Age-dependent therapeutic effects of liver X receptor-α activation in murine polymicrobial sepsis (original) (raw)
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Surgical Infections, 2011
Background: Liver X receptor (LXR) is a transcription factor of the nuclear receptor family, regulating genes involved in metabolism, inflammation, and apoptosis. In the present investigation, we examined the role of LXR in organ injury and systemic inflammation in rodent models of polymicrobial peritonitis caused by cecal ligation and puncture (CLP). Methods: Rats were subjected to CLP sepsis or a sham operation. Some were treated with the synthetic LXR agonist GW3965 0.3 mg/kg 30 min prior to the CLP procedure, and organs and plasma were harvested at 3, 10, 18, or 24 h. Organs were analyzed for RNA expression by quantitative polymerase chain reaction or for morphologic differences by histologic review. Organ injury and inflammatory markers were measured in plasma. Results: Expression of the LXRa gene was decreased in the livers of CLP rats compared with sham-operated rats. Administration of a synthetic agonist of LXR (GW3965) reduced biochemical indices of liver injury in the blood of CLP rats. We also demonstrated that liver injury associated with CLP is aggravated in LXRa-and LXRabdeficient mice compared with wild-type and LXRb-deficient mice, indicating a role for LXRa in protecting the liver. The enhanced liver injury in LXR-deficient mice was associated with elevated plasma concentrations of high mobility group box 1, a late mediator of inflammation and a known factor in the pathology of this model. Conclusions: Collectively, these results argue in favor of a role for LXRa in protection against liver injury in experimental sepsis induced by CLP.
Aged Mice Are Unable To Mount an Effective Myeloid Response to Sepsis
The Journal of Immunology, 2013
The elderly have increased morbidity and mortality following sepsis; however, the cause(s) remains unclear. We hypothesized that these poor outcomes are due in part to defects in innate immunity, rather than to an exaggerated early inflammatory response. Young (6-12 wk) or aged (20-24 mo) mice underwent polymicrobial sepsis, and subsequently, the aged mice had increased mortality and defective peritoneal bacterial clearance compared with young mice. No differences were found in the magnitude of the plasma cytokine responses. Although septic aged mice displayed equivalent or increased numbers of circulating, splenic, and bone marrow myeloid cells, some of these cells exhibited decreased phagocytosis, reactive oxygen species production, and chemotaxis. Blood leukocyte gene expression was less altered in aged versus young mice 1 d after sepsis. Aged mice had a relative inability to upregulate gene expression of pathways related to neutrophil-mediated protective immunity, chemokine/chemokine receptor binding, and responses to exogenous molecules. Expression of most MHC genes remained more downregulated in aged mice at day 3. Despite their increased myeloid response to sepsis, the increased susceptibility of aged mice to sepsis appears not to be due to an exaggerated inflammatory response, but rather, a failure to mount an effective innate immune response.
Shock, 2011
Liver X Receptor α is a nuclear transcription factor that regulates lipid metabolism. Recently, it has been shown that activation of LXRα with synthetic ligands has anti-inflammatory effects in atherosclerosis and chemical-induced dermatitis. Here, we investigated the effect of the LXRα agonist T0901317 on lung inflammation in a rodent model of hemorrhagic shock. Hemorrhagic shock was induced in male rats by withdrawing blood to a goal mean arterial blood pressure of 50 mmHg. Blood pressure was maintained at this level for 3 hours, at which point rats were rapidly resuscitated with shed blood. Animals were then treated with T0901317 (50 mg/kg) or vehicle intraperitoneally and sacrificed at 1, 2 and 3 hours after resuscitation. Treatment with T0901317 significantly improved the cardiac and stroke volume indices as well as heart rate of rats during the resuscitation period as compared to vehicle-treated rats. T0901317-treated animals showed significant improvement in the plasma level of lactate, while base deficit and bicarbonate levels both trended towards improvement. T0901317-treated animals also showed lower levels of the plasma cytokines and chemokines MCP-1, MIP-1α, TNF-α, KC and IL-6. Lung injury and neutrophil infiltration were reduced by treatment with T0901317 as evaluated by histology and myeloperoxidase assay. At molecular analysis, treatment with T0901317 increased nuclear LXRα expression and DNA binding while also inhibiting activation of NF-κB, a pro-inflammatory transcription factor, in the lung. Thus, our data suggest that LXRα is an important modulator of the inflammatory response and lung injury after severe hemorrhagic shock, likely through the inhibition of the NF-κB pathway.
The Journals of Gerontology: Series A, 2020
Increased age is a risk factor for poor outcomes from respiratory failure and acute respiratory distress syndrome (ARDS). In this study, we sought to define age-related differences in lung inflammation, muscle injury, and metabolism after intratracheal lipopolysaccharide (IT-LPS) acute lung injury (ALI) in adult (6 months) and aged (18–20 months) male C57BL/6 mice. We also investigated age-related changes in muscle fatty acid oxidation (FAO) and the consequences of systemic FAO inhibition with the drug etomoxir. Aged mice had a distinct lung injury course characterized by prolonged alveolar neutrophilia and lack of response to therapeutic exercise. To assess the metabolic consequences of ALI, aged and adult mice underwent whole body metabolic phenotyping before and after IT-LPS. Aged mice had prolonged anorexia and decreased respiratory exchange ratio, indicating increased reliance on FAO. Etomoxir increased mortality in aged but not adult ALI mice, confirming the importance of FAO ...
