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Yazlık MO, Mutluer İ, Kaya U, Özkan H, Müştak İB, Çolakoğlu HE, Altınbaş YF, Vural MR. The role of nutritional-immunological indices in estimating serum LPS and antioxidant enzyme activity and sepsis status in female dogs with pyometra caused by E. coli. Anim Reprod Sci 2023; 255:107276. [PMID: 37300916 DOI: 10.1016/j.anireprosci.2023.107276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 05/18/2023] [Accepted: 06/05/2023] [Indexed: 06/12/2023]
Abstract
The aim of this study was to diagnose pyometra and related sepsis status using cost-effective nutritional-immunological indices, antioxidants, and toxin levels in dogs and to investigate the utility of the indices in predicting toxin and antioxidant status. A total of 29 dogs were enrolled into the present study. Among these, 9 female dogs in their diestrus stages, were allocated for elective ovariohysterectomy. The pyometra group was also separated into two subgroups as Sepsis (+) and Sepsis (-). Blood samples were collected into two tubes containing EDTA for hematological analysis; without anticoagulant for serum progesterone, LPS concentration, and antioxidant levels at the time of diagnosis. Bacteriological and tissue samples of the uterus were collected after the ovariohysterectomy. Antioxidant activity, progesterone, and toxin concentration were determined by using commercial ELISA kits. Statistical analyses were performed using Stata version 16.1 and MedCalc 16 statistical software. Receiver operating characteristics curves were used for the threshold for evaluating pyometra and sepsis status. Pairwise comparisons were carried out of the area under the curve (AUC) for thresholds of nutritional immunologic indices (hemoglobin, albumin, lymphocyte, platelet (HALP) score; prognostic nutritional index (PNI); Albumin hemoglobin index (AHI)), serum LPS and antioxidant activity. Linear regression model was used for the estimation of serum LPS and antioxidant activity by using indices. Mean serum progesterone, LPS concentrations, and Nitric Oxide (NO) production were greater, while serum superoxide dismutase (SOD), tissue SOD, and glutathione peroxidase (GPx) activities were lower in dogs with pyometra. All nutritional-immunologic indices were lower in pyometra cases. Nutritional-immunologic indices (AUC of HALP:0.759; PNI:0.981; AHI 0.994), NO (AUC: 0.787) and SOD (AUC: 0.784) levels were useful for pyometra diagnosis. AHI and LPS were useful for the determination of sepsis status with the AUC values of 0.850 and 0.740, respectively. While AHI was useful for the estimation of serum LPS and NO concentration (p < 0.001), PNI was useful for serum SOD concentration (p = 0.003). In conclusion, PNI, HALP and AHI can be used in the diagnosis of pyometra, however, only AHI and LPS levels can be used in the diagnosis of sepsis. SOD and NO can be used to determine pyometra but have no effect on determining sepsis status. Additionally, the estimation of the levels of serum LPS, NO, and SOD activities can be done using the AHI and PNI values.
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Affiliation(s)
- Murat Onur Yazlık
- Ankara University, Faculty of Veterinary Medicine, Department of Obstetrics and Gynecology, 06110 Ankara, Turkiye.
| | - İpek Mutluer
- Ankara University, Faculty of Veterinary Medicine, Department of Obstetrics and Gynecology, 06110 Ankara, Turkiye
| | - Ufuk Kaya
- Hatay Mustafa Kemal University, Faculty of Veterinary Medicine, Department of Biostatistics, 31060 Hatay, Turkiye
| | - Hüseyin Özkan
- Hatay Mustafa Kemal University, Faculty of Veterinary Medicine, Department of Genetics, 31060 Hatay, Turkiye
| | - İnci Başak Müştak
- Ankara University Faculty of Veterinary Medicine Department of Microbiology, 06110 Ankara, Turkiye
| | - Hatice Esra Çolakoğlu
- Ankara University, Faculty of Veterinary Medicine, Department of Obstetrics and Gynecology, 06110 Ankara, Turkiye
| | - Yunus Furkan Altınbaş
- Ankara University, Faculty of Veterinary Medicine, Department of Obstetrics and Gynecology, 06110 Ankara, Turkiye
| | - Mehmet Rıfat Vural
- Ankara University, Faculty of Veterinary Medicine, Department of Obstetrics and Gynecology, 06110 Ankara, Turkiye.
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Namba T, Masaki N, Hitomi Y, Ishinoda Y, Iwashita M, Yumita Y, Kagami K, Yasuda R, Ikegami Y, Toya T, Nagatomo Y, Takase B, Soejima K, Adachi T. Association of serum nitric oxide metabolite level with mortality in patients undergoing coronary angiography. J Cardiol 2022; 80:578-584. [PMID: 35987881 DOI: 10.1016/j.jjcc.2022.07.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 07/14/2022] [Accepted: 07/20/2022] [Indexed: 10/15/2022]
Abstract
BACKGROUND Nitric oxide (NO) is a relevant molecule for vascular homeostasis. The level of serum NO metabolites (NOx), which consist of nitrite and nitrate, has been investigated as an alternative biomarker of NO production, but its clinical value has not yet been determined. METHODS AND RESULTS 143 patients (66 ± 12 years old) were followed up after coronary catheterization. During a median (inter-quartile range) observation period of 6.13 (3.32-9.21) years, there were 20 (14 %) all-cause deaths, including 11 (8 %) cardiovascular deaths, 17 (12 %) major adverse cardiovascular events, and 17 (12 %) hospital admissions for heart failure. Median NOx level was 34.5 μmol/L (23.9-54.3). NOx was a risk factor for all-cause death [hazard ratio (HR) by unit increase, 1.010, 95 % confidence interval (CI) 1.001-1.018; p = 0.021] and heart failure (HR 1.010, CI 1.001-1.019; p = 0.029). Even after adjustment for age, sex, coronary risk factors, C-reactive protein, log-transformed brain natriuretic peptide, estimated glomerular filtration rate, and nitrate treatment, NOx was a risk factor for all-cause death (HR 1.015, CI 1.004-1.027; p = 0.008) and admission with heart failure (HR 1.018, CI 1.005-1.018, p = 0.007). CONCLUSIONS An increase in serum NOx level does not herald a benign clinical course but is an independent predictor of high risk of any-cause mortality and heart failure.
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Affiliation(s)
- Takayuki Namba
- Department of Cardiology, National Defense Medical College, Tokorozawa, Japan; Department of Cardiology, Kyorin University School of Medicine, Mitaka, Japan
| | - Nobuyuki Masaki
- Department of Intensive Care Medicine, National Defense Medical College, Tokorozawa, Japan.
