Tuberculous pleural effusion (TBPE) is a common extrapulmonary tuberculous infection. Residual pleural thickening (RPT) is the most frequent complication associated with TBPE that may impair pulmonary function and causes dyspnea. Previous studies ever demonstrated higher porfibrotic and proinflammatory cytokines in TBPE with RPT than those without. However, the pathogenesis of and the clinically useful biomarkers for RPT in TBPE remain unclear. Metabolic markers in biofluids reflect changes of metabolic fluxes of various organs and cells. Several studies have revealed pleural fluid metabolites as diagnostic biomarkers for malignant pleural effusions. However, there are no studies addressing the metabolic profiling in the development of RPT in TBPE. Central hypothesis is that alteration of pleural fluid metabolites leads to RPT in TBPE and our preliminary metabolomic analysis disclosed 4 significantly altered metabolites, including platelet activating factor (PAF), in TBPE with RPT. Specific aim 1: To analyze the metabolic profiles between TBPE with and without RPT 1.1. Analyze the clinical data, pleural fluid characteristics and chest radiographs among patients with transudative effusion, TBPE without RPT and TBPE with RPT.1.2. Measure the pleural fluid metabolites among patients with transudative effusion, TBPE without RPT and TBPE with RPT by UPLC-QTOF/MS.1.3. Perform pathway analysis of the altered metabolites to find the most relevant metabolic pathways implicated in the pathogenesis of RPT in TBPE.Specific aim 2: To define the role of platelet-activating factor (PAF) in the development of RPT in TBPE2.1. To investigate role of PAF in regulation of epithelial mesenchymal transition (EMT) of PMCs by using PAF receptor expression vector and PAF acetylhydrolase 2 shRNA for gene overexpression2.2. To investigate role of PAF in regulation of thrombin–induced α-smooth muscle actin (SMA) and collagen expression and EMT of PMCs by overexpression of PAF gene2.3. To measure lung volume by CT scans and lung function using the flexiVent system in PAF acetylhydrolase 2 shRNA transfected murine models2.4. To measure the thrombin and endothelin-1 levels in bronchoalveolar and pleural fluids in PAF acetylhydrolase 2 shRNA transfected murine models2.5. To examine the effect of PAF acetylhydrolase 2 shRNA on the EMT and collagen production in murine modelsSpecific aim 3: To define altered pleural fluid metabolites including PAF as a biomarker or potential therapeutic target for the pleural thickening and fibrosis3.1. Correlate the significantly altered pleural fluid metabolites including PAF with clinical data, pleural fluid characteristics, effusion volume and RPT in TBPE patients to find a predictive biomarker.3.2. To survey whether genomic alterations and miRNAs are involved in the regulation of pleural thickening and fibrosis3.3. High throughput screening of the approved drugs and natural products targeting altered pleural fluid metabolites including PAF as potential treatment for pleural thickening and fibrosis
|Effective start/end date||8/1/18 → 7/1/19|
- Pleural effusion
- Tuberculous Pleural Effusions
- Residual pleural thickening
- Platelet-activating factor
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