ABSTRACT
BACKGROUND: Ethyl pyruvate (EP) was recently identified as an experimental therapeutic agent in a wide variety of model systems for inflammation-mediated tissue and cellular injury. OBJECTIVE: To evaluate the effect of ethyl EP on improving the survival in mice with LPS-induced acute lung injury (ALI). METHODS: ALI was induced by administering lipopolysaccharide (LPS) intratracheally. The mice were treated intraperitoneally (i.p.) with 100, 50 and 10 mg/kg EP immediately before intratracheal instillation of LPS, and 100 mg/kg EP was administered 0, 12, 24 and 48 hours after induction of ALI. The mortality rate was recorded and analyzed by the Kaplan-Meier method. Serum tumor necrosis factor (TNF)-alpha, interleukin (IL) -6 and IL-1 beta were measured in bronchial alveolar lavage fluid using an enzyme-linked immunosorbent assay. High-mobility group box 1 levels were measured by Western immunoblotting. RESULTS: Treatment with EP significantly inhibited the release of HMGB1, TNF-alpha, IL-6 and IL-1beta into bronchoalveolar lavage (BAL) fluids of ALI mice, and reduced the permeability index of the injured lung. High EP doses reduced the mortality from ALI and the permeability index (100 mg/kg and 50 mg/kg EP versus control; P < 0.0001). Early administration of high-dose EP significantly increased survival rate (0, 12 and 24 h versus control; P < 0.0001, P < 0.0001 and P = 0.01 respectively by log-rank test). There was no survival advantage when EP was initiated at 48 h. CONCLUSION: Ethyl pyruvate improves survival and reduces the lung permeability index in mice with LPS-induced ALI.
Subject(s)
Acute Lung Injury/drug therapy , Lung/drug effects , Pyruvates/pharmacology , Respiratory System Agents/pharmacology , Acute Lung Injury/chemically induced , Acute Lung Injury/immunology , Animals , Blotting, Western , Bronchoalveolar Lavage Fluid/immunology , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Administration Schedule , Enzyme-Linked Immunosorbent Assay , HMGB1 Protein/metabolism , Inflammation Mediators/metabolism , Injections, Intraperitoneal , Interleukin-1beta/metabolism , Interleukin-6/metabolism , Lipopolysaccharides , Lung/immunology , Male , Mice , Mice, Inbred BALB C , Permeability , Pyruvates/administration & dosage , Respiratory System Agents/administration & dosage , Severity of Illness Index , Time Factors , Tumor Necrosis Factor-alpha/metabolismABSTRACT
AIM: The role of high mobility group box protein 1 (HMGB1) in non-small cell lung cancer (NSCLC) is unknown. We investigated the contributions of HMGB1 in NSCLC, and analyze the correlation between HMGB1 and clinicopathologic outcomes. PATIENTS AND METHODS: A total of 145 patients with diagnosed NSCLC, and 77 patients with diagnosed chronic obstructive pulmonary disease (COPD) (51 chronic bronchitis and 26 obstructive pulmonary emphysema), and 49 healthy volunteers were enrolled from January 2005 through July 2008. HMGB1 levels were analyzed by Western blot analysis. RESULTS: The mean value of serum HMGB1 levels in 145 patients with lung cancer was 76.1+/-37.0ng/ml and was significantly higher than those in 77 COPD patients (39.8+/-10.8ng/ml), and 49 healthy control (7.7+/-6.1ng/ml, p<0.0001, respectively); The serum HMGB1 levels were 30.2+/-5.9ng/ml, 60.9+/-22.5ng/ml, 99.0+/-23.1ng/ml and 133.4+/-18.9ng/ml in patients with NSCLC of TNM stage I, II, III, and IV. There were significant differences among four groups (p<0.0001). Moreover, the significant positive correlation between the levels of serum HMGB1 and the size of tumor (r=0.799, p<0.001); The serum HMGB1 levels were 57.2+/-28.8ng/ml in patients with NSCLC before operation, and 26.5+/-14.7ng/ml one month after operation (p<0.0001). CONCLUSIONS: Our study suggests that HMGB1 may be a useful clinical marker for evaluating the NSCLC progression and is of potential prognostic value.
