Rationale: There is increasing evidence for the presence of autoantibodies in chronic obstructive pulmonary disease (COPD). Chronic oxidative stress is an essential component in COPD pathogenesis and can lead to increased levels of highly reactive carbonyls in the lung, which could result in the formation of highly immunogenic carbonyl adducts on "self" proteins. Objectives: To determine the presence of autoantibodies to carbonylmodified protein in patients with COPD and in a murine model of chronic ozone exposure. To assess the extent of activated immune responses toward carbonyl-modified proteins. Methods: Blood and peripheral lung were taken from patients with COPD, age-matched smokers, and nonsmokers with normal lung function, as well as patients with severe persistent asthma. Mice were exposed to ambient air or ozone for 6 weeks. Antibody titers were measured by ELISA, activated compliment deposition by immunohistochemistry, and cellular activation by ELISA and fluorescenceactivated cell sorter. Measurements and Main Results: Antibody titer against carbonylmodified self-protein was significantly increased in patients with Global Initiative for Chronic Obstructive Lung Disease stage III COPD compared with control subjects. Antibody levels inversely correlated with disease severity and showed a prevalence toward an IgG1 isotype. Deposition of activated complement in the vessels of COPD lung as well as autoantibodies against endothelial cells were also observed. Ozone-exposed mice similarly exhibited increased antibody titers to carbonyl-modified protein, as well as activated antigen-presenting cells in lung tissue and splenocytes sensitized to activation by carbonylmodified protein.Conclusions: Carbonyl-modified proteins, arising as a result of oxidative stress, promote antibody production, providing a link by which oxidative stress could drive an autoimmune response in COPD.Keywords: COPD; autoimmunity; oxidative stress; carbonyl Chronic obstructive pulmonary disease (COPD) is currently a leading cause of morbidity and mortality worldwide (1), with the main cause being long-term cigarette smoking in the western world (1, 2). Inflammation and remodeling of the small airways are major determinants for the progression and severity of COPD, as defined by the decline in FEV 1 (3). Accumulation of inflammatory mucous exudates in the lumen and infiltration of the wall by innate and adaptive inflammatory immune cells, such as CD4 1 cells, CD8 1 cells, B cells, macrophages, and neutrophils, and the formation of lymphoid follicles are all features of the observed inflammation that correlate with the severity of COPD (3, 4).Previous studies have suggested that autoimmune mechanisms may contribute to the pathogenesis of COPD. Serum autoantibodies against elastin (5) and bronchial epithelial cells along with corresponding IgG and complement (C3) deposition (6) have been observed in COPD lung. It has therefore been proposed that cigarette smoke-derived antigens may be responsible for driving this disease process in COPD (...

1. The study was designed to assess the impact of stocking density (6 and 13 birds/m² equivalent to 12·6 or 27·2 kg/m², respectively) on growth performance, meat quality, behaviour, and indicators of physiological and oxidative stress as measures of bird welfare. 2. The higher stocking density negatively affected final body weight and feed intake but not cumulative feed conversion rate. Muscle colour traits, pH₂₄, cooking loss and shear values were not affected. Birds reared at the lower density showed higher intramuscular fat, liver weight, liver NADP-isocitrate and NADP-malate dehydrogenase activity. 3. Higher stocking density was associated with decreased locomotor activity and increased physiological (H:L ratio and bursa weight) and oxidative (glutathione concentrations and reduced:oxidised glutathione ratios) stress indicators. 4. The results show that stocking density did not significantly affect broiler meat quality characteristics but higher density decreased growth performance, increased physiological and oxidative stress levels and decreased locomotor activity.

