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The aim of this study was to investigate genetic effects on the pathogenesis of chronic obstructive pulmonary disease (COPD). The study was conducted as a prospective case-control study in a medical center in southern Taiwan. The patient group consisted of 145 male patients with smoking-related COPD and a control group of 139 resistant smokers from July 2004 to September 2009. We compared allele and genotype frequencies of three tag single nucleotide polymorphisms (SNP) of the TNF-α gene promoter region at -308, -863, and -1031 in all subjects. We also analyzed the influence of each genetic variant on pulmonary function parameters, body mass index (BMI), serum TNF-α levels, and outcomes among heavy smokers with or without COPD. COPD patients had a significantly lower A allele frequency (9.7 vs. 15.1%, OR = 0.6, p = 0.048, false discovery rate q = 0.144) and a significantly lower A carrier genotype frequency (19.3 vs. 30.2%, OR = 0.52, p = 0.042, q = 0.135) than resistant smokers. The--863 CA genotype was associated with a better [FEV.sub.1]/FVC ratio (79 vs. 71.5%, p = 0.034), and higher BMI (24.9 vs. 23.6 kg/[m.sup.2], p = 0.048). In addition, COPD patients with the -1031 C carrier genotype had higher serum TNF-α levels (20.9 vs. 16.2 pg/ml, p = 0.01). BMI (hazard ratio = 0.84, 95% CI = 0.74-0.96, p = 0.008) was the only independent predictor for mortality. The TNF-α -863 A allele may confer a degree of resistance to the susceptibility to and muscle wasting of COPD among heavy smokers. Keywords TNF-α * Genetic polymorphism * COPD * Pulmonary function parameter, Introduction Chronic obstructive pulmonary disease (COPD) is a chronic systemic inflammatory disease characterized by progressive airflow obstruction. Increased concentrations of tumor necrosis factor (TNF)-α have been found in induced sputum, [...]

Lipopolysaccharide (LPS) induces acute lung injury (ALI) via Toll-like receptor 4 (TLR4)-mediated MAPK activation. The lipid A fraction of LPS is considered to be the active moiety, but whether the lipid A-TLR4 interaction accounts completely for ALI-associated MAPK activation in vivo has not been determined. The lipid A fraction of LPS induces a discrete MAPK activation pattern in murine ALI. Mice (C57BL/6J, C3H/HeJ) were treated with intratracheal instillations of purified lipid A or LPS (10, 30, and 100 [micro]g per mouse) or vehicle. ALI was assessed by histology. Chromogenic myeloperoxidase (MPO) activity was measured in lung homogenates. MAPK expression was quantified by immunoblotting. In vitro ERK inhibitor studies using thioglycollate-elicited macrophages were also performed. MPO increased in a dose- and time-responsive fashion. Notably, MPO was 2.4-fold greater after lipid A compared with LPS and vehicle at 6 h after instillation (lipid A, 0.88 [+ or -] 0.25 vs. LPS, 0.37 [+ or -] 0.21 optical density units*[min.sup.-1]*[mg.sup.-1]; P < 0.05). However, ALI scores were comparable at 6 and 24 h between LPS and lipid A. MPO was also comparable in vehicle-treated or C3H/HeJ mice treated with LPS or lipid A at 6 and 24 h. Phospho-ERK activation was pronounced at 6 and 24 h after lipid A but not LPS treatment. In vitro studies confirmed the relationship between phospho-ERK activation and cytokine expression in macrophage stimulated with either LPS or lipid A. Compared with whole LPS, the lipid A fraction is associated with amplified whole lung MPO and ERK activation 6 h after intratracheal instillation in mice. [Kdo.sub.2]-lipid A; lipopolysaccharide; extracellular signal-regulated kinase p44/42