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Kosyreva A, Vishnyakova P, Tsvetkov I, Kiseleva V, Dzhalilova DS, Miroshnichenko E, Lokhonina A, Makarova O, Fatkhudinov T. Advantages and disadvantages of treatment of experimental ARDS by M2-polarized RAW 264.7 macrophages. Heliyon 2023; 9:e21880. [PMID: 38027880 PMCID: PMC10658332 DOI: 10.1016/j.heliyon.2023.e21880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 09/20/2023] [Accepted: 10/31/2023] [Indexed: 12/01/2023] Open
Abstract
Innate immunity reactions are core to any immunological process, including systemic inflammation and such extremes as acute respiratory distress syndrome (ARDS) and cytokine storm. Macrophages, the key cells of innate immunity, show high phenotypic plasticity: depending on microenvironmental cues, they can polarize into M1 (classically activated, pro-inflammatory) or M2 (alternatively activated, anti-inflammatory). The anti-inflammatory M2 macrophage polarization-based cell therapies constitute a novel prospective modality. Systemic administration of 'educated' macrophages is intended at their homing in lungs in order to mitigate the pro-inflammatory cytokine production and reduce the risks of 'cytokine storm' and related severe complications. Acute respiratory distress syndrome (ARDS) is the main mortality factor in pneumonia including SARS-CoV-associated cases. This study aimed to evaluate the influence of infusions of RAW 264.7 murine macrophage cell line polarized towards M2 phenotype on the development of LPS-induced ARDS in mouse model. The results indicate that the M2-polarized RAW 264.7 macrophage infusions in the studied model of ARDS promote relocation of lymphocytes from their depots in immune organs to the lungs. In addition, the treatment facilitates expression of M2-polarization markers Arg1, Vegfa and Tgfb and decreases of M1-polarization marker Cd38 in lung tissues, which can indicate the anti-inflammatory response activation. However, treatment of ARDS with M2-polarized macrophages didn't change the neutrophil numbers in the lungs. Moreover, the level of the Arg1 protein in lungs decreased throughtout the treatment with M2 macrophages, which is probably because of the pro-inflammatory microenvironment influence on the polarization of macrophages towards M1. Thus, the chemical polarization of macrophages is unstable and depends on the microenvironment. This adverse effect can be reduced through the use of primary autologous macrophages or some alternative methods of M2 polarization, notably siRNA-mediated.
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Affiliation(s)
- A.M. Kosyreva
- Research Institute of Molecular and Cellular Medicine, Peoples' Friendship University of Russia named after Patrice Lumumba (RUDN), 6 Miklukho-Maklaya Street, 117198, Moscow, Russia
- Avtsyn Research Institute of Human Morphology of Petrovsky National Research Centre of Surgery, 3 Tsyurupy Street, 117418, Moscow, Russia
| | - P.A. Vishnyakova
- Research Institute of Molecular and Cellular Medicine, Peoples' Friendship University of Russia named after Patrice Lumumba (RUDN), 6 Miklukho-Maklaya Street, 117198, Moscow, Russia
- National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 4 Oparina Street, 117997, Moscow, Russia
| | - I.S. Tsvetkov
- Avtsyn Research Institute of Human Morphology of Petrovsky National Research Centre of Surgery, 3 Tsyurupy Street, 117418, Moscow, Russia
| | - V.V. Kiseleva
- Research Institute of Molecular and Cellular Medicine, Peoples' Friendship University of Russia named after Patrice Lumumba (RUDN), 6 Miklukho-Maklaya Street, 117198, Moscow, Russia
- National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 4 Oparina Street, 117997, Moscow, Russia
| | - D. Sh. Dzhalilova
- Research Institute of Molecular and Cellular Medicine, Peoples' Friendship University of Russia named after Patrice Lumumba (RUDN), 6 Miklukho-Maklaya Street, 117198, Moscow, Russia
- Avtsyn Research Institute of Human Morphology of Petrovsky National Research Centre of Surgery, 3 Tsyurupy Street, 117418, Moscow, Russia
| | - E.A. Miroshnichenko
- Research Institute of Molecular and Cellular Medicine, Peoples' Friendship University of Russia named after Patrice Lumumba (RUDN), 6 Miklukho-Maklaya Street, 117198, Moscow, Russia
- Avtsyn Research Institute of Human Morphology of Petrovsky National Research Centre of Surgery, 3 Tsyurupy Street, 117418, Moscow, Russia
| | - A.V. Lokhonina
- Research Institute of Molecular and Cellular Medicine, Peoples' Friendship University of Russia named after Patrice Lumumba (RUDN), 6 Miklukho-Maklaya Street, 117198, Moscow, Russia
- National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 4 Oparina Street, 117997, Moscow, Russia
| | - O.V. Makarova
- Avtsyn Research Institute of Human Morphology of Petrovsky National Research Centre of Surgery, 3 Tsyurupy Street, 117418, Moscow, Russia
| | - T.H. Fatkhudinov
- Research Institute of Molecular and Cellular Medicine, Peoples' Friendship University of Russia named after Patrice Lumumba (RUDN), 6 Miklukho-Maklaya Street, 117198, Moscow, Russia
- Avtsyn Research Institute of Human Morphology of Petrovsky National Research Centre of Surgery, 3 Tsyurupy Street, 117418, Moscow, Russia
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Effect of General Anesthesia Maintenance with Propofol or Sevoflurane on Fractional Exhaled Nitric Oxide and Eosinophil Blood Count: A Prospective, Single Blind, Randomized, Clinical Study on Patients Undergoing Thyroidectomy. J Pers Med 2022; 12:jpm12091455. [PMID: 36143240 PMCID: PMC9505258 DOI: 10.3390/jpm12091455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 08/31/2022] [Accepted: 09/01/2022] [Indexed: 11/30/2022] Open
Abstract
Background: Nitric oxide (NO) is considered a means of detecting airway hyperresponsiveness, since even non-asthmatic patients experiencing bronchospasm intraoperatively or postoperatively display higher levels of exhaled NO. It can also be used as a non-invasive biomarker of lung inflammation and injury. This prospective, single-blind, randomized study aimed to evaluate the impact of two different anesthesia maintenance techniques on fractional exhaled nitric oxide (FeΝO) in patients without respiratory disease undergoing total thyroidectomy under general anesthesia. Methods: Sixty patients without respiratory disease, atopy or known allergies undergoing total thyroidectomy were randomly allocated to receive either inhalational anesthesia maintenance with sevoflurane at a concentration that maintained Bispectral Index (BIS) values between 40 and 50 intraoperatively or intravenous anesthesia maintenance with propofol 1% targeting the same BIS values. FeΝO was measured immediately preoperatively (baseline), postoperatively in the Postanesthesia Care Unit and at 24 h post-extubation with a portable device. Other variables measured were eosinophil blood count preoperatively and postoperatively and respiratory parameters intraoperatively. Results: Patients in both groups presented lower than baseline values of FeΝO measurements postoperatively, which returned to baseline measurements at 24 h post-extubation. In the peripheral blood, a decrease in the percentage of eosinophils was demonstrated, which was significant only in the propofol group. Respiratory lung mechanics were better maintained in the propofol group as compared to the sevoflurane group. None of the patients suffered intraoperative bronchospasm. Conclusions: Both propofol and sevoflurane lead to the temporary inhibition of NO exhalation. They also seem to attenuate systemic hypersensitivity response by reducing the eosinophil count in the peripheral blood, with propofol displaying a more pronounced effect and ensuring a more favorable mechanical ventilation profile as compared to sevoflurane. The attenuation of NO exhalation by both agents may be one of the underlying mechanisms in the reduction in airway hyperreactivity. The clinical significance of this fluctuation remains to be studied in patients with respiratory disease.
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Heil LBB, Silva PL, Pelosi P, Rocco PRM. Immunomodulatory effects of anesthetics in obese patients. World J Crit Care Med 2017; 6:140-152. [PMID: 28828299 PMCID: PMC5547428 DOI: 10.5492/wjccm.v6.i3.140] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Revised: 04/27/2017] [Accepted: 07/10/2017] [Indexed: 02/06/2023] Open
Abstract
Anesthesia and surgery have an impact on inflammatory responses, which influences perioperative homeostasis. Inhalational and intravenous anesthesia can alter immune-system homeostasis through multiple processes that include activation of immune cells (such as monocytes, neutrophils, and specific tissue macrophages) with release of pro- or anti-inflammatory interleukins, upregulation of cell adhesion molecules, and overproduction of oxidative radicals. The response depends on the timing of anesthesia, anesthetic agents used, and mechanisms involved in the development of inflammation or immunosuppression. Obese patients are at increased risk for chronic diseases and may have the metabolic syndrome, which features insulin resistance and chronic low-grade inflammation. Evidence has shown that obesity has adverse impacts on surgical outcome, and that immune cells play an important role in this process. Understanding the effects of anesthetics on immune-system cells in obese patients is important to support proper selection of anesthetic agents, which may affect postoperative outcomes. This review article aims to integrate current knowledge regarding the effects of commonly used anesthetic agents on the lungs and immune response with the underlying immunology of obesity. Additionally, it identifies knowledge gaps for future research to guide optimal selection of anesthetic agents for obese patients from an immunomodulatory standpoint.