PLoS ONE, 2013
We combined in silico, in vivo, and in vitro studies to gain insights into age-dependent changes in acute inflammation in response to bacterial endotoxin (LPS). Time-course cytokine, chemokine, and NO 2 2/ NO 3 2 data from ''middle-aged'' (6-8 months old) C57BL/6 mice were used to re-parameterize a mechanistic mathematical model of acute inflammation originally calibrated for ''young'' (2-3 months old) mice. These studies suggested that macrophages from middle-aged mice are more susceptible to cell death, as well as producing higher levels of pro-inflammatory cytokines, vs. macrophages from young mice. In support of the in silico-derived hypotheses, resident peritoneal cells from endotoxemic middle-aged mice exhibited reduced viability and produced elevated levels of TNF-a, IL-6, IL-10, and KC/CXCL1 as compared to cells from young mice. Our studies demonstrate the utility of a combined in silico, in vivo, and in vitro approach to the study of acute inflammation in shock states, and suggest hypotheses with regard to the changes in the cytokine milieu that accompany aging.
Yaghag hoeji, 2021
Sepsis is an excessive and irregular host response against existing infection, wherein pathogen invasion is primarily responsible for the resulting damage. However, sepsis-related damage is substantially caused by excessive uncontrolled host response. The purpose of this study was to investigate the differences in immune response based on the strain, age, and sex of mice by examining the survival rate and latency following immune challenge. The results showed that there was no significant difference between strains (ICR and C57BL6) following lipopolysaccharide (LPS) treatment. Adolescent male mice (8 weeks old) had a higher survival rate and longer latency to death compared to those of adult mice (13 weeks old) following LPS treatment. Moreover, the onset of death in adolescent mice occurred substantially later compared to that in adult mice. Females displayed longer latency to death and higher survival rates compared to their male counterparts following immune challenge. Thus, the differences in survival rate and latency between young and adult mice and between male and female might contribute to age-and sex-specific adaptive host immunity, respectively. Our findings highlight the importance of considering the age, sex and strain of animals in experimental models of sepsis and provide a rationale to evaluate susceptibility in specific designs of sepsis immunotherapy. The clinical relevance of this study awaits further studies.
Novel Chitohexaose Analog Protects Young and Aged mice from CLP Induced Polymicrobial Sepsis
Scientific Reports
In Gram-negative bacterial sepsis, production of excess pro-inflammatory cytokines results in hyperinflammation and tissue injury. Anti-inflammatory cytokines such as IL-10 inhibit inflammation and enhance tissue healing. Here, we report a novel approach to treat septicemia associated with intraabdominal infection in a murine model by delicately balancing pro-and anti-inflammatory cytokines. A novel oligosaccharide compound AVR-25 selectively binds to the TLR4 protein (IC 50 = 0.15 µM) in human peripheral blood monocytes and stimulates IL-10 production. Following the cecal ligation and puncture (CLP) procedure, intravenous dosing of AVR-25 (10 mg/kg, 6-12 h post-CLP) alone and in combination with antibiotic imipenem protected both young adult (10-12 week old) and aged (16-18 month old) mice against polymicrobial infection, organ dysfunction, and death. Proinflammatory cytokines (TNFα, MIP-1, i-NOS) were decreased significantly and restoration of tissue damage was observed in all organs. A decrease in serum C-reactive protein (CRP) and bacterial colony forming unit (CFU) confirmed improved bacterial clearance. Together, these findings demonstrate the therapeutic ability of AVR-25 to mitigate the storm of inflammation and minimize tissue injury with high potential for adjunctive therapy in intra-abdominal sepsis. Sepsis is the leading cause of death in United States hospitals; and elderly and immunocompromised patients are particularly at risk. Sepsis is also among the top conditions for the most expensive hospital stays in the nation and worldwide. More than 900,000 sepsis cases occur each year in the United States, with an annual total cost of approximately $27 billion 1. To date, three broad approaches to adjunctive (non-antibiotic) therapy have been considered for the treatment of sepsis: (1) optimizing oxygen delivery through oxygenation/ventilation strategies and fluid/vasopressor use to maintain peripheral perfusion, (2) reducing bacterial virulence factors via anti-endotoxin antibodies and endotoxin removal columns and (3) targeting host response factors using corticosteroids, anti-cytokine drugs, and anticoagulants. However, current therapies with these agents are minimally effective in patients with sepsis and their lack of efficacy is more pronounced in immunocompromised and older patients 2. Hence, there is a huge unmet medical need to develop an effective sepsis therapy. Inflammatory mediators play a critical role in the pathogenesis and potential management of intra-abdominal sepsis. Animal and clinical data indicate that following bacterial peritonitis, an immense intraperitoneal compartmentalized cytokine response occurs with high levels of certain pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6) 3,4. This cytokine response may be responsible for the uncontrolled activation of the systemic inflammatory cascade. In sepsis cases caused by Gram-negative bacteria, the bacterial endotoxin lipopolysaccharide (LPS) activates the immune system through signaling via the MD2-toll-like receptor 4 (TLR4) complex to initiate the production