| | - Yasuhiro Hitomi
- Department of Cardiology, National Defense Medical College, Tokorozawa, Japan
| | - Yuki Ishinoda
- Department of Endocrinology, National Defense Medical College, Tokorozawa, Japan
| | - Midori Iwashita
- Department of Cardiology, National Defense Medical College, Tokorozawa, Japan
| | - Yusuke Yumita
- Department of Cardiology, National Defense Medical College, Tokorozawa, Japan
| | - Kazuki Kagami
- Department of Cardiology, National Defense Medical College, Tokorozawa, Japan
| | - Risako Yasuda
- Department of Cardiology, National Defense Medical College, Tokorozawa, Japan
| | - Yukinori Ikegami
- Department of Cardiology, National Defense Medical College, Tokorozawa, Japan
| | - Takumi Toya
- Department of Cardiology, National Defense Medical College, Tokorozawa, Japan; Department of Intensive Care Medicine, National Defense Medical College, Tokorozawa, Japan
| | - Yuji Nagatomo
- Department of Cardiology, National Defense Medical College, Tokorozawa, Japan
| | - Bonpei Takase
- Department of Intensive Care Medicine, National Defense Medical College, Tokorozawa, Japan
| | - Kyoko Soejima
- Department of Cardiology, Kyorin University School of Medicine, Mitaka, Japan
| | - Takeshi Adachi
- Department of Cardiology, National Defense Medical College, Tokorozawa, Japan
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Lorente L, Gómez-Bernal F, Martín M, Navarro-Gonzálvez J, Argueso M, Perez A, Ramos-Gómez L, Solé-Violán J, Marcos y Ramos J, Ojeda N, Jiménez A. High serum nitrates levels in non-survivor COVID-19 patients. MEDICINA INTENSIVA (ENGLISH EDITION) 2022; 46:132-139. [PMID: 35221002 PMCID: PMC8867537 DOI: 10.1016/j.medine.2020.10.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 10/25/2020] [Indexed: 02/07/2023]
Abstract
Objective Higher blood nitrate and nitrite levels have been found in coronavirus disease 2019 (COVID-19) patients than in healthy subjects. The present study explores the potential association between serum nitrate levels and mortality in COVID-19 patients. Design A prospective observation study was carried out. Setting Eight Intensive Care Units (ICUs) from 6 hospitals in the Canary Islands (Spain). Patients COVID-19 patients admitted to the ICU. Interventions Determination of serum nitrate levels at ICU admission. Main variable of interest Mortality at 30 days. Results Non-surviving (n = 11) compared to surviving patients (n = 42) showed higher APACHE-II (p < 0.001) and SOFA scores (p = 0.004), and higher serum nitrate levels (p = 0.001). Logistic regression analyses showed serum nitrate levels to be associated to 30-day mortality after controlling for SOFA (OR = 1.021; 95%CI = 1.006–1.036; p = 0.01) or APACHE-II (OR = 1.023; 95%CI = 1.006–1.041; p = 0.01). There were no differences in the area under the curve (AUC) for mortality prediction by serum nitrate levels (AUC = 83%; 95%CI = 73–92%; p < 0.001), APACHE II (AUC = 85%; 95%CI = 75–96%; p < 0.001) and SOFA (AUC = 78%; 95%CI = 63–92%; p = 0.005) based on the DeLong method. The Kaplan–Meier analysis found patients with serum nitrates levels > 68.4 μmol/l to have a higher mortality rate (hazard ratio = 138.8; 95%CI = 22.3–863.9; p < 0.001). Conclusions The main novel finding was the association between serum nitrate levels and mortality in COVID-19 patients controlling for the SOFA or APACHE-II scores, though larger studies are needed to confirm this observation.
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Hedetoft M, Jensen PØ, Moser C, Vinkel J, Hyldegaard O. Hyperbaric oxygen treatment impacts oxidative stress markers in patients with necrotizing soft-tissue infection. J Investig Med 2021; 69:1330-1338. [PMID: 34006573 PMCID: PMC8485130 DOI: 10.1136/jim-2021-001837] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/04/2021] [Indexed: 02/02/2023]
Abstract
Necrotizing soft-tissue infection (NSTI) is a rare, severe, and fast-progressing bacterial infection associated with a high risk of developing sepsis or septic shock. Increasing evidence indicates that oxidative stress is crucial in the development and progression of sepsis, but its role in NSTI specifically has not been investigated. Some patients with NSTI receive hyperbaric oxygen (HBO2) treatment as the restoration of oxidative stress balance is considered an important mechanism of action, which HBO2 facilitates. However, a gap in knowledge exists regarding the effect of HBO2 treatment on oxidative stress in patients with NSTI. In the present observational study, we aimed to investigate HBO2 treatment effects on known markers of oxidative stress in patients with NSTI. We measured plasma myeloperoxidase (MPO), superoxide dismutase (SOD), heme oxygenase-1 (HO-1) and nitrite+nitrate in 80 patients with NSTI immediately before and after their first HBO2 treatment, and on the following day. We found that HBO2 treatment was associated with a significant increase in MPO and SOD by a median of 3.4 and 8.8 ng/mL, respectively. Moreover, we observed an HBO2 treatment-associated increase in HO-1 in patients presenting with septic shock (n=39) by a median of 301.3 pg/mL. All markers were significantly higher in patients presenting with septic shock compared to patients without shock, and all markers correlated with disease severity. High baseline SOD was associated with 90-day mortality. In conclusion, HBO2 treatment was associated with an increase in MPO and SOD in patients with NSTI, and oxidative stress was more pronounced in patients with septic shock.
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Affiliation(s)
- Morten Hedetoft
- Department of Anaesthesia, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Peter Østrup Jensen
- Department of Clinical Microbiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.,Costerton Biofilm Center, Institute of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Claus Moser
- Department of Clinical Microbiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Julie Vinkel
- Department of Anaesthesia, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Ole Hyldegaard
- Department of Anaesthesia, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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Lorente L, Gómez-Bernal F, Martín MM, Navarro-Gonzálvez JA, Argueso M, Perez A, Ramos-Gómez L, Solé-Violán J, Marcos Y Ramos JA, Ojeda N, Jiménez A. High serum nitrates levels in non-survivor COVID-19 patients. Med Intensiva 2020; 46:S0210-5691(20)30336-3. [PMID: 33293102 PMCID: PMC7654288 DOI: 10.1016/j.medin.2020.10.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 10/13/2020] [Accepted: 10/25/2020] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Higher blood nitrate and nitrite levels have been found in coronavirus disease 2019 (COVID-19) patients than in healthy subjects. The present study explores the potential association between serum nitrate levels and mortality in COVID-19 patients. DESIGN A prospective observation study was carried out. SETTING Eight Intensive Care Units (ICUs) from 6 hospitals in the Canary Islands (Spain). PATIENTS COVID-19 patients admitted to the ICU. INTERVENTIONS Determination of serum nitrate levels at ICU admission. MAIN VARIABLE OF INTEREST Mortality at 30 days. RESULTS Non-surviving (n=11) compared to surviving patients (n=42) showed higher APACHE-II (p<0.001) and SOFA scores (p=0.004), and higher serum nitrate levels (p=0.001). Logistic regression analyses showed serum nitrate levels to be associated to 30-day mortality after controlling for SOFA (OR=1.021; 95%CI=1.006-1.036; p=0.01) or APACHE-II (OR=1.023; 95%CI=1.006-1.041; p=0.01). There were no differences in the area under the curve (AUC) for mortality prediction by serum nitrate levels (AUC=83%; 95%CI=73-92%; p<0.001), APACHE II (AUC=85%; 95%CI=75-96%; p<0.001) and SOFA (AUC=78%; 95%CI=63-92%; p=0.005) based on the DeLong method. The Kaplan-Meier analysis found patients with serum nitrates levels>68.4μmol/l to have a higher mortality rate (hazard ratio=138.8; 95%CI=22.3-863.9; p<0.001). CONCLUSIONS The main novel finding was the association between serum nitrate levels and mortality in COVID-19 patients controlling for the SOFA or APACHE-II scores, though larger studies are needed to confirm this observation.