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Du G, Wang S, Li Z, Liu J. Sevoflurane Posttreatment Attenuates Lung Injury Induced by Oleic Acid in Dogs. Anesth Analg 2017; 124:1555-1563. [PMID: 28431421 DOI: 10.1213/ane.0000000000002034] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND In animal models, both sevoflurane and propofol protect against acute lung injury (ALI), especially when administered prior to ALI onset. We hypothesized that when compared to propofol, sevoflurane administration after the onset of acute respiratory distress syndrome would mitigate oleic acid (OA)-induced ALI in dogs. METHODS Dogs were randomly assigned to receive intravenous OA to induce ALI (n = 7 for each OA group) or saline as an OA control (n = 6 for each control). Dogs were then mechanically ventilated for 6 hours during which propofol (5 mg/kg/h) or sevoflurane (1.0 minimum alveolar concentration) was administered for sedation. Study end points included PO2/FIO2 ratio, pulmonary arterial pressure, pulmonary edema, histology, and tumor nuclear factor-α. RESULTS In OA-injured animals, oxygenation was worse at 1, 2, 3, and 4 hours after 6-hour mechanical ventilation in sevoflurane-sedated animals compared with propofol-sedated animals, with mean difference (95% confidence interval; propofol minus sevoflurane) of 75 (39-111), 87 (55-119), 66 (44-87), and 67 (27-107) mm Hg for the respective time points. However, sevoflurane reduced the elevated pulmonary arterial pressure and vascular resistance, attenuated pulmonary edema as evidenced by reduced extravascular lung water index, and decreased tumor nuclear factor-α and diffuse alveolar damage score compared with propofol in the OA-injured lungs. CONCLUSIONS When compared with propofol, sevoflurane attenuates OA-induced lung damage. However, despite this effect on lung histology and inflammation, sevoflurane worsened oxygenation in OA-induced ALI, possibly via inhibition of hypoxic pulmonary vasoconstriction.
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Affiliation(s)
- Guizhi Du
- From the *Laboratory of Anesthesia and Critical Care Medicine, Department of Anesthesiology, West China Hospital of Sichuan University, Chengdu, Sichuan, China; †Department of Neurology, The Second People's Hospital of Chengdu, Chengdu, Sichuan, China; and ‡Department of Pharmacy, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, China
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Lin CC, Chen DY, Tang KT, Chao YH, Shen CH, Lui PW. Inhibitory effects of propofol on Th17 cell differentiation. Immunopharmacol Immunotoxicol 2017; 39:211-218. [PMID: 28555509 DOI: 10.1080/08923973.2017.1327962] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Propofol (2,6-diisopropylphenol) is probably the most widely used intravenous anesthetic agent in daily practice. It has been reported to show immunomodulatory activity. However, the effect of propofol on the differention of T cells remains unclear. In this study, we demonstrated for the first time that propofol inhibited both interleukin (IL)-6 plus transforming growth factor-β (TGF-β)-induced Th17 cell differentiation in vitro and in LPS-challenged mice. Propofol also suppressed the IL-6-induced phosphorylation of Janus kinase-2 (JAK2)/signal transducer and activator of transcription (STAT3) pathway, a cytokine-activated essential transcription factor in Th17 cell development, which occurred concomitantly with the enhancement of suppressor of cytokine signaling-3 (SOCS3) expression involved in the downregulation of STAT3 phosphorylation. These data extend our knowledge of the immunosuppressive effects of propofol and their underlying mechanism.
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Affiliation(s)
- Chi-Chien Lin
- a Institute of Biomedical Science, National Chung Hsing University , Taichung , Taiwan.,b Department of Medical Research , China Medical University Hospital , Taichung , Taiwan.,c Department of Biotechnology , Asia University , Taichung , Taiwan
| | - Der-Yuan Chen
- d Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine , Taichung Veterans General Hospital , Taichung , Taiwan.,e School of Medicine , National Yang-Ming University , Taipei , Taiwan.,f Department of Medical Research , Taichung Veterans General Hospital , Taichung , Taiwan
| | - Kuo-Tung Tang
- a Institute of Biomedical Science, National Chung Hsing University , Taichung , Taiwan.,d Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine , Taichung Veterans General Hospital , Taichung , Taiwan
| | - Ya-Hsuan Chao
- a Institute of Biomedical Science, National Chung Hsing University , Taichung , Taiwan
| | - Ching-Hui Shen
- e School of Medicine , National Yang-Ming University , Taipei , Taiwan.,g Department of Anesthesiology , Taichung Veterans General Hospital , Taichung , Taiwan
| | - Ping-Wing Lui
- a Institute of Biomedical Science, National Chung Hsing University , Taichung , Taiwan.,e School of Medicine , National Yang-Ming University , Taipei , Taiwan.,f Department of Medical Research , Taichung Veterans General Hospital , Taichung , Taiwan.,g Department of Anesthesiology , Taichung Veterans General Hospital , Taichung , Taiwan
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The Relationship Between Sedatives, Sedative Strategy, and Healthcare-Associated Infection: A Systematic Review. Infect Control Hosp Epidemiol 2016; 37:1234-42. [PMID: 27322888 DOI: 10.1017/ice.2016.129] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Healthcare-associated infections (HAIs) cause significant morbidity in critically ill patients. An underappreciated but potentially modifiable risk factor for infection is sedation strategy. Recent trials suggest that choice of sedative agent, depth of sedation, and sedative management can influence HAI risk in mechanically ventilated patients. OBJECTIVE To better characterize the relationships between sedation strategies and infection. METHODS Systematic literature review. RESULTS We found 500 articles and accepted 70 for review. The 3 most common sedatives for mechanically ventilated patients (benzodiazepines, propofol, and dexmedetomidine) have different pharmacologic and immunomodulatory effects that may impact infection risk. Clinical data are limited but retrospective observational series have found associations between sedative use and pneumonia whereas prospective studies of sedative interruptions have reported possible decreases in bloodstream infections, pneumonia, and ventilator-associated events. CONCLUSION Infection rates appear to be highest with benzodiazepines, intermediate with propofol, and lowest with dexmedetomidine. More data are needed but studies thus far suggest that a better understanding of sedation practices and infection risk may help hospital epidemiologists and critical care practitioners find new ways to mitigate infection risk in critically ill patients. Infect Control Hosp Epidemiol 2016;1-9.
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Fahmi ANA, Shehatou GSG, Shebl AM, Salem HA. Febuxostat protects rats against lipopolysaccharide-induced lung inflammation in a dose-dependent manner. Naunyn Schmiedebergs Arch Pharmacol 2015; 389:269-78. [PMID: 26713331 DOI: 10.1007/s00210-015-1202-6] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2015] [Accepted: 12/15/2015] [Indexed: 01/08/2023]
Abstract
The aim of the present work was to investigate possible protective effects of febuxostat, a highly potent xanthine oxidase inhibitor, against acute lung injury (ALI) induced by lipopolysaccharide (LPS) in rats. Male Sprague Dawley rats were randomly divided into six groups, as follows: (i) vehicle control group; (ii) and (iii) febuxostat 10 and febuxostat 15 groups, drug-treated controls; (iv) LPS group, receiving an intraperitoneal injection of LPS (7.5 mg/kg); (v) and (vi) febuxostat 10-LPS and febuxostat 15-LPS groups, receiving oral treatment of febuxostat (10 and 15 mg/kg/day, respectively) for 7 days before LPS. After 18 h administration of LPS, blood was collected for C-reactive protein (CRP) measurement. Bronchoalveolar lavage fluid (BALF) was examined for leukocyte infiltration, lactate dehydrogenase (LDH) activity, protein content, and total nitrate/nitrite. Lung weight gain was determined, and lung tissue homogenate was prepared and evaluated for oxidative stress. Tumor necrosis factor-α (TNF-α) was assessed in BALF and lung homogenate. Moreover, histological changes of lung tissues were evaluated. LPS elicited lung injury characterized by increased lung water content (by 1.2 fold), leukocyte infiltration (by 13 fold), inflammation and oxidative stress (indicated by increased malondialdehyde (MDA), by 3.4 fold), and reduced superoxide dismutase (SOD) activity (by 34 %). Febuxostat dose-dependently decreased LPS-induced lung edema and elevations in BALF protein content, infiltration of leukocytes, and LDH activity. Moreover, the elevated levels of TNF-α in BALF and lung tissue of LPS-treated rats were attenuated by febuxostat pretreatment. Febuxostat also displayed a potent antioxidant activity by decreasing lung tissue levels of MDA and enhancing SOD activity. Histological analysis of lung tissue further demonstrated that febuxostat dose-dependently reversed LPS-induced histopathological changes. These findings demonstrate a significant dose-dependent protection by febuxostat against LPS-induced lung inflammation in rats.
