Objective Epidemiological and recent clinical studies implicate periodontitis as an independent risk factor for cardiovascular disease. Previously, we demonstrated that rabbits with experimental periodontitis and cholesterol diet exhibit more aortic plaque compared to diet alone. We also showed that a proresolution mediator, Resolvin E1 (RvE1), reverses the experimental periodontitis. Here, we determined whether oral/topical application of RvE1 attenuates aortic atherosclerosis induced by both diet and periodontal inflammation. Approach and Results Thirty-nine rabbits on a 13-week regimen of 0.5% cholesterol diet were included. Periodontitis was induced by P. gingivalis in 24 rabbits and 15 rabbits were placed in no-periodontitis groups. Interventions were no-treatment, vehicle, and RvE1 treatment (4μg/site or 0.4 μg/site) topically applied 3-times/ week. At 13 weeks, both periodontitis and atherosclerosis were quantified. Atherosclerotic plaques were assessed by Sudan IV staining, histology and ex vivo MRI. Serum levels of C-reactive protein (CRP) were evaluated as a measure of systemic inflammation.RvE1, used as an oral/topical agent, significantly diminished atherogenesis and prevented periodontitis (p<0.05). In the absence of periodontal inflammation, oral/topical application of RvE1 resulted in significantly less arterial plaque, a lower intima/media ratio, and decreased inflammatory cell infiltration compared to no-treatment (p<0.001). Local oral RvE1 application significantly reduced systemic levels of CRP (p<0.05). Conclusions The results suggest that oral/topical RvE1 attenuates enhanced atherogenesis induced by periodontitis and prevents vascular inflammation and atherogenesis in the absence of periodontitis. The inhibition of vascular inflammation with endogenous mediators of resolution of inflammation provides a novel approach in the prevention of atherogenic events.

P450s are heme thiolate enzymes that catalyze the regio- and stereoselective functionalization of unactivated C-H bonds using molecular dioxygen and two electrons delivered by the reductase. We have developed hybrid P450 BM3 heme domains containing a covalently attached Ru(II) photosensitizer in order to circumvent the dependency on the reductase and perform P450 reactions upon visible light irradiation. A highly active hybrid enzyme with improved stability and a modified Ru(II) photosensitizer is able to catalyze the light-driven hydroxylation of lauric acid with total turnover numbers of 935 and initial reaction rate of 125 mol product / mol enzyme / min.

The immune responses of type 2 T helper cells (Th2) play an important role in asthma and promote the differentiation of alternatively activated (M2) macrophages. M2 macrophages have been increasingly understood to contribute to Th2 immunity. We hypothesized that M2 macrophages are altered in asthma and modulate Th2 responses. The aim of this study was to characterize the phenotype and function of human monocyte-derived M2 and bronchoalveolar lavage fluid (BALF) macrophages from healthy control subjects and subjects with asthma. Phenotypic characteristics and effector function of M2 macrophages were examined using monocyte-derived and BALF macrophages obtained from subjects with asthma (n = 28) and healthy volunteers (n = 9) by flow cytometry and quantitative PCR. Resting monocyte-derived (M0) and M2 macrophages were generated by the addition of macrophage colony-stimulating factor or macrophage colony-stimulating factor plus IL-4, respectively. M2 macrophage cytokine expression and their impact on dendritic and CD4 T cell activation were examined in vitro. High levels of CD206 and major histocompatibility complex class II expression identify macrophages with an M2 phenotype that are increased 2.9-fold in the BALF of subjects with asthma compared with control subjects. M2 macrophages have elevated IL-6, IL-10, and IL-12p40 production compared with conventional macrophages and modulate dendritic and CD4 T cell interactions. Histamine receptor 1 and E-cadherin expression identify M2 macrophage subsets associated with increased airflow obstruction. M2 macrophages have a distinct cell surface and effector phenotype and are found in increased numbers in subjects with asthma. These findings suggest that M2 macrophages may play an important role in allergic asthma through their bidirectional interactions with immune and structural cells, and inflammatory mediators.

Patients with obstructive sleep apnea (OSA) often exhibit fatigued or inefficient upper airway dilator and constrictor muscles; an upper airway dilator, the geniohyoid (GH) muscle, is a particular example. Intermittent hypoxia (IH) is a frequent concomitant of OSA, and it may trigger muscle fiber composition changes that are characteristic of a fatigable nature. We examined effects of short-term IH on diaphragmatic and GH muscle fiber composition and fatigue properties by exposing 24 rats to alternating 10.3% O(2)-balance N(2) and room air every 480 s (240 s duty cycle) for a total duration of 5, 10, 15, 20, or 30 h. Sternohyoid fiber composition was also examined. Control animals were exposed to room air on the same schedule. Single-fiber analyses showed that GH muscle fiber types changed completely from myosin heavy chain (MHC) type 2A to MHC type 2B after 10 h of exposure, and the conversion was maintained for at least 30 h. Sternohyoid muscle fibers showed a delayed transition from MHC type 2A/2B to MHC type 2B. In contrast, major fiber types of the diaphragm were not significantly altered. The GH muscles showed similar tension-frequency relationships in all groups, but an increased fatigability developed, proportional to the duration of IH treatment. We conclude that short-term IH exposure alters GH muscle composition and physical properties toward more fatigable, fast-twitch types and that it may account for the fatigable upper airway fiber types found in sleep-disturbed breathing.