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Affiliation(s)
- L Lorente
- Intensive Care Unit, Hospital Universitario de Canarias, La Laguna, Santa Cruz de Tenerife, Spain.
| | - F Gómez-Bernal
- Laboratory Department, Hospital Universitario de Canarias, San Cristóbal de La Laguna, Santa Cruz de Tenerife, Spain
| | - M M Martín
- Intensive Care Unit, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
| | - J A Navarro-Gonzálvez
- Laboratory Department, Hospital Universitario de Canarias, San Cristóbal de La Laguna, Santa Cruz de Tenerife, Spain
| | - M Argueso
- Intensive Care Unit, Complejo Hospitalario Universitario Insular, Las Palmas de Gran Canaria, Spain
| | - A Perez
- Internal Intensive Care Unit, Hospital Universitario de Canarias, San Cristóbal de La Laguna, Santa Cruz de Tenerife, Spain
| | - L Ramos-Gómez
- Intensive Care Unit, Hospital General La Palma, Breña Alta, Santa Cruz de Tenerife, Spain
| | - J Solé-Violán
- Intensive Care Unit, Hospital Universitario Dr. Negrín, Las Palmas de Gran Canaria, Spain
| | - J A Marcos Y Ramos
- Intensive Care Unit, Hospital Doctor José Molina Orosa, Arrecife, Las Palmas, Spain
| | - N Ojeda
- Department of Anesthesiology, Hospital Universitario Dr. Negrín, Las Palmas de Gran Canaria, Spain
| | - A Jiménez
- Research Unit, Hospital Universitario de Canarias, San Cristóbal de La Laguna, Santa Cruz de Tenerife, Spain
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Carmignani M, Zucchetti F, Sacco R, Bolognini S, Volpe AR. Shock Induction by Arterial Hypoperfusion of the Gut Involves Synergistic Interactions between the Peripheral Enkephalin and Nitric Oxide Systems. Int J Immunopathol Pharmacol 2016; 18:33-48. [PMID: 15698509 DOI: 10.1177/039463200501800105] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
To determine whether critical splanchnic artery hypoperfusion can provoke systemic shock and to identify the roles of the peripheral opioid and nitric oxide (NO) systems in this process, various degrees of superior mesenteric artery hypoperfusion (SMA-H) were produced in anesthetized adult rabbits (n=40), and hemodynamic and metabolic indices were measured. Metabolic acidosis and irreversible hypodynamic shock occurred with SMA-H at levels representing 25–20% of mean baseline SMA blood flow. In 112 other rabbits subjected to SMA-H at 20% (SMA-H20%), we studied plasma NO and enkephalin (ENK) levels, cardiovascular reactivity to selected physiological agonists, effects of ENKs on plasma NO levels, and effects of peripheral opioid receptor blockade and inducible NO synthase (iNOS) inhibition. SMA-H20% progressively increased systemic blood levels of NO and ENKs. Exogenous ENK administration accentuated SMA-H20%-induced increases in plasma NO levels, and their cardiovascular depressing effects were significantly greater when they were administered during SMA-H20% (vs. administration under baseline conditions). Selective blockade of cardiovascular δ-opioid receptors improved hemodynamics, prevented shock irreversibility and reduced plasma NO levels; similar effects were obtained by selective iNOS inhibition. These findings demonstrate that critical arterial hypoperfusion of the gut can induce hypodynamic systemic shock through ENK-induced hyperactivation of cardiovascular δ-opioid receptors, which leads to increased plasma levels of NO related in part to increased iNOS activity. Since pronounced splanchnic artery hypoperfusion occurs in all advanced systemic shock states, selective δ-opioid receptor antagonists and/or iNOS inhibitors may prove to be useful in improving shock hemodynamics and metabolic derangements and/or preventing progression toward irreversibility.
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Affiliation(s)
- M Carmignani
- Section of Pharmacology and Toxicology, Department of Basic and Applied Biology, University of L'Aquila, Coppito, Italy.
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Hansen MB, Simonsen U, Garred P, Hyldegaard O. Biomarkers of necrotising soft tissue infections: aspects of the innate immune response and effects of hyperbaric oxygenation-the protocol of the prospective cohort BIONEC study. BMJ Open 2015; 5:e006995. [PMID: 25967993 PMCID: PMC4431132 DOI: 10.1136/bmjopen-2014-006995] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
INTRODUCTION The mortality and amputation rates are still high in patients with necrotising soft tissue infections (NSTIs). It would be ideal to have a set of biomarkers that enables the clinician to identify high-risk patients with NSTI on admission. The objectives of this study are to evaluate inflammatory and vasoactive biomarkers as prognostic markers of severity and mortality in patients with NSTI and to investigate whether hyperbaric oxygen treatment (HBOT) is able to modulate these biomarkers. The overall hypothesis is that plasma biomarkers can be used as prognostic markers of severity and mortality in patients with NSTI and that HBOT reduces the inflammatory response. METHODS AND ANALYSIS This is a prospective, observational study being conducted in a tertiary referral centre. Biomarkers will be measured in 114 patients who have been operatively diagnosed with NSTI. On admission, baseline blood values will be obtained. Following surgery and HBOT, daily blood samples for measuring regular inflammatory and vasoactive biomarkers (pentraxin-3, interleukin-6 and nitrite) will be acquired. Samples will be analysed using validated ELISA assays, chemiluminescence and Griess reaction. Clinical data will be obtained during admission in the intensive care unit for a maximum of 7 days. The primary analysis will focus on pentraxin-3, interleukin-6 and nitrite as early markers of disease severity in patients with NSTI. ETHICS AND DISSEMINATION The study has been approved by the Regional Scientific Ethical Committee of Copenhagen (H-2-2014-071) and the Danish Data Protection Agency (J. no. 30-0900 and J. no. 30-1282). Results will be presented at national and international conferences and published in peer-reviewed scientific journals. TRIAL REGISTRATION NCT02180906.
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Affiliation(s)
- Marco Bo Hansen
- Department of Anaesthesia, Centre of Head and Orthopaedics, Copenhagen University Hospital, Rigshospitalet, Denmark
| | - Ulf Simonsen
- Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, University of Aarhus, Aarhus, Denmark
| | - Peter Garred
- Laboratory of Molecular Medicine, Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Denmark
| | - Ole Hyldegaard
- Department of Anaesthesia, Centre of Head and Orthopaedics, Copenhagen University Hospital, Rigshospitalet, Denmark
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Gender-Specific Differences in the In Situ Cardiac Function of Endotoxemic Rats Detected by Pressure-Volume Catheter. Shock 2014; 42:415-23. [DOI: 10.1097/shk.0000000000000226] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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Martin G, Asensi V, Montes AH, Collazos J, Alvarez V, Pérez-Is L, Carton JA, Taboada F, Valle-Garay E. Endothelial (NOS3 E298D) and inducible (NOS2 exon 22) nitric oxide synthase polymorphisms, as well as plasma NOx, influence sepsis development. Nitric Oxide 2014; 42:79-86. [PMID: 25239655 DOI: 10.1016/j.niox.2014.09.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2014] [Revised: 07/24/2014] [Accepted: 09/12/2014] [Indexed: 11/30/2022]
Abstract
INTRODUCTION Nitric oxide (NO) influences susceptibility to infection and hemodynamic failure (HF) in sepsis. NOS3 and NOS2 SNPs might modify plasma nitrite/nitrate (NOx) levels, sepsis development, hemodynamics and survival. METHODS 90 severely septic and 91 non-infected ICU patients were prospectively studied. NOS3 (E298D), NOS3 (-786 T/C), NOS3 (27 bp-VNTR), and NOS2A (exon 22) SNPs and plasma NOx levels were assessed. RESULTS 21 patients (11.6%) died, 7 with sepsis. TT homozygotes and T allele carriers of NOS3 (E298D) and AG carriers of the NOS2A (exon 22) SNPs were more frequent among septic compared to non-infected ICU patients (p < 0.05). Plasma NOx was higher in septic, especially in septic with hemodynamic failure (HF) or fatal outcome (p < 0.006). Plasma NOx was higher in carriers of the T allele of the NOS3 (E298D) SNP (p = 0.006). Sepsis independently associated with HF, increased NOx, peripheral neutrophils, and fibrinogen levels, decreased prothrombin and the presence of the NOS3 (E298D) and NOS2A (exon 22) SNPs. A low APACHE II score was the only variable associated with sepsis survival. NOx was independently associated with sepsis, HF, decreased neutrophils and higher APACHE. CONCLUSIONS NOS3 (E298D) and NOS2A (exon 22) SNPs, individually and in combination, and plasma NOx, associated with sepsis development. NOx associated with HF and fatal outcome.