Objective. To investigate the therapeutic effects and possible mechanisms of action of constitutive expression of interferon-␤ (IFN␤) by syngeneic fibroblasts from DBA/1 mice in the collagen-induced arthritis (CIA) model.Methods. Immortalized embryonic DBA/1 fibroblasts were infected with a retrovirus expressing murine IFN␤. IFN␤-expressing fibroblasts were then implanted intraperitoneally into mice immunized with bovine type II collagen. The effect of IFN␤ on paw swelling, anticollagen antibody levels, IgG1/IgG2a isotype profiles, arthritis score, histologic joint damage, and cytokine secretion from lymph node cells and from bone marrowderived macrophages was assessed.Results. A single injection of IFN␤-secreting fibroblasts was sufficient to prevent arthritis or to ameliorate existing disease. Thus, IFN␤ reduced the clinical score and paw swelling irrespective of whether the injection was administered before or after disease onset in treated mice, compared with that in the untreated control group (P < 0.05). Histologic findings in the IFN␤-treated mice were markedly less severe than in the control group (P < 0.001). This effect was accompanied by a decrease in total anticollagen IgG levels, a decrease in anticollagen IgG2a, and an increase in IgG1. In vitro, supernatants from these engineered fibroblasts inhibited collagen-induced interferon-␥ secretion from lymph node cells, and reduced the levels of tumor necrosis factor ␣ and interleukin-12 produced by lipopolysaccharide/IFN␥-treated bone marrow-derived macrophages. This effect was specific, since it was reversed with anti-IFN␤ polyclonal antibodies.Conclusion. These results indicate that IFN␤, which is currently used as a treatment for relapsing, remitting multiple sclerosis, is a potent immunomodulatory and antiinflammatory cytokine in CIA and should be considered for the treatment of rheumatoid arthritis.Interferons are known predominantly for their inhibitory effects on viral replication and cellular proliferation, as well as for their capacity to modulate immune responsiveness. Interferon-␥ (IFN␥), for example, plays an important role in promoting immune and inflammatory responses, partly by up-regulating the antigenpresenting capacity of different cell types and partly by priming macrophages for proinflammatory cytokine production. In contrast, there is evidence of a predominantly antiinflammatory role for interferon-␤ (IFN␤), a type I interferon. This evidence is based principally on the beneficial therapeutic effect of IFN␤ in patients with multiple sclerosis (MS) (1) as well as in chronic, relapsing experimental allergic encephalomyelitis (an animal model of MS) (2,3). Specifically, administration of IFN␤ to MS patients in clinical trials has been shown to reduce the level of disease activity and the frequency of attacks (4). Conversely, the administration of IFN␥ is associated with exacerbation of preexisting autoimmune diseases such as systemic lupus erythematosus and MS (5,6). These findings support the concept that IFN␤ and IFN␥ have opposing e...

Oxidative stress plays a role in the pathophysiology of emphysema through the activation of tissue proteases and apoptosis. We examined the effects of ozone exposure by exposing BALB/c mice to either a single 3-h exposure or multiple exposures over 3 or 6 wk, with two 3-h exposures per week. Compared with air-exposed mice, the increase in neutrophils in bronchoalveolar lavage fluid and lung inflammation index was greatest in mice exposed for 3 and 6 wk. Lung volumes were increased in 3- and 6-wk-exposed mice but not in single-exposed. Alveolar space and mean linear intercept were increased in 6- but not 3-wk-exposed mice. Caspase-3 and apoptosis protease activating factor-1 immunoreactivity was increased in the airway and alveolar epithelium and macrophages of 3- and 6-wk-exposed mice. Interleukin-13, keratinocyte chemoattractant, caspase-3, and IFN-γ mRNA were increased in the 6-wk-exposed group, but heme oxygenase-1 (HO-1) mRNA decreased. matrix metalloproteinase-12 (MMP-12) and caspase-3 protein expression increased in lungs of 6-wk-exposed mice. Collagen area increased and epithelial area decreased in airway wall at 3- and 6-wk exposure. Exposure of mice to ozone for 6 wk induced a chronic inflammatory process, with alveolar enlargement and damage linked to epithelial apoptosis and increased protease expression.

Epigenetic inheritance plays a crucial role in many biological processes, such as gene expression in early embryo development, imprinting and the silencing of transposons. It has recently been established that epigenetic effects can be inherited from one generation to the next. Here, we review examples of epigenetic mechanisms governing animal phenotype and behaviour, and we discuss the importance of these findings in respect to animal studies, and livestock in general. Epigenetic parameters orchestrating transgenerational effects, as well as heritable disorders, and the often-overlooked areas of livestock immunity and stress, are also discussed. We highlight the importance of nutrition and how it is linked to epigenetic alteration. Finally, we describe how our understanding of epigenetics is underpinning the latest cancer research and how this can be translated into directed efforts to improve animal health and welfare.