The absence of macrophage Nrf2 promotes early atherogenesis.

AIMS: The loss of nuclear factor E2-related factor 2 (Nrf2) has been shown to protect against atherogenesis in apoE-deficient mice. The mechanism by which Nrf2 deficiency affords atheroprotection in this model is currently unknown, but combined systemic and local vascular effects on lesion macrophages have been proposed. We investigated the effect of bone marrow-specific loss of Nrf2 on early atherogenesis in low-density lipoprotein (LDL) receptor-deficient (LDLR(-/-)) mice, and assessed the effect of Nrf2 on cellular accumulation of modified LDLs and the expression of inflammatory markers in macrophages. METHODS AND RESULTS: The effect of bone marrow-specific loss of Nrf2 on atherogenesis was studied using bone marrow transplantation of wild-type (WT) or Nrf2(-/-) bone marrow to LDLR(-/-) mice. Mice transplanted with Nrf2(-/-) bone marrow and fed a high-fat diet for 6 weeks exhibited significantly larger atherosclerotic lesions than WT bone marrow transplanted mice. Moreover, in thioglycollate-elicited Nrf2(-/-) macrophages, the uptake of acetylated and malondialdehyde-modified LDLs was increased in comparison with WT controls, with the concomitant increase in the expression of scavenger receptor A and toll-like receptor 4. In addition, the expression of pro-inflammatory monocyte chemoattractant protein-1 and interleukin-6 were increased in Nrf2(-/-) vs. WT macrophages. CONCLUSION: Nrf2 deficiency specific to bone marrow-derived cells aggravates atherosclerosis in LDLR(-/-) mice. Furthermore, the loss of Nrf2 in macrophages enhances foam cell formation and promotes the pro-inflammatory phenotype.

Comparison of conventional inserts and an add-on electron MLC for chest wall irradiation of left-sided breast cancer.

BACKGROUND: Collimation of irregularly shaped clinical electron beams is currently based on electron inserts made of low melting point alloys. The present investigation compares a conventional electron applicator with insert and add-on eMLC-based dose distributions in the postoperative chest wall irradiation of left-sided breast cancer. MATERIAL AND METHODS: Voxel Monte Carlo++ (VMC++) calculated dose distributions related to electron fields were compared with 10 left-sided breast cancer patients after radical mastectomy. The prescription dose was 50 Gy at a build-up maximum. The same dose was prescribed for the ipsilateral axillary, parasternal and supraclavicular lymph nodes that were treated with photons and calculated with a pencil beam algorithm. The insert beams were shaped with 1.5 cm thick Wood's metal electron inserts in an electron applicator of a Varian 2100 C/D linac. Doses for the eMLC-shaped beams were calculated for an eMLC prototype with 2 cm thick and 5 mm wide steel leaves. The same collimator-to-surface distance (CSD) of 5.8 cm was used for both collimators. RESULTS: The mean PTV dose was slightly higher for the eMLC plans (50.7 vs 49.5 Gy, p<0.001, respectively). The maximum doses assessed by D5% for the eMLC and insert were 60.9 and 59.1 Gy (p<0.001). The difference was due to the slightly higher doses near the field edges for the eMLC. The left lung V20 volumes were 34.5% and 34.0% (p<0.001). There was only a marginal difference in heart doses. DISCUSSION: Despite a slight increase of maximum dose in PTV the add-on electron MLC for chest wall irradiation results in practically no differences in dose distributions compared with the present insert-based collimation.

Minocycline reduces engraftment and activation of bone marrow-derived cells but sustains their phagocytic activity in a mouse model of Alzheimer's disease.

Bone marrow (BM)-derived monocytes contribute to the development of microglial reaction around beta-amyloid (Abeta) plaques in Alzheimer's disease (AD) and possibly clear Abeta. Therefore, it is of great importance to separate the proinflammatory actions of monocytic cells from Abeta phagocytic effects. We used minocycline (mino) to systemically downregulate microglial activation and studied proliferation, expression of markers for activated microglia, and Abeta removal in vitro and in vivo. Mino did not affect proliferation or phagocytic activity of BM-derived cells toward Abeta in vitro. Intrahippocampal LPS injection used to induce inflammation and increase recruitment of BM cells from periphery, reduced Abeta burden in BM-transplanted AD transgenic mice. All engrafted cells expressed CD45, approximately 50% expressed Iba-1, and <0.5% of these cells expressed CD3e. About 40% of the engrafted cells were mitotically active. LPS increased immunoreactivity for Iba-1, MHC II, a marker of antigen presenting cells, and CD68, a marker of lysosomal activity. The endogenous microglia largely contributed to these LPS-induced immunoreactivities. Mino reduced the engraftment of BM-derived cells and blocked the LPS-induced MHC II and Iba-1 immunoreactivities, but did not prevent the increased CD68-immunoreactivity or the reduced Abeta burden. Importantly, mino did not block the association of eGFP-positive cells with Abeta deposits and the percentage of mitotically active BM-derived cells. In conclusion, mino reduces overall inflammatory potential of BM-derived monocytic cells without preventing their phagocytic activity. The separation of harmful activation of microglia/monocytic cells from their Abeta clearing mechanism may hold important therapeutic potential.

Bone-marrow-derived cells contribute to the recruitment of microglial cells in response to beta-amyloid deposition in APP/PS1 double transgenic Alzheimer mice.

The role of microglia recruited from bone marrow (BM) into the CNS during the progression of Alzheimer's disease (AD) is poorly understood. To investigate whether beta-amyloid (Abeta) associated microglia are derived from blood monocytes, we transplanted BM cells from enhanced green fluorescent protein expressing mice into young or old transgenic AD mice and determined the engraftment of BM-derived cells into the brain and their relative distribution near Abeta deposits. When young transgenic mice were transplanted before the onset of AD-like pathology and the brains analyzed 6.5 months later, the number of engrafted cells was significantly higher than in age-matched wild type mice. Moreover, the number of BM-derived cells associated with Abeta was significantly higher than in old transgenic mice transplanted after the establishment of AD-like pathology. Local inflammation caused by intrahippocampal lipopolysaccharide injection significantly increased the engraftment of BM-derived cells in old AD mice and decreased the hippocampal Abeta burden. These results suggest that infiltration of BM-derived monocytic cells into the brain contributes to the development of microglial reaction in AD.