Novel Role for the Liver X Nuclear Receptor in the Suppression of Lung Inflammatory Responses
Journal of Biological Chemistry, 2007
The liver X receptors (LXR␣/) are part of the nuclear receptor family and are believed to regulate cholesterol and lipid homeostasis. It has also been suggested that LXR agonists possess anti-inflammatory properties. The aim of this work was to determine the effect of LXR agonists on the innate immune response in human primary lung macrophages and a pre-clinical rodent model of lung inflammation. Before profiling the impact of the agonist, we established that both the human macrophages and the rodent lungs expressed LXR␣/. We then used two structurally distinct LXR agonists to demonstrate that activation of this transcription factor reduces cytokine production in THP-1 cells and lung macrophages. Then, using the expression profile of ATP binding cassettes A1 (ABCA-1; a gene directly linked to LXR activation) as a biomarker for lung exposure of the compound, we demonstrated an LXR-dependent reduction in lung neutrophilia rodents in vivo. This inhibition was not associated with a suppression of c-Fos/c-Jun mRNA expression or NF-B/AP-1 DNA binding, suggesting that any anti-inflammatory activity of LXR agonists is not via inhibition of NF-B/AP-1 transcriptional activity. These data do not completely rule out an impact of these agonists on these two prominent transcription factors. In summary, this study is the first to demonstrate anti-inflammatory actions of LXRs in the lung. Chronic innate inflammatory responses observed in some airway diseases is thought to be central to disease pathogenesis. Therefore, data suggest that LXR ligands have utility in the treatment of lung diseases that involves chronic inflammation mediated by macrophages and neutrophils.
Protective Immunity and Defects in the Neonatal and Elderly Immune Response to Sepsis
The Journal of Immunology, 2014
Populations encompassing extremes of age, including neonates and elderly, have greater mortality from sepsis. We propose that the increased mortality observed in the neonatal and elderly populations after sepsis is due to fundamental differences in hostprotective immunity and is manifested at the level of the leukocyte transcriptome. Neonatal (5-7 d), young adult (6-12 wk), or elderly (20-24 mo) mice underwent a cecal slurry model of intra-abdominal sepsis. Both neonatal and elderly mice exhibited significantly greater mortality to sepsis (p < 0.05). Neonates in particular exhibited significant attenuation of their inflammatory response (p < 0.05), as well as reductions in cell recruitment and reactive oxygen species production (both p < 0.05), all of which could be confirmed at the level of the leukocyte transcriptome. In contrast, elderly mice were also more susceptible to abdominal peritonitis, but this was associated with no significant differences in the magnitude of the inflammatory response, reduced bacterial killing (p < 0.05), reduced early myeloid cell activation (p < 0.05), and a persistent inflammatory response that failed to resolve. Interestingly, elderly mice expressed a persistent inflammatory and immunosuppressive response at the level of the leukocyte transcriptome, with failure to return to baseline by 3 d. This study reveals that neonatal and elderly mice have profoundly different responses to sepsis that are manifested at the level of their circulating leukocyte transcriptome, although the net result of increased mortality is similar. Considering these differences are fundamental aspects of the genomic response to sepsis, interventional therapies will require individualization based on the age of the population.
P2X7 receptor deletion attenuates oxidative stress and liver damage in sepsis
Purinergic Signalling, 2020
Sepsis is a severe disease characterized by an uncontrolled systemic inflammation and consequent organ dysfunction generated in response to an infection. Extracellular ATP acting through the P2X7 receptor induces the maturation and release of proinflammatory cytokines (i.e., IL-1β) and the production of reactive nitrogen and oxygen species that lead to oxidative tissue damage. Here, we investigated the role of the P2X7 receptor in inflammation, oxidative stress, and liver injury in sepsis. Sepsis was induced by cecal ligation and puncture (CLP) in wild-type (WT) and P2X7 knockout (P2X7 −/−) mice. The oxidative stress in the liver of septic mice was assessed by 2′,7′-dichlorofluorescein oxidation reaction (DCF), thiobarbituric acid-reactive substances (TBARS), and nitrite levels dosage. The status of the endogenous defense system was evaluated through catalase (CAT) and superoxide dismutase (SOD) activities. The inflammation was assessed histologically and by determining the expression of inflammatory cytokines and chemokines by RT-qPCR. We observed an increase in the reactive species and lipid peroxidation in the liver of septic WT mice, but not in the liver from P2X7 −/− animals. We found an imbalance SOD/CAT ratio, also only WT septic animals. The number of inflammatory cells and the gene expression of IL-1 β, IL-6, TNF-α, IL-10, CXCL1, and CXCL2 were higher in the liver of WT septic mice in comparison to P2X7 −/− septic animals. In summary, our results suggest that the P2X7 receptor might be a therapeutic target to limit oxidative stress damage and liver injury during sepsis.