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Affiliation(s)
- Alaa N A Fahmi
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt
| | - George S G Shehatou
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
| | - Abdelhadi M Shebl
- Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Hatem A Salem
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt
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Zhou CH, Zhu YZ, Zhao PP, Xu CM, Zhang MX, Huang H, Li J, Liu L, Wu YQ. Propofol Inhibits Lipopolysaccharide-Induced Inflammatory Responses in Spinal Astrocytes via the Toll-Like Receptor 4/MyD88-Dependent Nuclear Factor-κB, Extracellular Signal-Regulated Protein Kinases1/2, and p38 Mitogen-Activated Protein Kinase Pathways. Anesth Analg 2015; 120:1361-8. [PMID: 25695672 DOI: 10.1213/ane.0000000000000645] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND In this study, we investigated the effect of propofol, a commonly used IV anesthetic, on lipopolysaccharide (LPS)-induced inflammatory responses in astrocytes and explored the molecular mechanisms by which it occurs. METHODS Astrocytes were stimulated with LPS (1.0 μg/mL) in the absence and presence of different concentrations of propofol. The expression of astrocyte marker glial fibrillary acidic protein (GFAP) in astrocytes was detected using immunofluorescence staining and Western blot analysis. The levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α were measured using an enzyme-linked immunosorbent assay. The mRNA level of Toll-like receptor 4 (TLR4) was determined by semiquantitative reverse transcriptase-polymerase chain reaction. The protein expressions of TLR4, myeloid differentiation factor 88 (MyD88), p- extracellular signal-regulated protein kinases (ERK)1/2, p-c-Jun N-terminal kinase, p-p38 mitogen-activated protein kinase (MAPK), p-I-κBα, I-κBα, and p-nuclear factor-κB (NF-κB)p65 were detected by Western blot. RESULTS Our results show that after stimulation with LPS, the levels of IL-1β, IL-6, and tumor necrosis factor-α and the expression of GFAP in astrocytes were up-regulated significantly. In addition, the expression of TLR4, MyD88, p-ERK1/2, p-c-Jun N-terminal kinase, p-p38 MAPK, and p-NF-κBp65 increased, whereas the expression of total I-κBα decreased upon stimulation with LPS. Propofol (10 μM) reduced the secretion of proinflammatory cytokines, inhibited the expressions of GFAP, TLR4, MyD88, p-ERK1/2, p-p38 MAPK, and p-NF-κBp65 in astrocytes challenged with LPS. CONCLUSIONS In the present study, propofol 10 μM but not lower clinically relevant or higher supra-clinical concentrations attenuated LPS-induced astrocyte activation and subsequent inflammatory responses by inhibiting the TLR4/MyD88-dependent NF-κB, ERK1/2, and p38 MAPK pathways.
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Affiliation(s)
- Cheng-Hua Zhou
- From the *Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical College, Xuzhou, PR China; †Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, PR China; and ‡Department of Anesthetic Pharmacology, Xuzhou Medical College, Xuzhou, PR China
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Effect of Therapeutic Hypercapnia on Inflammatory Responses to One-lung Ventilation in Lobectomy Patients. Anesthesiology 2015; 122:1235-52. [PMID: 25751232 DOI: 10.1097/aln.0000000000000627] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND One-lung ventilation (OLV) can result in local and systemic inflammation. This prospective, randomized trial was to evaluate the effect of therapeutic hypercapnia on lung injury after OLV. METHOD Fifty patients aged 20 to 60 yr undergoing lobectomy were randomly provided with air or carbon dioxide (partial pressure of carbon dioxide: 35 to 45 mmHg or 60 to 70 mmHg). Peak pressure, plateau pressure, and lung compliance were recorded. Bronchoalveolar lavage fluid (BALF) and blood samples were collected. Adverse events were monitored. The primary outcome was the concentration of BALF tumor necrosis factor, and the secondary outcomes were serum cytokine concentrations. RESULTS The BALF tumor necrosis factor was lower in the carbon dioxide group than in the air group (median [range], 51.1 [42.8 to 76.6] vs. 71.2 [44.8 to 92.7]; P = 0.034). Patients in the carbon dioxide group had lower concentrations of serum and BALF interleukin (IL)-1, IL-6, and IL-8, but higher serum concentrations of IL-10, accompanied by reduced numbers of cells and neutrophils as well as lower concentrations of protein in the BALF. Also, patients in the carbon dioxide group had lower peak (mean ± SD, 22.2 ± 2.9 vs. 29.8 ± 4.6) and plateau pressures (20.5 ± 2.4 vs. 27.1 ± 2.9), but higher dynamic compliance (46.6 ± 5.8 vs. 38.9 ± 6.5). Furthermore, patients in the carbon dioxide group had higher postoperation oxygenation index values. Ten patients experienced slightly increased blood pressure and heart rate during OLV in the carbon dioxide group. CONCLUSION Under intravenous anesthesia, therapeutic hypercapnia inhibits local and systematic inflammation and improves respiratory function after OLV in lobectomy patients without severe complications.
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Zhao LL, Hu GC, Zhu SS, Li JF, Liu GJ. Propofol pretreatment attenuates lipopolysaccharide-induced acute lung injury in rats by activating the phosphoinositide-3-kinase/Akt pathway. ACTA ACUST UNITED AC 2014. [PMID: 25387673 PMCID: PMC4244672 DOI: 10.1590/1414-431x20143949] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The aim of this study was to investigate the effect of propofol pretreatment on lipopolysaccharide (LPS)-induced acute lung injury (ALI) and the role of the phosphoinositide-3-kinase/protein kinase B (PI3K/Akt) pathway in this procedure. Survival was determined 48 h after LPS injection. At 1 h after LPS challenge, the lung wet- to dry-weight ratio was examined, and concentrations of protein, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in bronchoalveolar lavage fluid (BALF) were determined using the bicinchoninic acid method or ELISA. Lung injury was assayed via lung histological examination. PI3K and p-Akt expression levels in the lung tissue were determined by Western blotting. Propofol pretreatment prolonged survival, decreased the concentrations of protein, TNF-α, and IL-6 in BALF, attenuated ALI, and increased PI3K and p-Akt expression in the lung tissue of LPS-challenged rats, whereas treatment with wortmannin, a PI3K/Akt pathway specific inhibitor, blunted this effect. Our study indicates that propofol pretreatment attenuated LPS-induced ALI, partly by activation of the PI3K/Akt pathway.
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Affiliation(s)
- L L Zhao
- Department of Anesthesiology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu Province, China
| | - G C Hu
- Department of Pharmacology, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - S S Zhu
- Department of Anesthesiology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu Province, China
| | - J F Li
- Department of Anesthesiology, Tengzhou Central People's Hospital, Liaocheng, Shandong Province, China
| | - G J Liu
- Department of Anesthesiology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu Province, China
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Pei Z, Wang J. Propofol attenuates LPS-induced tumor necrosis factor-α, interleukin-6 and nitric oxide expression in canine peripheral blood mononuclear cells possibly through down-regulation of nuclear factor (NF)-κB activation. J Vet Med Sci 2014; 77:139-45. [PMID: 25312048 PMCID: PMC4363014 DOI: 10.1292/jvms.14-0212] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Sepsis is a major cause of mortality in intensive care medicine. Propofol, an intravenous general anesthetic, has been suggested to have anti-inflammatory properties and able to prevent sepsis induced by Gram-positive and Gram-negative bacteria by down-regulating the gene expression of pro-inflammatory cytokines. However, propofol’s anti-inflammatory effects upon canine peripheral blood mononuclear cells (PBMCs) have not yet been clarified. Here, we isolate canine PBMCs and investigate the effects of propofol on the gene expressions of both lipopolysaccharide (LPS)-induced interleukin-6 (IL-6) and tumor necrosis factor (TNF)-α and upon the production of nitric oxide (NO). Through real-time quantitative PCR and the Griess reagent system, we found that non-cytotoxic levels of propofol significantly inhibited the release of NO and IL-6 and TNF-α gene expression in LPS-induced canine PBMCs. Western blotting revealed that LPS
does significantly increase the expression of inducible NO synthase (iNOS) protein in canine PBMCs, while pretreatment with propofol significantly decreases the LPS-induced iNOS protein expression. Propofol, at concentration of 25 µM and 50 µM, also significantly inhibited the LPS-induced nuclear translocation of nuclear factor (NF)-κB p65 protein in canine PBMCs. This diminished TNF-α, IL-6 and iNOS expression, and NO production was in parallel to the respective decreased NF-κB p65 protein nuclear translocation in the LPS-activated canine PBMCs pretreated with 25 µM and 50 µM propofol. This suggests that non-cytotoxic levels of propofol pretreatment can down-regulate LPS-induced inflammatory responses in canine PBMCs, possibly by inhibiting the nuclear translocation of the NF-κB p65 protein.
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Affiliation(s)
- Zengyang Pei
- Department of Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou 310058, PR China
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Propofol inhibits lipopolysaccharide-induced tumor necrosis factor-alpha expression and myocardial depression through decreasing the generation of superoxide anion in cardiomyocytes. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2014; 2014:157376. [PMID: 25180066 PMCID: PMC4144395 DOI: 10.1155/2014/157376] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/18/2014] [Accepted: 07/16/2014] [Indexed: 11/17/2022]
Abstract
TNF-α has been shown to be a major factor responsible for myocardial depression in sepsis. The aim of this study was to investigate the effect of an anesthetic, propofol, on TNF-α expression in cardiomyocytes treated with LPS both in vivo and in vitro. In cultured cardiomyocytes, compared with control group, propofol significantly reduced protein expression of gp91phox and phosphorylation of extracellular regulated protein kinases 1/2 (ERK1/2) and p38 MAPK, which associates with reduced TNF-α production. In in vivo mice studies, propofol significantly improved myocardial depression and increased survival rate of mice after LPS treatment or during endotoxemia, which associates with reduced myocardial TNF-α production, gp91phox, ERK1/2, and p38 MAPK. It is concluded that propofol abrogates LPS-induced TNF-α production and alleviates cardiac depression through gp91phox/ERK1/2 or p38 MAPK signal pathway. These findings have great clinical importance in the application of propofol for patients enduring sepsis.
