Effect of Ibuprofen on the Pulmonary Renin-Angiotensin System in the Rat Model of LPS-Induced Acute Lung Injury
Project no. 25225 · Status: Kapanmış (Yayın bekleniyor) · 2022
Summary
<p>ARDS occurs in ~10% of all patients in intensive care units and in ~23% of mechanically ventilated patients in intensive care units. According to the Berlin definition: Respiratory symptoms must have started within one week of a known clinical injury or the patient must have new or worsening symptoms in the previous week. Bilateral opacities must be present on direct radiography or computed tomography (CT) scan and cannot be explained by pleural effusion, lobar collapse, lung collapse or pulmonary nodules. The definition of Acute Lung Injury (ALI) is used synonymously with ARDS in some studies and corresponds to mild/moderate ARDS in some classifications.</p><p>Lipopolysaccharide (LPS) is an important component of the cell wall of gram-negative bacteria. It is a glycolipid in the outer membrane of gram-negative bacteria consisting of a polar lipid head group (lipid A) and a chain of repetitive disaccharides. When administered to humans and animals, LPS induces important components of microvascular lung injury such as leukocyte accumulation in lung tissue, pulmonary edema, inflammation of lung tissue and mortality. It is an important cause of direct (pneumonia, etc.) and indirect lung injury (sepsis, etc.). Acute lung injury can be induced in rats by intranasal, intratracheal, intraperitoneal or intravenous administration of LPS or by the LPS two-hit method.</p><p>Ibuprofen is the first member of the propionic acid derivatives. It belongs to the Nonsteroidal Anti-inflammatory Drugs (NSAIDs) group. It is one of the most widely used analgesic, antipyretic, anti-inflammatory over-the-counter (OTC) drugs. The half-life of the drug is approximately 2 hours. In oral administration, peak serum concentrations are reached after 1-2 hours. It is a nonselective inhibitor of Cyclooxygenase-1 (COX-1) and Cyclooxygenase-2 (COX-2). As a result of a study, ibuprofen's effect on ACE2 cardiac levels and the fact that ACE2 is also the SARS-CoV-2 viral entry receptor raised questions about the use of ibuprofen in COVID-19 infection. In addition, the effects of NSAIDs on pulmonary RAS axes (ACE-AngII-AT1R and ACE2-Ang-(1-7)-Mas) have not been sufficiently elucidated.</p><p>In our study, rats were divided into 4 groups: Control group (7 days saline by oral gavage and 7th day i.p. saline, n:8), Ibuprofen group (7 days 40 mg/kg ibuprofen by oral gavage and 7th day i.p. saline on day 7, n:8), LPS group (saline by oral gavage for 7 days and 10 mg/kg LPS i.p. on day 7th, n:9), LPS+Ibuprofen group (40 mg/kg ibuprofen by oral gavage for 7 days and 10 mg/kg LPS i.p. on day 7th, n:9). The thoracic cavity of the animals was surgically opened at the 8th hour following intraperitoneal saline or LPS administration. Intracardiac blood sampling and lung tissue samples were obtained. Blood samples were analyzed for WBC, NEU, LYM, MONO, EOS, BASO, PLT, RBC, Hb and HTC parameters. ACE, ACE2, Ang II, Ang (1-7), Mas and IL1 beta were analyzed in lung homogenates. In addition, histopathologic and immunochemical staining of lung tissue was evaluated. Lung wet/dry weight test was performed.</p><p>In our study, ibuprofen administered to healthy rats at a dose of 40 mg/kg for 7 days decreased the levels of ACE 2, Ang II and Ang (1-7) in lung homogenates without changing the Mas receptor level, and also decreased the level of IL-1β, an important inflammatory mediator, but did not cause any histopathological changes in the lung tissue. LPS administration to rats at a dose of 10 mg/kg increased the wet/dry weight of the lung after 8 hours, thus causing pulmonary edema. This macroscopic finding was confirmed microscopically by histopathologic examination of the lung which showed parenchymal inflammation, interalveolar thickening, perivascular/interstitial edema and a significant increase in alveolar wall thickness; neutrophil infiltration in the alveolar spaces and interstitial space and the presence of debris materials in the air spaces. Ibuprofen administration markedly reduced LPS-induced pulmonary edema and lung injury scoring, but did not completely restore it to normal levels. This effect of ibuprofen was mediated by its suppression of COX2 and NFkappaB protein levels, which were increased in the lung injury model.</p><p>LPS administration systemically caused an increase in NEU count in rats, as well as lymphopenia and thrombocytopenia, whereas ibuprofen pretreatment did not alter these hemogram parameters. LPS administration did not cause any changes on ACE/AngII/AT1-R and ACE2/Ang(1-7)/Mas-R axis in lung tissue and ibuprofen treatment had no significant effect on these axes in the LPS-induced lung injury model. In conclusion, while ibuprofen reduces the levels of ACE 2, Ang II and Ang (1-7) in healthy rats; there was no significant effect on the RAS axis in LPS-administered rats.</p>