الفهرس 
IntroductionOnly 14 pages are availabe for public view
 |  | from | 157 |  |  |
| | | from | 157 | | |
Abstract
Acute lung injury (ALI) is a lung disease characterized by a severe inflammatory process causing diffuse alveolar damage and resulting in severe hypoxemia, poor lung compliance and responsible for significant morbidity and mortality. It is a frequent complication following sepsis in critically ill patients and mainly caused by lipopolysaccharide (LPS). The purpose of the current experimental study was to evaluate the protective effects of protocatechuic acid and molsidomine against LPS-mediated ALI using a murine model, and to underly their possible mechanisms. LPS-induced ALI model was established via administering male Sprague–Dawley rats with LPS (10 mg/kg, I.P.). Protocatechuic acid (50 and 100 mg/kg, P.O.) or molsidomine (1 and 2 mg/kg, I.P.) were given for 3 consecutive days before LPS administration. Twenty four hours after LPS injection, rats were sacrificed and lung/body weight ratio was determined. Bronchoalveolar lavage fluid (BALF) were collected to measure total and differential cell count, total protein content, lactate dehydrogenase (LDH), TNF-α and IL-1β levels. Lung tissues were also collected to assess lung histopathology, oxidative stress parameters, HIF-1α levels, P-AKT/AKT ratio and apoptosis parameters. Pretreatment with protocatechuic acid or molsidomine significantly and dose-dependently protected against LPS-induced ALI. As evidenced by preventing LPS-mediated histopathological changes in lung and abolishing inflammatory cells infiltration, protein content and LDH activity in BALF as well as decreasing lung/body weight ratio. In the meantime, protocatechuic acid or molsidomine reduced the levels of pro-inflammatory cytokines namely, TNF-α and IL-1β. Protocatechuic acid or molsidomine also decreased LPS-induced oxidative stress as revealed by decreased malondialdehyde content, and increased reduced glutathione level and superoxide dismutase activity in lung tissues. In addition, protocatechuic acid or molsidomine decreased the elevated level of pro-apoptotic protein BAX and increased the diminished level of anti-apoptotic protein BCL2, induced by LPS. Importantly, pretreatment with protocatechuic acid or molsidomine prevented the increase in HIF-1α and its upstream activator, AKT, induced by LPS. Conclusion: We found that protocatechuic acid or molsidomine exerted protective effects against acute endotoxemia-associated lung injury through their anti-inflammatory, antioxidative and antiapoptotic properties as well as through suppressing AKT-HIF-1α signaling pathway.