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Anderson SL, Duke-Novakovski T, Singh B. The immune response to anesthesia: part 2 sedatives, opioids, and injectable anesthetic agents. Vet Anaesth Analg 2014; 41:553-66. [PMID: 24962601 DOI: 10.1111/vaa.12191] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2014] [Accepted: 03/24/2014] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To review the immune response to injectable anesthetics and sedatives and to compare the immunomodulatory properties between inhalation and injectable anesthetic protocols. STUDY DESIGN Review. METHODS AND DATABASES Multiple literature searches were performed using PubMed and Google Scholar from March 2012 through November 2013. Relevant anesthetic and immune terms were used to search databases without year published or species constraints. The online database for Veterinary Anaesthesia and Analgesia and the Journal of Veterinary Emergency and Critical Care were searched by issue starting in 2000 for relevant articles. CONCLUSION Sedatives, injectable anesthetics, opioids, and local anesthetics have immunomodulatory effects that may have positive or negative consequences on disease processes such as endotoxemia, generalized sepsis, tumor growth and metastasis, and ischemia-reperfusion injury. Therefore, anesthetists should consider the immunomodulatory effects of anesthetic drugs when designing anesthetic protocols for their patients.
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Affiliation(s)
- Stacy L Anderson
- Department of Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK, Canada
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Zhao W, Zhou S, Yao W, Gan X, Su G, Yuan D, Hei Z. Propofol prevents lung injury after intestinal ischemia-reperfusion by inhibiting the interaction between mast cell activation and oxidative stress. Life Sci 2014; 108:80-7. [PMID: 24878149 DOI: 10.1016/j.lfs.2014.05.009] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2014] [Revised: 04/19/2014] [Accepted: 05/13/2014] [Indexed: 12/22/2022]
Abstract
AIMS Both mast cells and oxidative stress are involved in acute lung injury (ALI) induced by intestinal ischemia-reperfusion (IIR). The aim of this study was to investigate whether propofol could improve IIR-induced ALI through inhibiting their interaction. MAIN METHODS Repetitive, brief IIR or IIR+compound 48/80 was performed in adult Sprague-Dawley rats pretreated with saline, apocynin or propofol. And their lungs were excised for histology, ELISA and protein-expression measurements 2h after reperfusion. KEY FINDINGS Rats pretreated with saline developed critical ALI 2h after IIR. We found significant elevations in lung injury scores, lung wet/dry ratio and gp91phox, p47phox, intercellular cell adhesion molecule-1 protein expressions and higher level of malondialdehyde, interleukin-6 contents, and myeloperoxidase activities, as well as significant reductions in superoxide dismutase activities, accompanied with increases in mast cell degranulation evidenced by significant increases in mast cell counts, β-hexosaminidase concentrations, and tryptase expression. And the lung injury was aggravated in the presence of compound 48/80. However, pretreated with propofol and apocynin not only ameliorated the IIR-mediated pulmonary changes beyond the biochemical changes but also reversed the changes that were aggravated by compound 48/80. SIGNIFICANCE Propofol protects against IIR-mediated ALI, most likely by inhibiting the interaction between oxidative stress and mast cell degranulation.
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Affiliation(s)
- Weicheng Zhao
- Department of Anesthesiology, The First People's Hospital of Foshan, 81 North of Rinlan Road, Foshan 528000, China; Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Shaoli Zhou
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Weifeng Yao
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Xiaoliang Gan
- Department of Anesthesiology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 South of Xianlie Road, Guangzhou 510060, China
| | - Guangjie Su
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Dongdong Yuan
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Ziqing Hei
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.
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A combination of radiosurgery and soluble tissue factor enhances vascular targeting for experimental glioblastoma. BIOMED RESEARCH INTERNATIONAL 2013; 2013:390714. [PMID: 24307995 PMCID: PMC3838847 DOI: 10.1155/2013/390714] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/28/2013] [Accepted: 09/25/2013] [Indexed: 11/17/2022]
Abstract
Radiosurgery for glioblastoma is limited to the development of resistance, allowing tumor cells to survive and initiate tumor recurrence. Based on our previous work that coadministration of tissue factor and lipopolysaccharide following radiosurgery selectively induced thrombosis in cerebral arteriovenous malformations, achieving thrombosis of 69% of the capillaries and 39% of medium sized vessels, we hypothesized that a rapid and selective shutdown of the capillaries in glioblastoma vasculature would decrease the delivery of oxygen and nutrients, reducing tumor growth, preventing intracranial hypertension, and improving life expectancy. Glioblastoma was formed by implantation of GL261 cells into C57Bl/6 mouse brain. Mice were intravenously injected tissue factor, lipopolysaccharide, a combination of both, or placebo 24 hours after radiosurgery. Control mice received both agents after sham irradiation. Coadministration of tissue factor and lipopolysaccharide led to the formation of thrombi in up to 87 ± 8% of the capillaries and 46 ± 4% of medium sized vessels within glioblastoma. The survival rate of mice in this group was 80% versus no survivor in placebo controls 30 days after irradiation. Animal body weight increased with time in this group (r = 0.88, P = 0.0001). Thus, radiosurgery enhanced treatment with tissue factor, and lipopolysaccharide selectively induces thrombosis in glioblastoma vasculature, improving life expectancy.
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Smith MA, Hibino M, Falcione BA, Eichinger KM, Patel R, Empey KM. Immunosuppressive aspects of analgesics and sedatives used in mechanically ventilated patients: an underappreciated risk factor for the development of ventilator-associated pneumonia in critically ill patients. Ann Pharmacother 2013; 48:77-85. [PMID: 24259637 DOI: 10.1177/1060028013510698] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
OBJECTIVE To evaluate the evidence describing the immunosuppressive and pharmacokinetic properties of commonly used analgesic and sedation agents in critically ill patients. DATA SOURCES MEDLINE (January 1980-September 2013) was searched. STUDY SELECTION AND DATA EXTRACTION All in vitro and in vivo studies that evaluated the immune-modulating properties of analgesic and sedation agents commonly used in the critically ill were included. Full-text and abstract-only articles (noted) were included in this review. Inclusion criteria were met by 46 studies and were evaluated. DATA SYNTHESIS Analgesic and sedation agents have been shown to be immunosuppressive in a variety of models. In vitro models use a variety of immune cells to demonstrate the immunosuppressive properties of opioids, benzodiazepines, and to a lesser extent, propofol. In each case, animal studies provide more robust data supporting the concept that opioids, benzodiazepines, and propofol exhibit immunosuppressive activities ranging from innate to adaptive immune alterations. Human studies, though more limited, provide further support that these agents inhibit the immune response. In contrast, data have shown that dexmedetomidine may attenuate the immune system. Clinical trial data evaluating the immunosuppressive properties of these agents is limited. CONCLUSIONS Analgesic and sedation agents have clearly been shown to alter cellular function and other mediators of the immune system; yet the clinical impact remains to be fully elucidated. The mechanism by which sedation interruption reduces ventilator-associated pneumonia may in fact be a reduction in immunosuppressive effects. Studies linking the immune-modulating effects of analgesic and sedation agents in critically ill patients are needed.
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Ko HM, Kim SY, Joo SH, Cheong JH, Yang SI, Shin CY, Koo BN. Synergistic activation of lipopolysaccharide-stimulated glial cells by propofol. Biochem Biophys Res Commun 2013; 438:420-6. [PMID: 23899524 DOI: 10.1016/j.bbrc.2013.07.089] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2013] [Accepted: 07/22/2013] [Indexed: 02/08/2023]
Abstract
Despite the extensive use of propofol in general anesthetic procedures, the effects of propofol on glial cell were not completely understood. In lipopolysaccharide (LPS)-stimulated rat primary astrocytes and BV2 microglial cell lines, co-treatment of propofol synergistically induced inflammatory activation as evidenced by the increased production of NO, ROS and expression of iNOS, MMP-9 and several cytokines. Propofol augmented the activation of JNK and p38 MAPKs induced by LPS and the synergistic activation of glial cells by propofol was prevented by pretreatment of JNK and p38 inhibitors. When we treated BV2 cell culture supernatants treated with LPS plus propofol on cultured rat primary neuron, it induced a significant neuronal cell death. The results suggest that the repeated use of propofol in immunologically challenged situation may induce glial activation in brain.
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Affiliation(s)
- Hyun Myung Ko
- Department of Pharmacology, School of Medicine and SMART-IABS, Konkuk University, Seoul 143-701, Republic of Korea
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Ma L, Wu XY, Zhang LH, Chen WM, Uchiyama A, Mashimo T, Fujino Y. Propofol exerts anti-inflammatory effects in rats with lipopolysaccharide-induced acute lung injury by inhibition of CD14 and TLR4 expression. Braz J Med Biol Res 2013; 46:299-305. [PMID: 23532269 PMCID: PMC3854382 DOI: 10.1590/1414-431x20122379] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2012] [Accepted: 12/04/2012] [Indexed: 01/23/2023] Open
Abstract
We investigated the effect of propofol (Prop) administration (10 mg kg-1 h-1, intravenously) on lipopolysaccharide (LPS)-induced acute lung injury and its effect on cluster of differentiation (CD) 14 and Toll-like receptor (TLR) 4 expression in lung tissue of anesthetized, ventilated rats. Twenty-four male Wistar rats were randomly divided into three groups of 8 rats each: control, LPS, and LPS+Prop. Lung injury was assayed via blood gas analysis and lung histology, and tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) levels were determined in bronchoalveolar lavage fluid using ELISA. Real-time polymerase chain reaction was used to detect CD14 and TLR4 mRNA levels, and CD14 and TLR4 protein expression was determined by Western blot. The pathological scores were 1.2 ± 0.9, 3.3 ± 1.1, and 1.9 ± 1.0 for the control, LPS, and LPS+Prop groups, respectively, with statistically significant differences between control and LPS groups (P < 0.05) and between LPS and LPS+Prop groups (P < 0.05). The administration of LPS resulted in a significant increase in TNF-α and IL-1β levels, 7- and 3.5-fold, respectively (P < 0.05), while treatment with propofol partially blunted the secretion of both cytokines (P < 0.05). CD14 and TLR4 mRNA levels were increased in the LPS group (1.48 ± 0.05 and 1.26 ± 0.03, respectively) compared to the control group (1.00 ± 0.20 and 1.00 ± 0.02, respectively; P < 0.05), while propofol treatment blunted this effect (1.16 ± 0.05 and 1.12 ± 0.05, respectively; P < 0.05). Both CD14 and TLR4 protein levels were elevated in the LPS group compared to the control group (P < 0.05), while propofol treatment partially decreased the expression of CD14 and TLR4 protein versus LPS alone (P < 0.05). Our study indicates that propofol prevents lung injury, most likely by inhibition of CD14 and TLR4 expression.