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Affiliation(s)
- Guadalupe Martin
- Critical Care, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain
| | - Víctor Asensi
- Infectious Diseases Services, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain.
| | - A Hugo Montes
- Biochemistry and Molecular Biology, Oviedo University School of Medicine, Oviedo, Spain
| | - Julio Collazos
- Infectious Diseases Unit, Hospital de Galdácano, Vizcaya, Spain
| | - Victoria Alvarez
- Molecular Genetics Unit-Nephrology Research Institute, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain
| | - Laura Pérez-Is
- Biochemistry and Molecular Biology, Oviedo University School of Medicine, Oviedo, Spain
| | - José A Carton
- Infectious Diseases Services, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain
| | - Francisco Taboada
- Critical Care, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain
| | - Eulalia Valle-Garay
- Biochemistry and Molecular Biology, Oviedo University School of Medicine, Oviedo, Spain
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Alves JN, Pires KMP, Lanzetti M, Barroso MV, Benjamim CF, Costa CA, Resende AC, Santos JC, Ribeiro ML, Porto LC, Valença SS. Critical role for CCR2 and HMGB1 in induction of experimental endotoxic shock. Arch Biochem Biophys 2013; 537:72-81. [DOI: 10.1016/j.abb.2013.06.019] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2013] [Revised: 06/20/2013] [Accepted: 06/25/2013] [Indexed: 12/12/2022]
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Cytokines induced neutrophil extracellular traps formation: implication for the inflammatory disease condition. PLoS One 2012; 7:e48111. [PMID: 23110185 PMCID: PMC3482178 DOI: 10.1371/journal.pone.0048111] [Citation(s) in RCA: 285] [Impact Index Per Article: 21.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2012] [Accepted: 09/20/2012] [Indexed: 12/13/2022] Open
Abstract
Neutrophils (PMNs) and cytokines have a critical role to play in host defense and systemic inflammatory response syndrome (SIRS). Neutrophil extracellular traps (NETs) have been shown to extracellularly kill pathogens, and inflammatory potential of NETs has been shown. Microbial killing inside the phagosomes or by NETs is mediated by reactive oxygen and nitrogen species (ROS/RNS). The present study was undertaken to assess circulating NETs contents and frequency of NETs generation by isolated PMNs from SIRS patients. These patients displayed significant augmentation in the circulating myeloperoxidase (MPO) activity and DNA content, while PMA stimulated PMNs from these patients, generated more free radicals and NETs. Plasma obtained from SIRS patients, if added to the PMNs isolated from healthy subjects, enhanced NETs release and free radical formation. Expressions of inflammatory cytokines (IL-1β, TNFα and IL-8) in the PMNs as well as their circulating levels were significantly augmented in SIRS subjects. Treatment of neutrophils from healthy subjects with TNFα, IL-1β, or IL-8 enhanced free radicals generation and NETs formation, which was mediated through the activation of NADPH oxidase and MPO. Pre-incubation of plasma from SIRS with TNFα, IL-1β, or IL-8 antibodies reduced the NETs release. Role of IL-1β, TNFα and IL-8 thus seems to be involved in the enhanced release of NETs in SIRS subjects.
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12
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[Acute heart failure]. Med Klin Intensivmed Notfmed 2012; 107:397-423; quiz 424-5. [PMID: 22689257 DOI: 10.1007/s00063-012-0118-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2012] [Accepted: 05/14/2012] [Indexed: 01/10/2023]
Abstract
Acute decompensated heart failure (ADHF) is a major public health problem throughout the world and its importance is continuing to grow. More than 50% of ADHF patients have coronary artery disease, which is generally associated with a history of hypertension. Recent data suggest that half of the patients presenting with acute heart failure have preserved left ventricular systolic function. The diagnosis of ADHF may be difficult at times, and the clinical assessment and patient profiling is essential for appropriate therapy. Immediate therapeutic goals are not only to improve symptoms, restore oxygenation and stabilize hemodynamic conditions, but also to improve short- and long-term survival. In addition to general supportive measures such as oxygen supplementation, noninvasive ventilation, analgesia, diuretics, vasodilators together with inotropic agents and/or vasopressors remain the cornerstone of therapy in patients with ADHF.
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KOTHARI N, BOGRA J, KOHLI M, MALIK A, KOTHARI D, SRIVASTAVA S, KESHARI R, SINGH V, BARTHWAL M, DIKSHIT M. Role of active nitrogen molecules in progression of septic shock. Acta Anaesthesiol Scand 2012; 56:307-15. [PMID: 22192332 DOI: 10.1111/j.1399-6576.2011.02607.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/16/2011] [Indexed: 11/28/2022]
Abstract
INTRODUCTION Active nitrogen molecules are formed as a result of cell metabolism. They are essential for cell metabolism, but when produced in excess, they contribute to the pathogenesis of several disease processes. These nitrogen molecules play an important role in vascular instability of septic shock. This study was planned to detect the role of active nitrogen molecules in the progression of septic shock. MATERIALS AND METHODS Blood samples were collected from 118 critically ill patients admitted in ICU and from 95 healthy relatives accompanying the patients. Patients were categorized into three groups: systemic inflammatory response syndrome (n = 54), sepsis (n = 35) and septic shock (n = 29). Plasma total nitrite (nitrites and nitrates), cytokines like tumour necrosis factor-α (TNF-α) and plasma lactate were measured to assess inflammatory activity and severity of septic shock. RESULTS High plasma levels of nitrite and nitrate (No₂-/No₃-) were observed in critically ill patients (mean level 78.92 μmol/l in sepsis and 97.20 μmol/l in septic shock). Mean plasma TNF-α level in sepsis was 213.50 pg/ml and septic shock was 227.38 pg/ml. CONCLUSION Plasma No₂-/No₃- and TNF-α levels were high in patients with sepsis and septic shock, which increased with severity of sepsis.
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Affiliation(s)
- N. KOTHARI
- Department of Anaesthesia; CSM Medical University; Lucknow; India
| | - J. BOGRA
- Department of Anaesthesia; CSM Medical University; Lucknow; India
| | - M. KOHLI
- Department of Anaesthesia; CSM Medical University; Lucknow; India
| | - A. MALIK
- Department of Anaesthesia; CSM Medical University; Lucknow; India
| | - D. KOTHARI
- Department of Periodontics; Dental Faculty; CSM Medical University; Lucknow; India
| | - S. SRIVASTAVA
- Research Cell; CSM Medical University; Lucknow; India
| | - R.S. KESHARI
- Pharmacology Division CSIR-Central Drug Research Institute; Lucknow; India
| | - V. SINGH
- Pharmacology Division CSIR-Central Drug Research Institute; Lucknow; India
| | - M.K. BARTHWAL
- Pharmacology Division CSIR-Central Drug Research Institute; Lucknow; India
| | - M. DIKSHIT
- Pharmacology Division CSIR-Central Drug Research Institute; Lucknow; India
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14
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Abstract
Sepsis is one of the leading causes of death in critically ill patients in the intensive care unit. Sepsis accounts for significant morbidity and mortality in critically ill children as well. The pathophysiology of sepsis is characterized by a complex systemic inflammatory response, endothelial dysfunction, and alterations in the coagulation system, which lead to perturbations in the delivery of oxygen and metabolic substrates to the tissues, end-organ dysfunction, and ultimately death. Oxidative stress plays a crucial role as both a promoter and mediator of the systemic inflammatory response, suggesting potential targets for the treatment of critically ill children with the sepsis syndrome. Herein, we will provide a brief review of the role of oxidative and nitrosative stress in the pathophysiology of sepsis.
