It is both an ideal and an assumption of traditional conceptions of justice for liberal democracies that citizens are autonomous, self-governing persons. Yet standard accounts of the self and of ...self-government at work in such theories are hotly disputed and often roundly criticized in most of their guises. John Christman offers a sustained critical analysis of both the idea of the 'self' and of autonomy as these ideas function in political theory, offering interpretations of these ideas which avoid such disputes and withstand such criticisms. Christman's model of individual autonomy takes into account the socially constructed nature of persons and their complex cultural and social identities, and he shows how this model can provide a foundation for principles of justice for complex democracies marked by radical difference among citizens. His book will interest a wide range of readers in philosophy, politics, and the social sciences.
Our previous research demonstrated that PU.1 regulates expression of the genes involved in inflammation in macrophages. Selective knockdown of PU.1 in macrophages ameliorated LPS-induced acute lung ...injury (ALI) in bone marrow chimera mice. Inhibitors that block the transcriptional activity of PU.1 in macrophages have the potential to mitigate the pathophysiology of LPS-induced ALI. However, complete inactivation of PU.1 gene disrupts normal myelopoiesis. Although the green tea polyphenol Epigallocatechin gallate (EGCG) has been shown to regulate inflammatory genes in various cell types, it is not known if EGCG alters the transcriptional activity of PU.1 protein. Using Schrodinger Glide docking, we have identified that EGCG binds with PU.1 protein, altering its DNA-binding and self-dimerization activity. In silico analysis shows that EGCG forms Hydrogen bonds with Glutamic Acid 209, Leucine 250 in DNA binding and Lysine 196, Tryptophan 193, and Leucine 182 in the self-dimerization domain of the PU.1 protein. Experimental validation using mouse bone marrow-derived macrophages (BMDM) confirmed that EGCG inhibits both DNA binding by PU.1 and self-dimerization. Importantly, EGCG had no impact on expression of the total PU.1 protein levels but significantly reduced expression of various inflammatory genes and generation of ROS. In summary, we report that EGCG acts as an inhibitor of the PU.1 transcription factor in macrophages.
The incretins GLP-1 and GIP have important roles in insulin sensitivity and have been shown to be effective in pharmacological treatment of type 2 diabetes (T2D) . Therefore, we studied these ...incretin level changes with remission of T2D and weight loss using a high protein (HP) diet in 12 obese women and men with T2D. Our studies have shown that subjects with T2D on a 6 month HP diet (30%protein,30%fat, 40%CHO) had 100% remission of T2D compared to only 33% on a HC diet (15%protein,30%fat, 55%CHO) . Effects of HP and HC diets on ghrelin levels were determined since HP subjects had increased satiety compared to HC diet. GLP-1, GIP, and Ghrelin levels were determined with a Meal Tolerance Test (MTT) at baseline and after 6 mo on HP and HC diets where all food was provided. Since cardiovascular risk factors (CVRF) decreased more in the HP than the HC diet, we determined if the B-Type Natriuretic Peptide (BNP) released from the heart was affected by either diet. As shown in Table, HP diet had a greater increase in GLP-1 and GIP than the HC diet. BNP decrease demonstrates improvement in heart tissue with the HP diet having a greater effect than the HC diet. Weight loss was similar (9.8% in HP vs. 11.3% in HC, p=0.692) . this study demonstrates that the HP diet increases GLP-1 and GIP which may be responsible in part for the improved insulin sensitivity and decreased BNP with greater improvement in CVRF with remission of T2D
Disclosure
F.B.Stentz: None. A.Ammons: None. J.V.Christman: None.
Funding
AD Baskin Research Grant
Treatment with bone-marrow-derived mesenchymal stromal cells (MSCs) has shown benefits in preclinical models of acute respiratory distress syndrome (ARDS). Safety has not been established for ...administration of MSCs in critically ill patients with ARDS. We did a phase 2a trial to assess safety after administration of MSCs to patients with moderate to severe ARDS.
We did a prospective, double-blind, multicentre, randomised trial to assess treatment with one intravenous dose of MSCs compared with placebo. We recruited ventilated patients with moderate to severe ARDS (ratio of partial pressure of oxygen to fractional inspired oxygen <27 kPa and positive end-expiratory pressure PEEP ≥8 cm H
O) in five university medical centres in the USA. Patients were randomly assigned 2:1 to receive either 10 × 10
/kg predicted bodyweight MSCs or placebo, according to a computer-generated schedule with a variable block design and stratified by site. We excluded patients younger than 18 years, those with trauma or moderate to severe liver disease, and those who had received cancer treatment in the previous 2 years. The primary endpoint was safety and all analyses were done by intention to treat. We also measured biomarkers in plasma. MSC viability was tested in a post-hoc analysis. This trial is registered with ClinicalTrials.gov, number NCT02097641.