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Affiliation(s)
- Ling Ma
- Department of Anesthesiology, Shengjing Hospital, China Medical University, Shenyang, China.
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Gui B, Su M, Chen J, Jin L, Wan R, Qian Y. Neuroprotective effects of pretreatment with propofol in LPS-induced BV-2 microglia cells: role of TLR4 and GSK-3β. Inflammation 2013; 35:1632-40. [PMID: 22588329 DOI: 10.1007/s10753-012-9478-x] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Surgery often leads to neuroinflammation, which mainly acts as the activation of microglia cells. Propofol is always used for induction and maintenance of anesthesia prior to surgical trauma, whereas whether or not it could attenuate neuroinflammation used prophylactically is not well defined. In the present study, we incubated BV-2 microglia cells with 1 μg/ml lipopolysaccharide (LPS) to mimic neuroinflammation in vitro. Firstly, cell viability was measured using 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay and the data indicated that propofol would not reduce cell viability unless its concentration reached 300 μM. Secondly, BV-2 microglia cells were pretreated with 30 μM propofol (clinically relevant concentration), and then stimulated with LPS. The results showed that the production of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-10 was considerably increased by LPS, but the change could be markedly attenuated by pretreatment with propofol. Meanwhile, pretreatment with propofol inhibited LPS-induced augmentation of toll-like receptor 4 (TLR4) expression at both mRNA and protein levels and further upregulated LPS-induced inactivation of glycogen synthase kinase-3β (GSK-3β) in BV-2 microglia cells. These results indicated, at least in part, that pretreatment with propofol can protect BV-2 microglia cells against LPS-induced inflammation. Downregulation of TLR4 expression and inactivation of GSK-3β may be involved in its protective effect.
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Affiliation(s)
- Bo Gui
- Department of Anesthesiology, The First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China
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20
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Cui WY, Tian AY, Bai T. Protective effects of propofol on endotoxemia-induced acute kidney injury in rats. Clin Exp Pharmacol Physiol 2012; 38:747-54. [PMID: 21824173 DOI: 10.1111/j.1440-1681.2011.05584.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
1. Animal studies suggest that propofol protects against endotoxaemia-induced lung and kidney injury. Upregulation of aquaporin expression in lung tissue mediates these effects, but the mechanism of action in the kidney is unclear. The present study examined the protective effects of propofol on endotoxaemia-induced acute kidney injury in rats. 2. A rat model of endotoxaemia was established using lipopolysaccharide (LPS). We determined the effects of 10% propofol administration 1 h before, during and 1 h after LPS-induced endotoxaemia on expression of aquaporin (AQP)-2, tumour necrosis factor (TNF)-α, intercellular adhesion molecule (ICAM)-1, caspase 3, Bcl-2 and Bax using reverse transcription-polymerase chain reaction, western blotting and immunocytochemistry. Renal morphology, superstructure, apoptosis and function were also assessed. 3. Normal renal tubular structure was seen in the propofol pretreated group, but LPS treatment resulted in changes to renal tissue morphology. Propofol treatment improved renal function in LPS-treated rats. Pretreatment with propofol 1 h before LPS normalized urine and serum osmolality, serum creatinine and blood urea nitrogen to control levels. Lipopolysaccharide downregulated expression of AQP-2 and downregulated the expression of ICAM-1 and TNF-α. These effects were reversed by propofol treatment. Lipopolysaccharide reduced the Bcl2 : Bax ratio and induced renal cell apoptosis and these effects were reduced by propofol treatment. Overall, propofol pretreatment had greater effects than concurrent treatment or propofol administration after LPS induction of endotoxaemia. 4. In conclusion, propofol pretreatment protected renal function in a rat model of endotoxaemia. Further studies are necessary to confirm this effect in other experimental models and in humans.
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Affiliation(s)
- Wen-Yao Cui
- Department of Anaesthesiology, The First University Hospital of China Medical University, Shenyang, China
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Tang J, Chen X, Tu W, Guo Y, Zhao Z, Xue Q, Lin C, Xiao J, Sun X, Tao T, Gu M, Liu Y. Propofol inhibits the activation of p38 through up-regulating the expression of annexin A1 to exert its anti-inflammation effect. PLoS One 2011; 6:e27890. [PMID: 22164217 PMCID: PMC3229486 DOI: 10.1371/journal.pone.0027890] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2011] [Accepted: 10/27/2011] [Indexed: 11/30/2022] Open
Abstract
Inflammatory response is a kind of nonspecific immune response, with the central link of vascular response, which is mainly manifested by changes in neutrophils and vascular endothelial cells. In recent years, the in vivo and in vitro role of intravenous anesthetic propofol in inhibiting inflammatory response has been attracting more and more attention, but the anti-inflammatory mechanisms of propofol for mononuclear cells still remain undefined. In this study, proteomics analysis was applied to investigate protein expression profile changes in serum mononuclear cells following intervention of rats with endotoxemia using propofol. After two-dimensional electrophoresis and mass spectrometric identification, it has been found that the protein Annexin A1 was up-regulated in the propofol intervention group. Annexin A1 is a glucocorticoid-dependent anti-inflammatory protein. After detection using ELISA and Western blot assays, it has also been found that propofol can not only promote the expression of Annexin A1, but also inhibit the phosphorylation level of p38 and release of inflammatory factors (IL-1β, IL-6 and TNF-α) in rats with endotoxemia. In order to further determine the role of up-regulated expression of Annexin A1 in anti-inflammation of propofol, this gene was silenced in vitro in human THP-1 cells, to detect the phosphorylation status of p38 and release of inflammatory factors. The results show that Annexin A1 can negatively regulate phosphorylation of p38 and release of IL-1β, IL-6 and TNF-α in THP-1 cells following propofol intervention and lipopolysaccharide (LPS) stimulation. Our results clearly indicate that propofol can up-regulate Annexin A1 to inhibit the phosphorylation level of p38 and release of IL-1β, IL-6 and TNF-α, so as to inhibit inflammatory response. Therefore, it can be speculated that Annexin A1 might be the key signaling protein in the in vivo and in vitro anti-inflammatory mechanisms of propofol.
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Affiliation(s)
- Jing Tang
- Department of Anesthesia, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Xi Chen
- Department of Anesthesia, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, People's Republic of China
| | - Weifeng Tu
- Department of Anesthesia, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, People's Republic of China
| | - Yuanbo Guo
- Department of Anesthesia, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Zhenlong Zhao
- Department of Anesthesia, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Qiong Xue
- Department of Anesthesia, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Chunshui Lin
- Department of Anesthesia, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Jinfang Xiao
- Department of Anesthesia, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Xuegang Sun
- The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, People's Republic of China
| | - Tao Tao
- Department of Anesthesia, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
- * E-mail: (MG); (TT); (YL)
| | - Miaoning Gu
- Department of Anesthesia, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
- * E-mail: (MG); (TT); (YL)
| | - Youtan Liu
- Department of Anesthesia, Shenzhen Hospital, The University of Hong Kong, Shenzhen, People's Republic of China
- * E-mail: (MG); (TT); (YL)
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Effects of Propofol on the Outcomes of Rats with Sepsis. J Surg Res 2011; 168:e111-5. [DOI: 10.1016/j.jss.2010.12.034] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2010] [Revised: 12/07/2010] [Accepted: 12/22/2010] [Indexed: 11/22/2022]
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Yang W, Qiang D, Zhang M, Ma L, Zhang Y, Qing C, Xu Y, Zhen C, Liu J, Chen YH. Isoforskolin pretreatment attenuates lipopolysaccharide-induced acute lung injury in animal models. Int Immunopharmacol 2011; 11:683-92. [DOI: 10.1016/j.intimp.2011.01.011] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2010] [Revised: 01/06/2011] [Accepted: 01/11/2011] [Indexed: 11/29/2022]
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Yeh CH, Cho W, So E, Chu CC, Lin MC, Wang JJ, Hsing CH. Propofol inhibits lipopolysaccharide-induced lung epithelial cell injury by reducing hypoxia-inducible factor-1α expression. Br J Anaesth 2011; 106:590-599. [DOI: 10.1093/bja/aer005] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023] Open
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Effects of propofol on pro-inflammatory cytokines and nuclear factor kappaB during polymicrobial sepsis in rats. Mol Biol Rep 2009; 36:2345-51. [PMID: 19190997 DOI: 10.1007/s11033-009-9456-z] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2008] [Accepted: 12/03/2008] [Indexed: 11/27/2022]
Abstract
Nuclear factor kappa B (NF-kappaB) plays a central role in regulating the transcription of several genes associated with sepsis/septic shock. Therefore, the author investigated the effects of propofol on the plasma tumor necrosis factor alpha and interleukin 6 (TNF-alpha and IL-6) levels and NF-kappaB activation during polymicrobial sepsis in rats. Male Sprague-Dawlay rats were subjected to cecal ligation and puncture (CLP, a model of polymicrobial sepsis) or sham operation. The animals were randomly assigned into four equal groups (n = 10): sham CLP group, CLP group, PPF (propofol) I group and PPF II group. Thirty minutes before CLP, propofol (5 and 10 mg kg(-1) h(-1), respectively) was infused continuously through the left femoral vein cannula in PPF I group or PPF II group, CLP group and sham CLP group receiving 0.9% saline only at the rates of 5 ml kg(-1) h(-1). The right femoral artery was cannulated to monitor mean arterial pressure (MAP) and heart rates (HR). CLP produced progressive hypotension and a first increase followed by a decrease in HR. The plasma TNF-alpha and IL-6 levels and the hepatic NF-kappaB activation significantly increased after CLP alone. Compared with CLP group, propofol treatment reversed hypotension, slightly steadied heartbeats, and decreased the plasma TNF-alpha and IL-6 levels, and significantly suppressed NF-kappaB activation. Propofol has inhibited the hepatic NF-kappaB activation and the pro-inflammatory cytokine response during polymicrobial sepsis in rats.