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Affiliation(s)
- Derek S Wheeler
- Clinical Director, Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center. The Kindervelt Laboratory for Critical Care Medicine Research, Cincinnati Children's Research Foundation. Associate Professor of Clinical Pediatrics, University of Cincinnati College of Medicine
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15
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Circulating levels of peroxiredoxin 4 as a novel biomarker of oxidative stress in patients with sepsis. Shock 2011; 35:460-5. [PMID: 21283059 DOI: 10.1097/shk.0b013e3182115f40] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Oxidative stress, a situation with increased reactive oxygen species production and/or decreased antioxidant defense mechanisms, is evident in the pathogenesis of sepsis. Peroxiredoxin 4 (Prx4) is a hydrogen peroxide degrading peroxidase recently found circulating in blood of septic patients and potentially reflecting an antioxidant system in imbalance. We studied Prx4 serum levels of 79 consecutively enrolled medical intensive care unit patients. The diagnostic and prognostic performance of Prx4 was compared with other biomarkers, the APACHE II score and the SOFA score. Median Prx4 serum levels gradually increased with disease severity in patients classified on admission as having systemic immune response syndrome (2.32 arbitrary [arb.] U/L), sepsis (5.02 arb. U/L), severe sepsis (11.7 arb. U/L), or septic shock (11.4 arb. U/L). A positive correlation was found with the severity score Acute Physiological and Chronic Health Evaluation II (r = 0.27, P < 0.05) and the organ failure score Sequential Organ Failure Assessment (r = 0.55, P < 0.0001). Peroxiredoxin 4 correlated with the sepsis marker procalcitonin (r = 0.61, P < 0.0001), the inflammatory markers C-reactive protein (r = 0.65, P < 0.0001) and interleukin 6 (r = 0.62, P < 0.0001), and antioxidant blood compounds total bilirubin (r = 0.37, P < 0.001) and albumin (r = -0.54, P < 0.0001). Peroxiredoxin 4 distinguished noninfectious from infectious inflammatory response syndrome with an area under the receiver operating characteristic (ROC) curve of 0.82. [corrected] High Prx4 serum levels were associated with a poor prognosis of septic patients and revealed an area under the ROC curve of 0.76 in prediction of in-hospital mortality. In this study, elevated serum levels of the antioxidant Prx4 were associated with an increased disease severity and adverse outcome of critically ill patients with sepsis. Peroxiredoxin 4 may therefore be a helpful new biomarker for diagnosing, monitoring, and risk assessing these patients. The pathophysiological mechanisms behind the observed increase remain to be elucidated.
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Osterbur K, Whitehead Z, Sharp CR, DeClue AE. Plasma nitrate/nitrite concentrations in dogs with naturally developing sepsis and non-infectious forms of the systemic inflammatory response syndrome. Vet Rec 2011; 169:554. [PMID: 21908551 DOI: 10.1136/vr.d5137] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
The aim of this prospective observational study was to evaluate the differences in plasma nitrate/nitrite concentrations between dogs with sepsis and those with non-infectious forms of the systemic inflammatory response syndrome (SIRS). Eighteen dogs with sepsis, 20 dogs with SIRS and 29 healthy control dogs were enrolled. Blood samples were obtained from the dogs within 12 hours of admission to the University of Missouri Veterinary Medical Teaching Hospital (MU VMTH) Intensive Care Unit (ICU) in lithium heparin blood tubes. Plasma nitrate/nitrite concentrations were measured using the Greiss reaction. Plasma nitrate/nitrite concentrations at presentation, clinical parameters, organ dysfunction and in-hospital mortality were compared between groups. Plasma total nitrate/nitrite was significantly greater in the sepsis group compared with the control group (P=0.005) and SIRS group (P=0.037). There was no statistical difference in plasma nitrate/nitrite concentration between the SIRS and control groups (P=0.489). The sensitivity was 66.7 per cent (95 per cent CI, 41 to 87 per cent) and the specificity was 75.5 per cent (95 per cent CI, 61 to 87 per cent) for differentiating dogs with sepsis from dogs without sepsis.
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Affiliation(s)
- K Osterbur
- Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri, 900 E. Campus Dr Columbia, MO 65211, USA
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17
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Ojeda Ojeda M, Larrondo Muguercia H, Magdariaga Figuerola A, Sánchez Valdivia A, Rodríguez Alonso I, Valenzuela Silva C, García Iglesias E, Domínguez Alonso E, Buurman WA, Araña Rosaínz MDJ. Temporal trends of circulating nitric oxide and pro-inflammatory cytokine responses ex vivo in intra-abdominal sepsis: results from a cohort study. Inflamm Res 2010; 60:289-97. [PMID: 20976525 DOI: 10.1007/s00011-010-0267-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2009] [Revised: 09/09/2010] [Accepted: 10/04/2010] [Indexed: 01/22/2023] Open
Abstract
OBJECTIVE AND DESIGN To evaluate the association of pro-inflammatory mediators with organ dysfunction and adverse outcome in intra-abdominal sepsis patients. SUBJECTS Twenty-one patients admitted to the Intensive Care Unit (ICU) were prospectively included in the study. Only patients with surgical diagnosis of intra-abdominal sepsis were enrolled. RESULTS Tumor necrosis factor-α (TNFα) and interleukin (IL)-6 produced ex vivo were significantly lower in non-survivors on admission (p = 0.021) and day 2 (p = 0.013), respectively. Nitric oxide (NO(x)) levels were significantly higher in non-survivors from the onset of sepsis and until day 4 after diagnosis (p < 0.05). Circulating lymphocyte counts were lower in non-survivors after admission over time, but there was no association with impaired cytokine production in this group of patients during the entire follow-up. All non-survivors developed nosocomial pneumonia concomitantly with multiple organ dysfunction and septic shock. There was a significant correlation between nitric oxide (NO(x)) concentrations and the sequential organ failure assessment (SOFA) score at day 2 (r = 0.598, p = 0.009), and ICU stay (r = 0.605, p = 0.006). Continuously high NO(x) levels correlated with organ failure. The pro-inflammatory mediators TNFα, IL-6 and NO(x), and also the Simplified Acute Physiology Score II (SAPS-II), discriminate survivors from non-survivors. According to logistic regression models, although these parameters are independently associated with the outcome, they do not improve the predictive power of the SAPS-II score for mortality risk. CONCLUSIONS Disturbances in inflammatory responses and increase in NO(x) generation seem to characterize early intra-abdominal sepsis, in which immune suppression is associated with an increased susceptibility to nosocomial infections. Sequential NO(x) determinations could be a useful approach for improving the management of patients with intra-abdominal sepsis.
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Affiliation(s)
- Miriam Ojeda Ojeda
- Division of Pharmaceuticals, Center for Genetic Engineering and Biotechnology, Havana, Cuba.
