الفهرس 
List of AbbreviationsOnly 14 pages are availabe for public view
 |  | from | 198 |  |  |
| | | from | 198 | | |
Abstract
Pulmonary fibrosis is one of the most common types of interstitial lung diseases affecting over 5 million individuals worldwide with an average survival time of 3 years. It is a chronic, progressive respiratory disorder characterized by significant swelling and scarring of the alveoli and interstitial tissues of the lung, causing patients’ lungs to stiffen and making breathing increasingly difficult. Its pathogenesis remains incompletely understood, but increasing evidences suggest that alveolar epithelial injury, inflammation, excessive ROS generation and abnormal lesion healing involving excessive extracellular matrix deposition are main events involved in progression of pulmonary fibrosis. To date, lung transplantation is the only effective approach for management of pulmonary fibrosis, which associated with high risks and many possible medical complications. The current study was designed to Investigate the ability of four drugs, targeting different checkpoints in the pathological pathway of pulmonary inflammation and fibrosis; halofuginone (0.2 mg/kg, oral), POTABA (1.1 g/kg, oral), flavocoxid (20 mg/kg, oral) and crocin (20 mg/kg, oral) to protect against lung fibrosis induced by intra-tracheal instillation of 5 mg/kg BLM. Pulmonary fibrosis was induced by intra-tracheal instillation of BLM (5 mg/kg) for 4 weeks. BLM instillation significantly increased lung/body weight index, BALF’s LDH activity, total cell counts and total protein content, lung MDA content with significant decrease in lung GSH content, lung SOD activity, and serum total antioxidant capacity. Noteworthy, lung Nrf2, HO-1, TLR4, IL-10, TNF-α, TGF-β1 content and lung collagen content significantly increased with concomitant impairment of pulmonary architecture, vascular response to KCl, PE and carbacol and tracheal response to carbachol. Daily oral treatment with halofuginone (0.2 mg/kg), POTABA (1.1g/kg), flavocoxid (20 mg/kg) and crocin (20 mg/kg) one week prior and 4 weeks post BLM instillation successfully ameliorated BLM-induced pulmonary damage. All compounds under investigation significantly restored impaired oxidant/antioxidant balance and mitigated BLM-induced alterations in Nrf2, HO-1, TLR4, IL-10. In conclusion; all investigated compounds; halofuginone, POTABA, flavocoxide and crocin confer significant ameliorative influence against BLM-induced pulmonary fibrosis. Combined antioxidant, anti-inflammatory and anti-fibrotic effects are believed to be implicated in the observed efficacy. Modulation of Nrf2 and HO-1 pathways is the main mechanism involved in the observed antioxidant effects. Down-regulation of TLR4, IL-10 expression is the major pathway involved in the observed anti-inflammatory effects and finally, down-regulation of tissue expression of TNF-α and TGF-β1 is the major pathways implicated in the observed anti-fibrotic activities.