From March 24, 2014, to Feb 9, 2017 we screened 1038 patients, of whom 60 were eligible for and received treatment. No patient experienced any of the predefined MSC-related haemodynamic or respiratory adverse events. One patient in the MSC group died within 24 h of MSC infusion, but death was judged to be probably unrelated. 28-day mortality did not differ between the groups (30% in the MSC group vs 15% in the placebo group, odds ratio 2·4, 95% CI 0·5-15·1). At baseline, the MSC group had numerically higher mean scores than the placebo group for Acute Physiology and Chronic Health Evaluation III (APACHE III; 104 SD 31 vs 89 33), minute ventilation (11·1 3·2 vs 9·6 2·4 L/min), and PEEP (12·4 3·7 vs 10·8 2·6 cm H
O). After adjustment for APACHE III score, the hazard ratio for mortality at 28 days was 1·43 (95% CI 0·40-5·12, p=0·58). Viability of MSCs ranged from 36% to 85%.
One dose of intravenous MSCs was safe in patients with moderate to severe ARDS. Larger trials are needed to assess efficacy, and the viability of MSCs must be improved.
National Heart, Lung, and Blood Institute.
Although alveolar macrophages (AMs) from patients with asthma are known to be functionally different from those of healthy individuals, the mechanism by which this transformation occurs has not been ...fully elucidated in asthma. The goal of this study was to define the mechanisms that control AM phenotypic and functional transformation in response to acute allergic airway inflammation. The phenotype and functional characteristics of AMs obtained from human subjects with asthma after subsegmental bronchoprovocation with allergen was studied. Using macrophage-depleted mice, the role and trafficking of AM populations was determined using an acute allergic lung inflammation model. We observed that depletion of AMs in a mouse allergic asthma model attenuates Th2-type allergic lung inflammation and its consequent airway remodeling. In both human and mouse, endobronchial challenge with allergen induced a marked increase in monocyte chemotactic proteins (MCPs) in bronchoalveolar fluid, concomitant with the rapid appearance of a monocyte-derived population of AMs. Furthermore, airway allergen challenge of allergic subjects with mild asthma skewed the pattern of AM gene expression toward high levels of the receptor for MCP1 (CCR2/MCP1R) and expression of M2 phenotypic proteins, whereas most proinflammatory genes were highly suppressed. CCL2/MCP-1 gene expression was prominent in bronchial epithelial cells in a mouse allergic asthma model, and in vitro studies indicate that bronchial epithelial cells produced abundant MCP-1 in response to house dust mite allergen. Thus, our study indicates that bronchial allergen challenge induces the recruitment of blood monocytes along a chemotactic gradient generated by allergen-exposed bronchial epithelial cells.
Cyclooxygenase (COX)-2 expression and release of prostaglandins (PGs) by macrophages are consistent features of lipopolysaccharide (LPS)-induced macrophage inflammation. The two major PGs, PGE(2) and ...PGD(2), are synthesized by the prostanoid isomerases, PGE synthases (PGES) and PGD synthases (PGDS), respectively. Since the expression profile and the individual role of these prostanoid isomerases-mediated inflammation in macrophages has not been defined, we examined the LPS-stimulated PGs production pattern and the expression profile of their synthases in the primary cultured mouse bone marrow derived macrophages (BMDM). Our data show that LPS induced both PGE(2) and PGD(2) production, which was evident by ∼8 hrs and remained at a similar ratio (∼1∶1) in the early phase (≤12 hrs) of LPS treatment. However, PGE(2) production continued increase further in the late phase (16-24 hrs); whereas the production of PGD(2) remained at a stable level from 12 to 24 hrs post-treatment. In response to LPS-treatment, the expression of both COX-2 and inducible nitric oxide synthase (iNOS) was detected within 2 to 4 hrs; whereas the increased expression of microsomal PGES (mPGES)-1 and a myeloid cell transcription factor PU.1 did not appear until later phase (≥12 hrs). In contrast, the expression of COX-1, hematopoietic-PGDS (H-PGDS), cytosolic-PGES (c-PGES), or mPGES-2 in BMDM was not affected by LPS treatment. Selective inhibition of mPGES-1 with either siRNA or isoform-selective inhibitor CAY10526, but not mPGES-2, c-PGES or PU.1, attenuated LPS-induced burst of PGE(2) production indicating that mPGES-1 mediates LPS-induced PGE(2) production in BMDM. Interestingly, selective inhibition of mPGES-1 was also associated with a decrease in LPS-induced iNOS expression. In summary, our data show that mPGES-1, but not mPGES-2 or c-PGES isomerase, mediates LPS-induced late-phase burst of PGE(2) generation, and regulates LPS-induced iNOS expression in BMDM.
