5s-12r-18r-trihydroxy-6z-8e-10e-14z-16e-eicosapentaenoic-acid and Bronchial-Hyperreactivity

Endogenous mediators, such as RvE1 (resolvin E1), promote resolution of an inflammatory response and have potential as novel therapeutic agents. In the present study, we investigated the activity of RvE1 in a model of an acute exacerbation of chronic allergic asthma in mice. Animals sensitized to OVA (ovalbumin) received controlled low-level challenge with aerosolized antigen for 4 weeks, followed by a single moderate-level challenge to simulate an allergen-induced exacerbation of asthmatic inflammation. Induction of an exacerbation was associated with rapid recruitment of neutrophils, lymphocytes and eosinophils, together with increased levels of Th2 and pro-inflammatory cytokines. When administered before the final moderate-level challenge, RvE1 had only a modest effect on airway inflammation. To assess its effects when administered after induction of an exacerbation, we first characterized the cellular and molecular events associated with spontaneous resolution of airway inflammation over the following 96 h. Subsequently, we showed that administration of RvE1 at 2 and 8 h after the final challenge accelerated this process significantly. Specifically, RvE1 promoted a decline in the number of inflammatory cells, concentration of cytokines in lavage fluid and expression of mRNA for cytokines by macrophages, confirming its pro-resolution activity. In vitro, RvE1 had no apparent effect on lymphocytes, but suppressed significantly cytokine production by pulmonary macrophages, with evidence of down-regulation of the nuclear translocation of NF-κB (nuclear factor κB) p65 in these cells. The present study provides novel evidence that RvE1 can facilitate resolution of airway inflammation in a clinically relevant model of an acute exacerbation of asthma, possibly via its effects on activated pulmonary macrophages.

Topics: Active Transport, Cell Nucleus; Animals; Asthma; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Cell Line; Cytokines; Disease Models, Animal; Eicosapentaenoic Acid; Female; Hypersensitivity; Immunohistochemistry; Inflammation; Leukocytes; Macrophages; Mice; Mice, Inbred BALB C; NF-kappa B; Ovalbumin; RNA, Messenger; Time Factors

Resolvin E1 (RvE1) is an anti-inflammatory lipid mediator derived from the omega-3 fatty acid eicosapentaenoic acid (EPA), and strongly acts in the resolution of inflammation. We previously reported that RvE1 dampens airway inflammation and hyperresponsiveness in a murine model of asthma. In the present study, to elucidate the effects of RvE1 on the development of asthmatic airway inflammation, we investigated whether RvE1 acts on different phases of an OVA-sensitized and -challenged mouse model of asthma. RvE1 treatments at the time of either OVA sensitization or at the time of OVA challenge were investigated and compared with RvE1 treatments at the time of both OVA sensitization and challenge. After RvE1 was administered to mice intraperitoneally at the time of both OVA sensitization and challenge, there were decreases in airway eosinophil and lymphocyte recruitment, as well as a reduction in Th2 cytokine and airway hyperresponsiveness. RvE1 treatment at the time of either OVA sensitization or challenge also improved AHR and airway inflammation. Our results suggest that RvE1 acts on several phases of asthmatic inflammation and may have anti-inflammatory effects on various cell types.

Topics: Animals; Asthma; Bronchial Hyperreactivity; Disease Models, Animal; Eicosapentaenoic Acid; Female; Mice; Mice, Inbred BALB C; Ovalbumin; Pneumonia

Resolvin E1 (RvE1; 5S, 12R, 18R-trihydroxyeicosapentaenoic acid) is an anti-inflammatory lipid mediator derived from the omega-3 fatty acid eicosapentaenoic acid (EPA). It has been recently shown that RvE1 is involved in the resolution of inflammation. However, it is not known whether RvE1 is involved in the resolution of asthmatic inflammation. To investigate the anti-inflammatory effect of RvE1 in asthma, a murine model of asthma was studied. After RvE1 was administered to mice intraperitoneally, there were decreases in: airway eosinophil and lymphocyte recruitment, specific Th2 cytokine, IL-13, ovalbumin-specific IgE, and airway hyperresponsiveness (AHR) to inhaled methacholine. Moreover, RvE1-treated mice had significantly lower mucus scores compared to vehicle-treated mice based on the number of goblet cells stained with periodic acid-schiff (PAS). These findings provide evidence that RvE1 is a pivotal counterregulatory signal in allergic inflammation and offer novel multi-pronged therapeutic approaches for human asthma.

Topics: Animals; Asthma; Bronchial Hyperreactivity; Disease Models, Animal; Dose-Response Relationship, Drug; Eicosapentaenoic Acid; Female; Lung; Mice; Mice, Inbred BALB C; Pneumonia