd years): To explore the role of CTGF in pleural and pulmonary fibrosis in patient with tuberculosis Hypothesis 4: CTGF expression is required for the differentiation of pleural fibroblasts and circulating fibrocytes to myofibroblasts in patient with tuberculosis
|Effective start/end date||8/1/13 → 7/31/14|
- connective tissue growth factor (CTGF)
- pulmonary fibrosis
- pleural fibrosis
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