Idiopathic pulmonary fibrosis (IPF) is a highly lethal pathological process that is characterized by inflammation, fibroblast accumulation, and excessive collagen deposition. Although AKT2-mediated ...signaling pathways modulate inflammatory responses, their role in IPF has not been defined. We report that AKT2 deficiency (
) protected against bleomycin-induced pulmonary fibrosis and inflammation. Adoptive transfer of wild-type macrophages or administration of IL-13 to
mice could restore pulmonary fibrosis. In response to IL-33 treatment,
macrophages displayed decreased production of IL-13 and TGF-β1 and attenuated phosphorylation of FoxO3a compared with
macrophages. Furthermore, the expression of IL-13 was increased by small interfering RNA knockdown of FoxO3a or in FoxO3a-deficient macrophages. By evaluating lung sections from pulmonary fibrosis patients, we found that the phosphorylation of AKT2 and FoxO3a was remarkably upregulated. Collectively, these results indicate that AKT2 modulates pulmonary fibrosis through inducing TGF-β1 and IL-13 production by macrophages, and inhibition of AKT2 may be a potential strategy for treating IPF.
The purpose of this study was to determine if remission of type 2 diabetes(T2D) and a decrease in inflammatory cytokines (IC) can be achieved by macronutrients dietary changes without diabetes ...medications. High Protein (HP)(30% protein, 30% fat, 40% carbohydrates) or High Carbohydrate (HC)(15% protein, 30% fat, 55% carbohydrates) diets were used to study remission of type 2 diabetes(T2D) to Normal Glucose Tolerance(NGT), inflammatory cytokines, weight loss, body composition, and metabolic parameters in this randomized controlled clinical trial feeding study for 6 month(mo). Obese, age 20-65 years subjects withT2D were randomized to a HP or HC diet for 6 mo with all food provided. Caloric need for weight loss was determined by Resting Metabolic Rate-500 calories/day. Oral Glucose Tolerance Tests (OGTT) were performed at Baseline (BL) and 6 mo to determine T2D/NGT status. Glucose BL≥126 mg/dl and HbA1c≥6.5% and 2 hr glucose >199mg/dl was considered T2D and remission at 6 mo was glucose BL<126 mg/ml and HbA1c<6.5% and 2 hr glucose <140 mg/dl. DXA was done at BL and 6 mo. Food pick up and weight checks were weekly.T2D subjects on HP diet had 100% remission to NGT while HC diet subjects had 16% remission. IC were significantly decreased in HP compared to HC subjects at 6 mo for TNFa pg/ml (p=0.001) HP 3.9±0.7 vs. HC 12.6±1.9 and IL-6 pg/ml (p=0.005) HP 4.7±0.5 vs. HC 9.1±0.9. Both diet groups had improvement in insulin sensitivity: HOMA IR HP(BL 5.3±0.29; 6 mo 2.1±0.13), HC(BL 5.2±0.27; 6 mo 4.4±0.26) and decrease in HbA1c HP(BL 7.7±.05; 6 mo 5.6±.02), HC(BL 7.8±.04; 6 mo 6.6±.06). While both HP and HC groups has similar weight loss (HP =15.4±5 lb, HC=19.9±5 lb), HP group had a 2.7± 0.4% increase in lean body mass(LM) and 2.9± 0.4% decrease in fat mass(FM) while the HC group had a 1.9±0.3% LM and 3.3±0.9 % FM decrease respectively. The HP diet demonstrated improvement in glucose tolerance and insulin sensitivity with 100% remission of T2D to NGT and a significant decrease in inflammatory cytokines.
Disclosure
F. B. Stentz: None. A. Ammons: None. J. V. Christman: None.
Funding
AD Baskin (R073316012)
Mechanical ventilation generates injurious forces that exacerbate lung injury. These forces disrupt lung barrier integrity, trigger proinflammatory mediator release, and differentially regulate genes ...and non-coding oligonucleotides including microRNAs. In this study, we identify miR-146a as a mechanosensitive microRNA in alveolar macrophages that has therapeutic potential to mitigate lung injury during mechanical ventilation. We use humanized in-vitro systems, mouse models, and biospecimens from patients to elucidate the expression dynamics of miR-146a needed to decrease lung injury during mechanical ventilation. We find that the endogenous increase in miR-146a following injurious ventilation is not sufficient to prevent lung injury. However, when miR-146a is highly overexpressed using a nanoparticle delivery platform it is sufficient to prevent injury. These data indicate that the endogenous increase in microRNA-146a during mechanical ventilation is a compensatory response that partially limits injury and that nanoparticle delivery of miR-146a is an effective strategy for mitigating lung injury during mechanical ventilation.
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