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Haitsma JJ, Lachmann B, Papadakos PJ. Additives in intravenous anesthesia modulate pulmonary inflammation in a model of LPS-induced respiratory distress. Acta Anaesthesiol Scand 2009; 53:176-82. [PMID: 19175577 DOI: 10.1111/j.1399-6576.2008.01844.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND It has been suggested that propofol with ethylenediaminetetraacetic acid (EDTA) can modulate the systemic inflammatory response. Prolonged higher levels of pulmonary inflammation are associated with poor outcome of patients with acute lung injury. In the present study, we hypothesized that pulmonary inflammation could be modulated by propofol with EDTA compared with propofol with sulfite. METHODS Respiratory distress was induced in rats (n=25) by intratracheal nebulization of lipopolysaccharide (LPS). After 24 h, animals were randomized to either propofol with EDTA (Propofol(EDTA)), propofol with sulfite (Propofol(sulfite)) or ketamine/midazolam (Ket/Mid); control animals received saline (n=30). Animals were ventilated for 4 h and blood gases were measured hourly. Bronchoalveolar lavage (BAL) was performed for cytokine analysis of: tumor necrosis factor (TNF), interleukin (IL)-6 and macrophage inflammatory protein (MIP)-2. RESULTS LPS led to increased pulmonary inflammation in all groups compared with the control groups. Gas exchange deteriorated over time only in the LPS Propofol(sulfite) group and was significantly lower than the Ket/Mid group. Only IL-6 was significantly higher in the LPS Propofol(sulfite) group compared with both the Ket/Mid group and the Propofol(EDTA) group. CONCLUSION Pulmonary IL-6 can be modulated by additives in systemic anesthesia. IMPLICATION STATEMENT This study demonstrates that pulmonary inflammation caused by direct lung injury can be modulated by intravenous anesthesia used in critically ill patients.
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Affiliation(s)
- J J Haitsma
- Departments of Anesthesiology, Surgery and Neurosurgery, University of Rochester, School of Medicine and Dentistry, Rochester, NY, USA
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Toda N, Toda H, Hatano Y. Anesthetic modulation of immune reactions mediated by nitric oxide. J Anesth 2008; 22:155-62. [PMID: 18500613 DOI: 10.1007/s00540-007-0590-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2007] [Accepted: 11/01/2007] [Indexed: 01/09/2023]
Abstract
Nitric oxide (NO), when produced via inducible NO synthase (iNOS) in excess under pathological conditions (e.g., inflammation, endotoxemia, and septic shock), may lead to tissue injury and organ dysfunction. The bioavailability of NO and the activity and expression of iNOS are regulated by anesthetic agents. Volatile anesthetics mostly suppress, but in some instances may upregulate, the lipopolysaccharide-and cytokine-induced expression of iNOS in blood vessels and macrophages. Intravenous anesthetics inhibit iNOS expression in macrophages and the liver. Local anesthetics decrease the production of NO by inhibiting iNOS expression in macrophages and increase NO production in glial cells. Based on the literature reported so far, the effects of anesthetics on iNOS expression and activity under conditions of inflammation are controversial, with the observed effects depending on the experimental methods and animal species used. On the other hand, it has been shown that volatile and intravenous anesthetics consistently prevent the development of multiple organ failure elicited by endotoxemia or septic shock. Information, although still insufficient, regarding the interactions between anesthetic agents and the detrimental effects of NO formed during inflammatory processes may help us to construct advanced strategies for anesthetizing and sedating patients with inflammation and sepsis and for anesthetic preconditioning against ischemic injury.
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Affiliation(s)
- Noboru Toda
- Toyama Institute for Cardiovascular Pharmacology Research, Osaka, Japan
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Protective effects of propofol on acute lung injury induced by oleic acid in conscious rats. Crit Care Med 2008; 36:1214-21. [PMID: 18379248 DOI: 10.1097/ccm.0b013e31816a0607] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
OBJECTIVES Oleic acid has been used to induce acute lung injury (ALI) in animals. In patients with acute respiratory distress syndrome (ARDS), the blood level of oleic acid was increased. The mechanism and therapeutic regimen of ARDS and oleic acid-induced ALI remain undefined. In the present study, we investigated the oleic acid-induced changes in lung variables for the measure of ALI, inflammatory mediators, and neutrophil-derived substances. We evaluated the effects of pretreatment and posttreatment with propofol. DESIGN Randomized, controlled animal study. SETTING University research laboratory. SUBJECTS Fifty adult male Sprague-Dawley rats weighing 250-300 g. INTERVENTIONS We employed a conscious and unrestrained rat model. Oleic acid at a dose of 100 mg/kg was administered intravenously. Propofol (30 mg/kg) was given by intravenous infusion (6 mg/kg/min for 5 mins) 30 mins before (pretreatment) and 30 mins after (posttreatment) oleic acid. MEASUREMENTS AND MAIN RESULTS We monitored the arterial pressure, heart rate, and blood gas. The lung weight changes, exhaled nitric oxide, protein concentration in bronchoalveolar lavage, and Evans blue content in lung tissue were determined. The plasma nitrate/nitrite, methylguanidine, cytokines (tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, and interleukin-10), neutrophil elastase, myeloperoxidase, malondialdehyde, and sodium- and potassium-activated adenosine triphosphatase (Na+-K+-ATPase) were detected. Histopathological examination of the lung was performed. Oleic acid caused systemic hypotension and severe ALI as evidenced by the increases in the extent of ALI, impairment of pulmonary functions (blood gas variables), and lung pathology. In addition, oleic acid significantly increased inflammatory mediators and neutrophil-derived factors but depressed Na+-K+-ATPase. The inducible nitric oxide synthase was up-regulated. Pre- or posttreatment with propofol was capable of reversing the oleic acid-induced changes and attenuating the extent of ALI. CONCLUSIONS Oleic acid resulted in sepsis-like responses including ALI, inflammatory reaction, and increased neutrophil-derived factors. It depressed the Na+-K+-ATPase activity but up-regulated inducible nitric oxide synthase. Treatment with propofol abrogated or reversed the oleic acid-induced changes.
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Duvigneau JC, Piskernik C, Haindl S, Kloesch B, Hartl RT, Hüttemann M, Lee I, Ebel T, Moldzio R, Gemeiner M, Redl H, Kozlov AV. A novel endotoxin-induced pathway: upregulation of heme oxygenase 1, accumulation of free iron, and free iron-mediated mitochondrial dysfunction. J Transl Med 2008; 88:70-7. [PMID: 17982471 DOI: 10.1038/labinvest.3700691] [Citation(s) in RCA: 81] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Mitochondria are involved in the development of organ failure in critical care diseases. However, the mechanisms underlying mitochondrial dysfunction are not clear yet. Inducible hemoxygenase (HO-1), a member of the heat shock protein family, is upregulated in critical care diseases and considered to confer cytoprotection against oxidative stress. However, one of the products of HO-1 is Fe2+ which multiplies the damaging potential of reactive oxygen species catalyzing Fenton reaction. The aim of this study was to clarify the relevance of free iron metabolism to the oxidative damage of the liver in endotoxic shock and its impact on mitochondrial function. Endotoxic shock in rats was induced by injection of lipopolysaccharide (LPS) at a dose of 8 mg/kg (i.v.). We observed that the pro-inflammatory cytokine TNF-alpha and the liver necrosis marker aspartate aminotransferase were increased in blood, confirming inflammatory response to LPS and damage to liver tissue, respectively. The levels of free iron in the liver were significantly increased at 4 and 8 h after onset of endotoxic shock, which did not coincide with the decrease of transferrin iron levels in the blood, but rather with expression of the inducible form of heme oxygenase (HO-1). The proteins important for sequestering free iron (ferritin) and the export of iron out of the cells (ferroportin) were downregulated facilitating the accumulation of free iron in cells. The temporarily increased concentration of free iron in the liver correlated with the temporary impairment of both mitochondrial function and tissue ATP levels. Addition of exogenous iron ions to mitochondria isolated from control animals resulted in an impairment of mitochondrial respiration similar to that observed in endotoxic shock in vivo. Our data suggest that free iron released by HO-1 causes mitochondrial dysfunction in pathological situations accompanied by endotoxic shock.
