Does leflunomide attenuate the sepsis-induced acute lung injury?

Abstract

The organ that is affected first and most severely in intraabdominal sepsis is the lung. Oxygen radicals and active neutrophils in the lung are important sources for severe pulmonary inflammation leading to acute lung injury (ALI)/acute respiratory distress syndrome. The aim of this study was to investigate the effects of leflunomide, an immunomodulatory agent, on oxidant/antioxidant status with nitric oxide (NO) level and myeloperoxidase (MPO) activity in rats with sepsis-induced ALI. Fifty male Wistar albino rats were divided into five groups: control, sham, sepsis, leflunomide (10 mg/kg, intragastrically for two doses with an 8 h interval prior to the experiment) and sepsis + leflunomide. After the animals were anesthetized with ketamine and xylazine, the abdominal cavity was opened and ligated just below the ileocaecal valve with 3-0 silk. The antimesentric surface of the cecum was perforated and the cecum was gently compressed until fecal matter was extruded to induce sepsis. None of the rats received antibiotics during the experimental procedures. The experiment was ended 24 h after cecal ligation puncture (CLP) with the cervical dislocation under anesthesia. The lung tissues were removed for analysis of biochemical parameters and light microscopic investigation. The lung superoxide dismutase (SOD), catalase and glutathione peroxidase activities were decreased in the sepsis group as compared to the group control, sham, leflunomide and sepsis + leflunomide (P < 0.05), and SOD activity were significantly higher in group sepsis + leflunomide than sham, control, leflunomide and sepsis group (P < 0.05). The lung MPO, malondialdehyde (MDA), protein carbonyl and NO levels were higher in the sepsis group when compared to group control, sham, leflunomide and sepsis + leflunomide (P < 0.05), and MPO, MDA and NO levels were higher in the sepsis + leflunomide group than in the sham, control and leflunomide group (P < 0.05). The light microscopic evaluation showed that pulmonary architecture was preserved, and infiltration of neutrophil and edema decreased in sepsis + leflunomide group. The grade of alveolar damage was significantly decreased in sepsis + leflunomide group in comparison with sepsis group (P < 0.05). Our findings suggested that leflunomide attenuated the lung injury after CLP-induced sepsis by inhibition of neutrophils accumulation and increasing endogenous antioxidant capacity.

Targeting Neutrophils to Prevent Malaria-Associated Acute Lung Injury/Acute Respiratory Distress Syndrome in Mice

“…In other models of lung injury, it has been shown that treatment with immunoregulatory drugs decreases the production of ROS and MPO [36,37]. We hypothesize that the same effect would occur in PbA-induced ALI/ARDS, predicting that without ROS and MPO, NET formation would not occur; however, this remains to be demonstrated.…”

Protective Effects of Leflunomide on Intestinal Ischemia-Reperfusion Injury

“…The leflunomide treatment also reversed this high SOD activity. Ozturk et al [34] demonstrated that leflunomide treatment against a sepsis model in rats reversed the MDA level and MPO activities in lung tissue. They found that sepsis caused the decrease in antioxidant enzyme activities, including CAT, GSH-Px and SOD.…”

“…CAT and GSH-Px are two major endogen antioxidant enzymes that detoxify hydrogen peroxide to water. However, SOD catalyzes the specific reaction that yields hydrogen peroxide, one of the major ROS [34]. Overexpression of SOD results in increased dismutation of superoxide anion to hydrogen peroxide.…”

“…Leflunomide is also one of the possible agents that can affect both the inflammatory process and free radical production together with its anti-inflammatory and antioxidant effects. Previous studies demonstrated that leflunomide had strong anti-inflammatory and immunoregulator effects and had therapeutic actions on experimental acute and chronic disease [32][33][34].…”

Ozone Therapy and Hyperbaric Oxygen Treatment in Lung Injury in Septic Rats

“…Systemic elevations in the levels of proinflammatory cytokines such as tumor necrosis factor (TNF-α) and several interleukins (i.e., IL-1, IL-6 and IL-10) play a chief role within this phenomenon 4. The lung is the organ which is affected initially, and sepsis leads to severe injury in lung tissue 5. It has been shown that pericytes in lung tissue produce proinflammatory cytokines in response to lipopolysaccharide (LPS) 6.…”