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Sauriasari R, Sakano N, Wang DH, Takaki J, Takemoto K, Wang B, Sugiyama H, Sato Y, Takigawa T, Takahashi N, Kanbara S, Hitomi Y, Nakamura H, Ogino K. C-reactive protein is associated with cigarette smoking-induced hyperfiltration and proteinuria in an apparently healthy population. Hypertens Res 2010; 33:1129-36. [DOI: 10.1038/hr.2010.154] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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Becker KL, Snider R, Nylen ES. Procalcitonin in sepsis and systemic inflammation: a harmful biomarker and a therapeutic target. Br J Pharmacol 2010; 159:253-64. [PMID: 20002097 PMCID: PMC2825349 DOI: 10.1111/j.1476-5381.2009.00433.x] [Citation(s) in RCA: 190] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2009] [Revised: 06/17/2009] [Accepted: 06/29/2009] [Indexed: 02/06/2023] Open
Abstract
The worldwide yearly mortality from sepsis is substantial, greater than that of cancer of the lung and breast combined. Moreover, its incidence is increasing, and its response to therapy has not appreciably improved. In this condition, the secretion of procalcitonin (ProCT), the prohormone of calcitonin, is augmented greatly, attaining levels up to thousands of fold of normal. This hypersecretion emanates from multiple tissues throughout the body that are not traditionally viewed as being endocrine. The serum values of ProCT correlate with the severity of sepsis; they recede with its improvement and worsen with exacerbation. Accordingly, as highlighted in this review, serum ProCT has become useful as a biomarker to assist in the diagnosis of sepsis, as well as related infectious or inflammatory conditions. It is also a useful monitor of the clinical course and prognosis, and sensitive and specific assays have been developed for its measurement. Moreover, it has been demonstrated that the administration of ProCT to septic animals greatly increases mortality, and several toxic effects of ProCT have been elucidated by in vitro experimental studies. Antibodies have been developed that neutralize the harmful effects of ProCT, and their use markedly decreases the symptomatology and mortality of animals that harbour a highly virulent sepsis analogous to that occurring in humans. This therapy is facilitated by the long duration of serum ProCT elevation, which allows for a broad window of therapeutic opportunity. An experimental groundwork has been established that suggests a potential applicability of such therapy in septic humans.
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Affiliation(s)
- Kenneth L Becker
- George Washington University and Veterans Affairs Medical Center, Washington, DC 20422, USA.
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20
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Viaro F, Baldo CF, Capellini VK, Celotto AC, Bassetto S, Rodrigues AJ, Evora PRB. Plasma nitrate/nitrite (NOx) is not a useful biomarker to predict inherent cardiopulmonary bypass inflammatory response. J Card Surg 2008; 23:336-8. [PMID: 18598323 DOI: 10.1111/j.1540-8191.2008.00649.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
BACKGROUND AND AIM There were strong evidences that nitric oxide has capital importance in the progressive vasodilatation associated with varied circulatory shock forms, including systemic inflammatory response syndrome (SIRS), in patients undergoing cardiac surgeries for cardiopulmonary bypass (CPB). If CPB procedures, per se, are the inciting stimulus for inflammation, plasma nitrate/nitrite (NOx) excretion would be expected to be higher in these patients rather than in patients operated without CPB. In consequence, we hypothesized that increased levels of NOx would be predictive for vasoplegic syndrome. METHODS Thirty patients were assigned to three groups: Group 1--coronary artery bypass graft (CABG) roller pump CPB; Group 2--CABG centrifugal vortex pump CPB; and Group 3--heart valve surgery roller pump CPB. Sampling of venous blood for chemiluminescence plasma NOx dosage was achieved at the following time points: (1) before anesthesia induction; (2) after anesthesia induction; (3) before heparin infusion; (4) after heparin infusion; (5) CPB-30 minutes; (6) CPB-60 minutes; (7) before protamine infusion; (8) after protamine infusion; and (9) on return to the recovery area. RESULTS There were no intergroup differences regarding age and anesthetic regimen, and the number of arteries grafted was not different between the CABG groups. There were no NOx statistic differences, neither among the three groups of patients or among the surgery time. In addition, there was no correlation among NOx, lactate, and hemoglobin. CONCLUSIONS Considering the inflammatory process intrinsic to CPB, this study reinforces the idea that plasma NOx is not useful as a biomarker of inflammatory response onset, which may or may not lead to SIRS and/or vasoplegic syndrome.
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Affiliation(s)
- Fernanda Viaro
- Division of Thoracic and Cardiovascular Surgery, Department of Surgery and Anatomy, Ribeirão Preto Faculty of Medicine,University of São Paulo, Ribeirão Preto, São Paulo, Brazil
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21
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Multicenter, randomized, placebo-controlled study of the nitric oxide scavenger pyridoxalated hemoglobin polyoxyethylene in distributive shock*. Crit Care Med 2008; 36:1999-2007. [DOI: 10.1097/ccm.0b013e31817bfe84] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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22
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Joviliano EE, Piccinato CE, Cherri J, Viaro F, Moryia T, Celotto AC, Bonaventura D, Evora PRB. In vitro pharmacological study of femoral artery vascular reactivity after inferior canine hindlimb ischemia/reperfusion: effects of in vivo nitric oxide blocker infusion. Ann Vasc Surg 2007; 21:618-28. [PMID: 17823044 DOI: 10.1016/j.avsg.2007.07.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2006] [Revised: 04/10/2007] [Accepted: 07/13/2007] [Indexed: 11/25/2022]
Abstract
The aim of the investigation was to study the possible effects of in vivo infusion of nitric oxide (NO) blockers upon the in vitro endothelium-dependent femoral reactivity. The experimental model tested herein was the inferior canine hindlimb global ischemia induced by infrarenal abdominal aortic cross-clamping followed by reperfusion. The NO blockers employed in the tests were N(G)-nitro-l-arginine methyl ester (L-NAME), aminoguanidine (AMG), and methylene blue (MB), which were infused immediately after the anesthesia induction. The research protocol was standardized in two main experimental groups, control and ischemia/reperfusion (I/R) injury, randomized in eight subgroups including controls and NO blockers. The femoral artery vascular reactivity was studied in vitro with the aid of a setup consisting of eight organ chambers, where segments of 4-5 mm were suspended and connected to force transducers in the presence of indomethacin to block the cyclooxygenase pathway. The NO-release pathway was evaluated by using specific pharmacological agonists in the in vitro experiments. The L-NAME in vivo infusion led to in vitro endothelium dysfunction in both groups and was associated with high mortality in the animals submitted to I/R. AMG and MB, two clinically used drugs, did not cause in vitro endothelium dysfunction in either of the two groups, which gives evidence that these drugs are not deleterious in the milieu of I/R injury. Nitrite/nitrate plasma levels were not significant except for the L-NAME groups, which presented significant NO decrease.
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Affiliation(s)
- Edwaldo E Joviliano
- Department of Surgery and Anatomy, Ribeirão Preto Faculty of Medicine, University of São Paulo, São Paulo, Brazil
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23
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Abstract
PURPOSE OF REVIEW Although enthusiasm of intensivists has been raised during the last 2-3 years due to several successful clinical trials, severe sepsis and septic shock still have an increasing incidence with more or less unchanged mortality. Within the last 12 months, the progress in sepsis research covering definitions, epidemiology, pathophysiology, diagnosis, standard and adjunctive therapy, as well as experimental approaches is encouraging. In this review, state-of-the-art publications of 2003 are presented to elucidate the possible impact on clinical routine. RECENT FINDINGS The rationale for using a new definition based on the PIRO system has been widely acknowledged, although it is not yet applicable in clinical practice. This includes genomic information for stratifying subgroups of patients, and a broader field of laboratory diagnostics due to clinical studies and basic research on the cellular mechanisms of inflammation and organ dysfunction. Early diagnosis is important for a fast implementation of specific therapies, and it has been confirmed that the time until the start of therapy has an impact on patient outcome. Thorough data analysis of successful trials with activated protein C has revealed encouraging details on long-term outcome and subgroup effects. Together with new findings on low-dose hydrocortisone, this stresses the relevance of adjunctive therapy in severe sepsis and septic shock. SUMMARY Scientific progress in areas of sepsis has been continuing throughout 2003, although the challenges are still enormous. The identification of more specific markers and new therapeutic approaches will hopefully improve the diagnosis, monitoring of therapy, and outcome in the septic patient.