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Effects of propofol on the leukocyte nitric oxide pathway: in vitro and ex vivo studies in surgical patients. Naunyn Schmiedebergs Arch Pharmacol 2007; 376:331-9. [DOI: 10.1007/s00210-007-0220-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2007] [Accepted: 11/08/2007] [Indexed: 10/22/2022]
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Storer K, Tu J, Karunanayaka A, Smee R, Short R, Thorpe P, Stoodley M. Coadministration of low-dose lipopolysaccharide and soluble tissue factor induces thrombosis after radiosurgery in an animal arteriovenous malformation model. Neurosurgery 2007; 61:604-10; discussion 610-1. [PMID: 17881975 DOI: 10.1227/01.neu.0000290909.32600.a8] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
OBJECTIVE Radiosurgery for arteriovenous malformations is limited to small lesions and may take 3 years to produce total occlusion. It has recently been shown that coadministration of low-dose lipopolysaccharide (LPS) and soluble tissue factor (sTF) selectively induces thrombosis in murine tumor models, attributable perhaps to the prothrombotic phenotype of tumor vasculature. Radiosurgery may induce changes in endothelial prothrombotic molecules similar to those found in tumors. This study aimed to determine if a similar strategy could be used to stimulate thrombus formation in an animal arteriovenous malformation model. METHODS Seventeen rats underwent creation of a carotid-to-jugular anastomosis. Animals were intravenously injected with sTF, low-dose LPS, a combination of both, or placebo 24 hours after stereotactic irradiation of the anastomosis. Control animals received both agents after sham irradiation. RESULTS Coadministration of sTF and LPS led to the formation of thrombi in up to 69% of small vessels and 39% of medium-sized vessels within the target region. The irradiated vasculature demonstrated intermediate rates of thrombosis after treatment with either sTF or LPS alone as did vessels within the fistula in the control group. Logistic regression analysis demonstrated significant associations between development of thrombi and treatment with radiation, sTF, or LPS (P < 0.005). There was no evidence of systemic thrombus formation or toxicity in any group. CONCLUSION Treatment with sTF and LPS selectively induces thrombosis of irradiated vessels in a rat model of arteriovenous malformation. Stimulation of thrombosis may improve the efficacy of radiosurgery, increasing the treatable lesion size and reducing latency.
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Affiliation(s)
- Kingsley Storer
- Prince of Wales Medical Research Institute, University of New South Wales, Sydney, Australia
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Votta-Velis EG, Minshall RD, Visintine DJ, Castellon M, Balyasnikova IV. Propofol Attenuates Endotoxin-Induced Endothelial Cell Injury, Angiotensin-Converting Enzyme Shedding, and Lung Edema. Anesth Analg 2007; 105:1363-70, table of contents. [DOI: 10.1213/01.ane.0000281144.06703.0d] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Sun J, Wang L, Shen J, Wang Z, Qian Y. Effect of propofol on mucous permeability and inflammatory mediators expression in the intestine following traumatic brain injury in rats. Cytokine 2007; 40:151-6. [DOI: 10.1016/j.cyto.2007.09.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2007] [Revised: 08/06/2007] [Accepted: 09/06/2007] [Indexed: 10/22/2022]
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Yang FL, Li CH, Hsu BG, Tsai NM, Lin SZ, Harn HJ, Chen HI, Liao KW, Lee RP. The reduction of tumor necrosis factor-alpha release and tissue damage by pentobarbital in the experimental endotoxemia model. Shock 2007; 28:309-16. [PMID: 17545946 DOI: 10.1097/shk.0b013e31803dd04d] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Sepsis is the leading cause of death for intensive care patients. Lipopolysaccharide (LPS) administration to animals under anesthesia is a strategy for the study of uncontrolled release of proinflammatory cytokines. Anesthetics have been indicated that they can specially affect immune responses, such as the inflammatory response. Pentobarbital is an anesthetic used mainly in animal studies. Thus, the effect of pentobarbital on tumor necrosis factor-alpha (TNF-alpha) release was determined. The results revealed that pentobarbital suppressed the expression of TNF-alpha mRNA and its proteins, which may result from the decrease in the activities of nuclear factor-kappaB and activator protein 1 and the reduction of the expression of p38 mitogen-activated protein kinase by pentobarbital. After the inhibitory activity of the pentobarbital for TNF-alpha release was proven in vivo, the cytotoxic effects of LPS were examined in vivo with or without pentobarbital treatments. In vivo results indicated that plasma levels of alanine aminotransferase, aspartate aminotransferase, lactic dehydrogenase, creatine kinase, serum urea nitrogen, and amylase decreased dramatically in the anesthetic group with pentobarbital administration. Finally, the effect of pentobarbital on TNF-alpha-related cell death was monitored in vitro, and the results indicated the pentobarbital could directly enhance the viabilities of cells under the treatment of TNF-alpha and protected cells from apoptosis induced by deferoxamine mesylate-induced hypoxia. These results suggest that pentobarbital significantly influences the LPS-induced inflammatory response and protects cells from death directly and indirectly induced by TNF-alpha. The information provides a perspective to re-evaluate the results of the experiments in which animals were anesthetized with pentobarbital. The anti-inflammatory effects of the drugs may have been caused by the synergistic effect of pentobarbital.
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Affiliation(s)
- Fwu Lin Yang
- Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan, Republic of China
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Jin SW, Zhang L, Lian QQ, Liu D, Wu P, Yao SL, Ye DY. Posttreatment with aspirin-triggered lipoxin A4 analog attenuates lipopolysaccharide-induced acute lung injury in mice: the role of heme oxygenase-1. Anesth Analg 2007; 104:369-77. [PMID: 17242094 DOI: 10.1213/01.ane.0000252414.00363.c4] [Citation(s) in RCA: 96] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
BACKGROUND We hypothesized that posttreatment with 15-epi-16-parafluoro-phenoxy lipoxin A4 (ATL) could attenuate lipopolysaccharide (LPS)-induced acute lung injury in mice. METHODS All the animals were randomly assigned to one of six groups (n = 6 per group). In the sham-vehicle group, mice were treated with 0.9% saline 60 min after they were challenged with saline. The sham-ATL group was identical to the sham-vehicle group except that ATL (0.7 mg/kg, IV) was administered, and the sham-ZnPP group was identical to the sham-vehicle group except that Zinc protoporphyrin IX (ZnPP, 25 mg/kg IV) was administered. In the LPS-vehicle group, mice were treated with vehicle 60 min after they were challenged with LPS. The LPS-ATL group was identical to the LPS-vehicle group but received ATL. The ZnPP-ATL-LPS group was identical to the LPS-ATL group, but ZnPP was administered 30 min before ATL. RESULTS Inhalation of LPS increased inflammatory cell counts, tumor necrosis factor-alpha, and protein concentration in bronchoalveolar lavage fluid and also induced lung histological injury and edema. Posttreatment with ATL inhibited tumor necrosis factor-alpha, nitric oxide, and malondialdehyde production, with the outcome of decreased pulmonary edema, lipid peroxidation, and the infiltration of neutrophils in lung tissues. In addition, ATL promoted the formation of heme oxygenase-1 in the lung tissues. Heme oxygenase-1 activity was also increased in the lung tissues after ATL stimulation. The beneficial effects of ATL were abolished by ZnPP. CONCLUSIONS This study demonstrates that posttreatment with ATL significantly reduces LPS-induced acute lung injury in mice.
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Affiliation(s)
- Sheng-Wei Jin
- Department of Anesthesiology, Second Affiliated Hospital, Wenzhou Medical College, Wenzhou, China.
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Xia Z, Liu HM, Tang QZ. Does propofol suppress nitrosative stress during aortic surgery in pigs? Can J Anaesth 2006; 53:1267-8. [PMID: 17142666 DOI: 10.1007/bf03021593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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Rae C, Cherry JI, Land FM, Land SC. Endotoxin-induced nitric oxide production rescues airway growth and maturation in atrophic fetal rat lung explants. Biochem Biophys Res Commun 2006; 349:416-25. [PMID: 16934757 DOI: 10.1016/j.bbrc.2006.08.067] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2006] [Accepted: 08/12/2006] [Indexed: 11/16/2022]
Abstract
Inflammation induces premature maturation of the fetal lung but the signals causing this effect remain unclear. We determined if nitric oxide (NO) synthesis, evoked by Escherichia coli lipopolysaccharide (LPS, 2 microg ml-1), participated in this process. Fetal rat lung airway surface complexity rose 2.5-fold over 96h in response to LPS and was associated with increased iNOS protein expression and activity. iNOS inhibition by N6-(1-iminoethyl)-L-lysine-2HCl (L-NIL) abolished this and induced airway atrophy similar to untreated explants. Surfactant protein-C (SP-C) expression was also induced by LPS and abolished by L-NIL. As TGFbeta suppresses iNOS activity, we determined if feedback regulation modulated NO-dependent maturation. LPS induced TGFbeta1 release and SMAD4 nuclear translocation 96 h after treatment. Treatment of explants with a blocking antibody against TGFbeta1 sustained NO production and airway morphogenesis whereas recombinant TGFbeta1 antagonized these effects. Feedback regulation of NO synthesis by TGFbeta may, thus, modulate airway branching and maturation of the fetal lung.
