Background DPP-4 inhibitors are increasingly used to accomplish glycemic targets in patients with Type II diabetes (T2DM). Since DPP-4 is expressed in inflammatory cells, we hypothesized that its inhibition will exert favorable effects in atherosclerosis. Methods and Results Male LDLR-/- mice (6 weeks) were fed with a high fat diet (HFD) or normal chow diet (NCD) for 4 weeks and then randomized to vehicle or Alogliptin, a high affinity DPP-4 inhibitor (40 mg/kg/day) for 12 weeks. Metabolic parameters, blood pressure, vascular function, atherosclerosis burden and indices of inflammation were obtained in target tissues including the vasculature, adipose and bone marrow with assessment of global and cell specific inflammatory pathways. In-vitro and in-vivo assays of DPP-4 inhibition (DPP-4i) on monocyte activation/migration were conducted in both human and murine cells and in a short-term ApoE-/- mouse model. DPP-4i improved markers of insulin resistance and reduced blood pressure. DPP-4i reduced visceral adipose tissue macrophage content (ATMs; CD11b+, CD11c+, Ly6Chi) concomitant with up-regulation of CD163. DPP-4 was highly expressed inbone-marrow derived CD11b+ cells with DPP-4i down-regulating pro-inflammatory genes in these cells. DPP-4i decreased aortic plaque with a striking reduction in plaque macrophages. DPP-4i prevented monocyte migration and actin polymerization in in-vitro assays via Rac dependent mechanisms and prevented in-vivo migration of labeled monocytes to the aorta in response to exogenous TNFα and DPP-4. Conclusion DPP-4i exerts anti-atherosclerotic effects and reduces inflammation via inhibition of monocyte activation/chemotaxis. These findings have important implications for the use of this class of drugs in atherosclerosis.
BackgroundThe development of insulin resistance (IR) in mouse models of obesity and type 2 diabetes mellitus (DM) is characterized by progressive accumulation of inflammatory macrophages and subpopulations of T cells in the visceral adipose. Regulatory T cells (Tregs) may play a critical role in modulating tissue inflammation via their interactions with both adaptive and innate immune mechanisms. We hypothesized that an imbalance in Tregs is a critical determinant of adipose inflammation and investigated the role of Tregs in IR/obesity through coordinated studies in mice and humans.Methods and Findings Foxp3-green fluorescent protein (GFP) “knock-in” mice were randomized to a high-fat diet intervention for a duration of 12 weeks to induce DIO/IR. Morbidly obese humans without overt type 2 DM (n = 13) and lean controls (n = 7) were recruited prospectively for assessment of visceral adipose inflammation. DIO resulted in increased CD3+CD4+, and CD3+CD8+ cells in visceral adipose with a striking decrease in visceral adipose Tregs. Treg numbers in visceral adipose inversely correlated with CD11b+CD11c+ adipose tissue macrophages (ATMs). Splenic Treg numbers were increased with up-regulation of homing receptors CXCR3 and CCR7 and marker of activation CD44. In-vitro differentiation assays showed an inhibition of Treg differentiation in response to conditioned media from inflammatory macrophages. Human visceral adipose in morbid obesity was characterized by an increase in CD11c+ ATMs and a decrease in foxp3 expression.ConclusionsOur experiments indicate that obesity in mice and humans results in adipose Treg depletion. These changes appear to occur via reduced local differentiation rather than impaired homing. Our findings implicate a role for Tregs as determinants of adipose inflammation.
Rationale Chronic exposure to ambient air-borne particulate matter <2.5 µm (PM2.5) increases cardiovascular risk. The mechanisms by which inhaled ambient particles are sensed and how these effects are systemically transduced remain elusive. Objective To investigate the molecular mechanisms by which PM2.5 mediates inflammatory responses in a mouse model of chronic exposure. Methods and Results Here we show that chronic exposure to ambient PM2.5 promotes Ly6Chigh inflammatory monocyte egress from bone-marrow and mediates their entry into tissue niches where they generate reactive oxygen species via NADPH oxidase. Toll-like receptor-4 (TLR4) and Nox2 (gp91phox) deficiency prevented monocyte NADPH oxidase activation in response to PM2.5 and was associated with restoration of systemic vascular dysfunction. TLR4 activation appeared to be a prerequisite for NAPDH oxidase activation as evidenced by reduced p47phox phosphorylation in TLR4 deficient animals. PM2.5 exposure markedly increased oxidized phospholipid derivatives of 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (oxPAPC) in bronchioalveolar lavage fluid. Correspondingly, exposure of bone-marrow derived macrophages to oxPAPC but not PAPC recapitulated effects of chronic PM2.5 exposure while TLR4 deficiency attenuated this response. Conclusions Taken together, our findings suggest that PM2.5 triggers an increase in oxidized phospholipids in lungs that then mediates a systemic cellular inflammatory response through TLR4/NADPH oxidase dependent mechanisms.
To investigate the opportunity for hospitals to achieve better care at lower cost, we examine two key process quality measures, conformance quality and experiential quality, and two measures of performance, readmission rate and cost per discharge. Conformance quality represents a hospital’s level of adherence to evidence-based standards of care, whereas experiential quality represents the level of interaction between hospital’s caregivers and patients. Analyzing six years of data from 3,474 U.S. acute care hospitals, we find that combining conformance and experiential quality results in lower readmission rates. However, conformance quality and experiential quality each independently increase cost per discharge, which suggests that a readmissions–costs trade-off is unavoidable. To investigate this further, we conduct post hoc analyses by distinguishing between the granular elements of experiential quality (EQ) based on task type: response-focused EQ and communication-focused EQ. Response-focused EQ measures caregivers’ ability to respond to patient’s explicit needs, whereas communication-focused EQ measures caregivers’ ability to engage in meaningful conversations with the patient. We find that combining communication-focused EQ with conformance quality reduces readmission rates. Moreover, as conformance quality increases, the cost of improving communication-focused EQ decreases, indicating complementarity. Response-focused EQ in combination with conformance quality also results in reduced readmission rates. However, as conformance quality increases, the cost of improving response-focused EQ also increases, suggesting that these dimensions might compete for resources. Taken together, our results suggest that hospital administrators can mitigate the trade-off between reducing readmissions and controlling costs by prioritizing communication-focused EQ over response-focused EQ. This paper was accepted by Serguei Netessine, operations management.
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