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Affiliation(s)
- Herwig Gerlach
- Department of Anaesthesiology and Intensive Care, Vivantes--Neukoelln Clinic, Berlin, Germany.
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24
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Abd El-Gaw TA, . SAES, . AMAR, . EAG, . EAER. Plasma Levels of Nitric Oxide and Carbon Monoxide in Critically Ill Children with Septic Syndrome. JOURNAL OF MEDICAL SCIENCES 2007. [DOI: 10.3923/jms.2007.769.775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
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Lee KS, Kim YS, Lee HN, Park JH, Oh YJ, Sheen SS, Choi YH, Park KJ, Hwang SC. Correlation of Nitric Oxide and Corticosteroids Along the Course of Sepsis. Tuberc Respir Dis (Seoul) 2007. [DOI: 10.4046/trd.2007.62.4.308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Affiliation(s)
- Keu Sung Lee
- Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Suwon, Korea
| | - Young Sun Kim
- Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Suwon, Korea
| | - Hyoung No Lee
- Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Suwon, Korea
| | - Joo Hun Park
- Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Suwon, Korea
| | - Yoon Jung Oh
- Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Suwon, Korea
| | - Seung Soo Sheen
- Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Suwon, Korea
| | - Young Hwa Choi
- Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Suwon, Korea
| | - Kwang Joo Park
- Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Suwon, Korea
| | - Sung Chul Hwang
- Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Suwon, Korea
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26
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Maciel EAP, Athanazio DA, Reis EA, Cunha FQ, Queiroz A, Almeida D, McBride AJA, Ko AI, Reis MG. High serum nitric oxide levels in patients with severe leptospirosis. Acta Trop 2006; 100:256-60. [PMID: 17196920 PMCID: PMC1805659 DOI: 10.1016/j.actatropica.2006.11.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2006] [Revised: 11/07/2006] [Accepted: 11/19/2006] [Indexed: 10/23/2022]
Abstract
Leptospirosis is a globally distributed zoonosis of major public health importance and is associated with severe disease manifestations such as acute renal failure and pulmonary haemorrhage syndrome. However, the extent to which the pathogenesis of leptospirosis mimics sepsis caused by Gram-negative bacteria remains unknown. The aim of this study was to evaluate serum levels of nitric oxide (NO) in patients diagnosed with severe leptospirosis. Sera from 35 confirmed cases of severe leptospirosis and 13 healthy subjects were analysed. Patients with severe leptospirosis had significantly higher NO levels compared to healthy individuals (30.82+/-10.90 microM versus 3.86+/-1.34 microM, P < 0.001), indicating that this immune mediator plays a role in the underlying systemic inflammatory response.
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Affiliation(s)
- Elves A. P. Maciel
- Gonçalo Moniz Research Centre, Oswaldo Cruz Foundation, Ministry of Health, Salvador, Brazil
| | - Daniel A. Athanazio
- Gonçalo Moniz Research Centre, Oswaldo Cruz Foundation, Ministry of Health, Salvador, Brazil
- Federal University of Bahia, Salvador, Brazil
| | - Eliana A.G. Reis
- Gonçalo Moniz Research Centre, Oswaldo Cruz Foundation, Ministry of Health, Salvador, Brazil
| | - Fernando Q. Cunha
- Ribeirao Preto Faculty of Medicine, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Adriano Queiroz
- Gonçalo Moniz Research Centre, Oswaldo Cruz Foundation, Ministry of Health, Salvador, Brazil
- Federal University of Bahia, Salvador, Brazil
| | - Deusdelia Almeida
- Gonçalo Moniz Research Centre, Oswaldo Cruz Foundation, Ministry of Health, Salvador, Brazil
- Federal University of Bahia, Salvador, Brazil
| | - Alan J. A. McBride
- Gonçalo Moniz Research Centre, Oswaldo Cruz Foundation, Ministry of Health, Salvador, Brazil
| | - Albert I. Ko
- Gonçalo Moniz Research Centre, Oswaldo Cruz Foundation, Ministry of Health, Salvador, Brazil
- Division of International Medicine and Infectious Disease, Weill Medical College of Cornell University, New York, USA
| | - Mitermayer G. Reis
- Gonçalo Moniz Research Centre, Oswaldo Cruz Foundation, Ministry of Health, Salvador, Brazil
- Federal University of Bahia, Salvador, Brazil
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27
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Abstract
AIM: To study the effect of blocking intestinal lymphatic circulation in two-hit rats and explore the significance of intestinal lymphatic circulation in two-hit.
METHODS: Wistar rats were divided equally into three groups: mesenteric lymph duct ligation group, non-ligation group and sham group. Mesenteric lymph was diverted by ligation of mesenteric lymph duct, and the two-hit model was established by hemorrhage and lipopolysaccharide (LPS) methods. All rats were sampled for serum pre-experiment and 24 h post-experiment. The organs including kidney, liver, lung and heart were collected for pathomorphologic observation and biochemical investigation. The nitric oxide (NO), malondialdehyde (MDA) and superoxide dismutase (SOD) were determined in serum and tissue homogenate.
RESULTS: Pathomorphology study showed that the structures of kidney, lung, liver and heart tissues were normal in sham group; congestion, degeneration and necrosis in non-ligation group; but only mild lesions in ligation group. After two-hits, the contents of AST, ALT, BUN, Cr and LDH-1 in the serum of non-ligation group and ligation group were obviously higher than that in pre-experiment group and sham group, but obviously lower than that in non-ligation group. The contents of NO2-/NO3-, NOS, iNOS and MDA in the serum of non-ligation group were significantly increased, compared with pre-experiment and sham group, but SOD was significantly lower. These parameters were significantly different in ligation group compared with that in sham group, but NO2-/NO3-, iNOS and MDA in ligation group were significantly lower than that in non-ligation group.
CONCLUSION: Ligation of mesenteric lymph duct could improve the disturbance of organic function and morphologic damage in two-hit rats; the lymphatic mechanism in two-hit should be emphasized.
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Affiliation(s)
- Chun-Yu Niu
- Institute of Cell Biology, Zhejiang University, Hangzhou 310003, Zhejiang Province, China.
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28
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Jobgen WS, Jobgen SC, Li H, Meininger CJ, Wu G. Analysis of nitrite and nitrate in biological samples using high-performance liquid chromatography. J Chromatogr B Analyt Technol Biomed Life Sci 2006; 851:71-82. [PMID: 16904955 DOI: 10.1016/j.jchromb.2006.07.018] [Citation(s) in RCA: 118] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2006] [Revised: 07/16/2006] [Accepted: 07/19/2006] [Indexed: 12/21/2022]
Abstract
Various analytical techniques have been developed to determine nitrite and nitrate, oxidation metabolites of nitric oxide (NO), in biological samples. HPLC is a widely used method to quantify these two anions in plasma, serum, urine, saliva, cerebrospinal fluid, tissue extracts, and fetal fluids, as well as meats and cell culture medium. The detection principles include UV and VIS absorbance, electrochemistry, chemiluminescence, and fluorescence. UV or VIS absorbance and electrochemistry allow simultaneous detection of nitrite and nitrate but are vulnerable to the severe interference from chloride present in biological samples. Chemiluminescence and fluorescence detection improve the assay sensitivity and are unaffected by chloride but cannot be applied to a simultaneous analysis of nitrite and nitrate. The choice of a detection method largely depends on sample type and facility availability. The recently developed fluorometric HPLC method, which involves pre-column derivatization of nitrite with 2,3-diaminonaphthalene (DAN) and the enzymatic conversion of nitrate into nitrite, offers the advantages of easy sample preparation, simple derivatization, stable fluorescent derivatives, rapid analysis, high sensitivity and specificity, lack of interferences, and easy automation for determining nitrite and nitrate in all biological samples including cell culture medium. To ensure accurate analysis, care should be taken in sample collection, processing, and derivatization as well as preparation of reagent solutions and mobile phases, to prevent environmental contamination. HPLC methods provide a useful research tool for studying NO biochemistry, physiology and pharmacology.