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Affiliation(s)
- C Rae
- Division of Maternal and Child Health Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY Scotland, UK
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Yu HP, Lui PW, Hwang TL, Yen CH, Lau YT. Propofol improves endothelial dysfunction and attenuates vascular superoxide production in septic rats. Crit Care Med 2006; 34:453-60. [PMID: 16424728 DOI: 10.1097/01.ccm.0000198530.68343.21] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE To determine the effects of propofol on vascular functions, plasma and endothelium-derived nitric oxide (EDNO), vascular NO, and cyclic guanosine monophosphate (cGMP), as well as vascular production of superoxide anion (O2*-), in septic animals. DESIGN Prospective, multiexperimental, randomized, controlled studies. SETTING University research laboratory. SUBJECTS Male adult Sprague-Dawley rats weighing 350-400 g. INTERVENTIONS Cecal ligation and puncture (CLP), with and without propofol (25 mg/kg/hr) infusion, after sham or CLP (24 hrs postsurgery). MEASUREMENTS AND MAIN RESULTS Plasma NOx, basal aortic NOx, and cGMP concentrations all increased, whereas acetylcholine-induced endothelium-dependent relaxation (EDR), contractile response, and EDNO all decreased in CLP vs. sham rats (p < .001). Acetylcholine stimulated aortic NOx and cGMP significantly in sham and CLP-propofol (p < .01) but not CLP rats. Thus, propofol ameliorated the CLP-induced increases in plasma NOx, basal aortic NOx, and cGMP. It restored the CLP-induced impairment of EDR, EDNO, and acetylcholine-stimulated aortic NOx and cGMP levels. More O2*- production (measured by lucigenin-enhanced chemiluminescence) was noted in carotid arteries from CLP vs. sham rats (p < .001). Nicotinamide adenine dinucleotide (NADH; 1 mM) stimulated O2*- production in all rings, with significantly more increase in CLP vs. sham (p < .001). Propofol attenuated the excessive increase in O2*- production of CLP rings. CONCLUSIONS Propofol treatment attenuated the overproduction of NO and O2*-, thus restoring the acetylcholine-responsive NO-cGMP pathway in CLP-induced sepsis. It also significantly improved the CLP-impaired EDR and EDNO in a parallel manner. These beneficial effects of propofol could be accounted for by improvement of the disturbed NO/O2*- balance in sepsis.
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Affiliation(s)
- Huang-Ping Yu
- Department of Anesthesiology, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan
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Liu D, Zeng BX, Zhang SH, Wang YL, Zeng L, Geng ZL, Zhang SF. Rosiglitazone, a peroxisome proliferator-activated receptor-gamma agonist, reduces acute lung injury in endotoxemic rats. Crit Care Med 2005; 33:2309-16. [PMID: 16215386 DOI: 10.1097/01.ccm.0000183161.81503.7d] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Rosiglitazone, a potent agonist of peroxisome proliferator-activated receptor (PPAR)-gamma, exerts anti-inflammatory effects in vitro and in vivo. This study was designated to determine the effects of rosiglitazone on endotoxin-induced acute lung injury in rats. DESIGN Prospective, experimental study. SETTING University research laboratory. SUBJECTS Thirty-six male Wistar rats. INTERVENTIONS All the animals were randomly assigned to one of six groups (n = 6 per group) and were given either lipopolysaccharide (6 mg/kg intravenously) or saline, pretreated with rosiglitazone (0.3 mg/kg intravenously) or vehicle (10% dimethyl sulphoxide) 30 mins before lipopolysaccharide. The selective PPAR-gamma antagonist GW9662 (0.3 mg/kg intravenously) or its vehicle (10% dimethyl sulphoxide) was given 20 mins before rosiglitazone. MEASUREMENTS AND MAIN RESULTS Endotoxemia for 4 hrs induced evident lung histologic injury and edema, both of which were significantly attenuated by rosiglitazone pretreatment. The protective effects of rosiglitazone were correlated with the reduction by 71% of the increase of myeloperoxidase activity and the reduction by 84% of the increase of malondialdehyde in the lung tissue. The pulmonary hyperproduction of nitric oxide was reduced by 82% of the increase related to lipopolysaccharide challenge. Pretreatment with rosiglitazone also markedly suppressed lipopolysaccharide-induced expression of inducible nitric oxide synthase messenger RNA and protein in the lung, as demonstrated by reverse transcription-polymerase chain reaction or Western blot analysis. Immunohistochemical analysis revealed that rosiglitazone inhibited the formation of nitrotyrosine, a marker for peroxynitrite reactivity, in the lung tissue. In addition, the specific PPAR-gamma antagonist GW9662 antagonized the effects of rosiglitazone. CONCLUSIONS This study provides evidence, for the first time, that the PPAR-gamma agonist rosiglitazone significantly reduces endotoxin-induced acute lung injury in rats.
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Affiliation(s)
- Dong Liu
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Shibakawa YS, Sasaki Y, Goshima Y, Echigo N, Kamiya Y, Kurahashi K, Yamada Y, Andoh T. Effects of ketamine and propofol on inflammatory responses of primary glial cell cultures stimulated with lipopolysaccharide. Br J Anaesth 2005; 95:803-10. [PMID: 16227338 DOI: 10.1093/bja/aei256] [Citation(s) in RCA: 75] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Ketamine has been reported to exert anti-inflammatory effects on macrophages stimulated with lipopolysaccharide (LPS) in vitro and in vivo. Several studies have reported conflicting results regarding the effects of propofol on cytokine production from immune cells. However, there have been no reports of the effects of these agents on inflammatory responses in glial cells. We investigated the effects of ketamine and propofol on LPS-induced production of nitric oxide, tumour necrosis factor-alpha (TNF-alpha) and prostaglandin E(2) (PGE(2)) from primary cultures of rat glial cells in vitro. METHODS Glial cells were stimulated with LPS in the absence and presence of various concentrations of ketamine (30-1000 microM) or propofol (30 and 300 microM). Nitric oxide released into the culture media was determined by measuring nitrite using the Griess reaction, and concentrations of TNF-alpha and PGE(2) were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS Ketamine reduced LPS-induced TNF-alpha production without significant inhibition of nitrite release in mixed glial cells, astrocyte cultures and microglial cultures. Ketamine also inhibited LPS-induced production of PGE(2) in astrocyte cultures. In contrast, propofol had no effect on LPS-induced nitrite or TNF-alpha production in mixed glial cells. CONCLUSIONS The data demonstrate that ketamine inhibited some of the inflammatory responses of both astrocytes and microglial cells treated with LPS without causing major change in nitric oxide release. Propofol had no effect on the production of nitric oxide or TNF-alpha from LPS-stimulated glial cells.
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Affiliation(s)
- Y Saito Shibakawa
- Departments of Anesthesiology and Critical Care Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
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Abstract
Propofol (2,6-diisopropylphenol) is a potent intravenous hypnotic agent widely administered for induction and maintenance of anesthesia and for sedation in the intensive care unit. Propofol is insoluble in water and therefore is formulated in a lipid emulsion. In addition, a preservative (ethylenediaminetetraacetic acid [EDTA] or sodium metabisulfite) is added to retard bacterial growth. Propofol has antiinflammatory properties, decreasing production of proinflammatory cytokines, altering expression of nitric oxide, and inhibiting neutrophil function. Propofol also is a potent antioxidant. The added preservatives have biologic activity; EDTA has antiinflammatory properties, whereas metabisulfite may cause lipid peroxidation. The antiinflammatory and antioxidant properties of propofol may have beneficial effects in patients with sepsis and systemic inflammatory response syndrome.
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Affiliation(s)
- Paul E Marik
- Division of Pulmonary and Critical Care Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
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Abstract
Endotoxin causes acute lung injury (ALI) through many mediators of inflammatory and immune responses. Propofol is an antiinflammatory and immunosuppressive drug. We conducted this study to evaluate whether propofol attenuates ALI associated with endotoxemia. Thirty-two anesthetized rabbits were randomly divided into four groups (n = 8 each). ALI was induced by IV endotoxin 5 mg/kg over 30 min in 3 groups. In 2 of the ALI groups, IV administration of propofol (2 or 5 mg/kg as a bolus followed by continuous infusion at 4 or 15 mg x kg(-1) x h(-1)) was started 15 min before endotoxin. The other ALI group received soybean-oil emulsion. The nonlung injury control group received infusion of both vehicles. The lungs were mechanically ventilated with 40% oxygen for 6 h after endotoxin. Hemodynamics did not differ among groups. The large dose of propofol attenuated lung leukosequestration, pulmonary edema (as assessed by lung wet/dry weight ratio), and pulmonary hyperpermeability (as assessed by albumin levels in bronchoalveolar lavage fluid) and resulted in better oxygenation, lung mechanics, and histological change. The small dose of propofol failed to do so. Our findings suggest that a large dose of propofol successfully mitigates physiological, biochemical, and histological deterioration in ALI in endotoxemia.
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Affiliation(s)
- Yumiko Takao
- Department of Anesthesia & Perioperative Medicine, Faculty of Medical Sciences, Kobe University Graduate School of Medicine, Kobe, Japan
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