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Affiliation(s)
- Wenjuan S Jobgen
- Department of Animal Science and Faculty of Nutrition, Texas A&M University, College Station, TX 77843, USA
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Heemskerk S, Pickkers P, Bouw MPWJM, Draisma A, van der Hoeven JG, Peters WHM, Smits P, Russel FGM, Masereeuw R. Upregulation of Renal Inducible Nitric Oxide Synthase during Human Endotoxemia and Sepsis Is Associated with Proximal Tubule Injury. Clin J Am Soc Nephrol 2006; 1:853-62. [PMID: 17699297 DOI: 10.2215/cjn.00490206] [Citation(s) in RCA: 75] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The incidence and the mortality of septic acute kidney injury are high, partly because the pathogenesis of sepsis-induced renal dysfunction is not clear. The objective of this study was to investigate the upregulation of renal inducible nitric oxide synthase (iNOS) in human endotoxemia and sepsis and the effect of NO on tubular integrity. Septic patients and endotoxemia that was induced by a bolus injection of 2 ng/kg Escherichia coli LPS in human volunteers were studied. In addition, the effect of co-administration of the selective iNOS inhibitor aminoguanidine was evaluated. The urinary excretion of the cytosolic glutathione-S-transferase-A1 (GSTA1-1) and GSTP1-1, markers for proximal and distal tubule damage, respectively, was determined. In septic patients, an almost 40-fold induction of iNOS mRNA in cells that were isolated from urine was found accompanied by a significant increase in NO metabolites in blood. The mRNA expression of iNOS was induced 34-fold after endotoxin administration. LPS-treated healthy volunteers showed a higher urinary excretion of NO metabolites compared with control subjects. Urinary NO metabolite excretion correlated with urinary GSTA1-1 excretion, indicating proximal tubule damage, whereas no distal tubular damage was observed. Co-administration of aminoguanidine reduced the upregulation of iNOS mRNA, urinary NO metabolite, and GSTA1-1 excretion, indicating that upregulation of iNOS and subsequent NO production may be responsible for renal proximal tubule damage observed.
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Affiliation(s)
- Suzanne Heemskerk
- Department of Pharmacology and Toxicology (149), Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands
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30
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Schildknecht S, Heinz K, Daiber A, Hamacher J, Kavaklí C, Ullrich V, Bachschmid M. Autocatalytic tyrosine nitration of prostaglandin endoperoxide synthase-2 in LPS-stimulated RAW 264.7 macrophages. Biochem Biophys Res Commun 2006; 340:318-25. [PMID: 16375865 DOI: 10.1016/j.bbrc.2005.12.009] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2005] [Accepted: 12/03/2005] [Indexed: 10/25/2022]
Abstract
In the literature, biological tyrosine nitrations have been reported to depend not only on peroxynitrite but also on nitrite/hydrogen peroxide linked to catalysis by myeloperoxidase. In endotoxin-stimulated RAW 264.7 macrophages, we have detected a major nitrotyrosine positive protein band around 72 kDa and identified it as prostaglandin endoperoxide synthase-2 (PGHS-2). Isolated PGHS-2 in absence of its substrate arachidonate was not only tyrosine-nitrated with peroxynitrite, but also with nitrite/hydrogen peroxide in complete absence of myeloperoxidase. Our data favor an autocatalytic activation of nitrite by PGHS-2 with a subsequent nitration of the essential tyrosine residue in the cyclooxygenase domain. Under inflammatory conditions, nitrite formed via NO-synthase-2 may therefore act as an endogenous regulator for PGHS-2 in stimulated macrophages. Nitration of PGHS-2 by the autocatalytic activation of nitrite further depends on the intracellular concentration of arachidonate since arachidonate reacted competitively with nitrite and could prevent PGHS-2 from nitration when excessively present.
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31
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Kong CW, Huang CH, Hsu TG, Tsai KKC, Hsu CF, Huang MC, Chen LC. Leukocyte mitochondrial alterations after cardiac surgery involving cardiopulmonary bypass: clinical correlations. Shock 2005; 21:315-9. [PMID: 15179131 DOI: 10.1097/00024382-200404000-00005] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Cardiac surgery with the use of cardiopulmonary bypass (CPB) is known to initiate systemic inflammatory responses that are associated with immune dysregulations, but the pathomechanisms underlying these changes remain elusive. Mitochondrial transmembrane potential (MTP) is an important determinant of leukocytic functions and viability, and may be altered as a part of the cellular responses to systemic inflammatory insults. Therefore, we examined MTP in three subsets of peripheral leukocytes in 18 patients receiving uncomplicated cardiac surgery involving CPB. The MTP of neutrophils and lymphocytes significantly increased, whereas that of monocytes significantly declined, after the surgery. The alterations in leukocytic MTP were transient, normalizing 3 days to 1 week after the surgery, and were accompanied by transient overproduction of intracellular oxidants, including nitric oxide and superoxide. Despite these perturbations, the viability status of leukocytes remained unaltered. Positive correlations were found between the changes of leukocyte MTP and various clinical parameters, implying that leukocyte mitochondrial alterations are parts of the systemic immune perturbations induced by the bypass surgery.
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Affiliation(s)
- Chi-Woon Kong
- Division of Critical Care, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
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32
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Mehta S. The effects of nitric oxide in acute lung injury. Vascul Pharmacol 2005; 43:390-403. [PMID: 16256443 DOI: 10.1016/j.vph.2005.08.013] [Citation(s) in RCA: 78] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2005] [Accepted: 08/03/2005] [Indexed: 10/25/2022]
Abstract
Acute lung injury (ALI) is a common clinical problem associated with significant morbidity and mortality. Ongoing clinical and basic research and a greater understanding of the pathophysiology of ALI have not been translated into new anti-inflammatory therapeutic options for patients with ALI, or into a significant improvement in the outcome of ALI. In both animal models and humans with ALI, there is increased endogenous production of nitric oxide (NO) due to enhanced expression and activity of inducible NO synthase (iNOS). This increased presence of iNOS and NO in ALI contributes importantly to the pathophysiology of ALI. However, inhibition of total NO production or selective inhibition of iNOS has not been effective in the treatment of ALI. We have recently suggested that there may be differential effects of NO derived from different cell populations in ALI. This concept of cell-source-specific effects of NO in ALI has potential therapeutic relevance, as targeted iNOS inhibition specifically to key individual cells may be an effective therapeutic approach in patients with ALI. In this paper, we will explore the potential role for endogenous iNOS-derived NO in ALI. We will review the evidence for increased iNOS expression and NO production, the effects of non-selective NOS inhibition, the effects of selective inhibition or deficiency of iNOS, and this concept of cell-source-specific effects of iNOS in both animal models and human ALI.
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Affiliation(s)
- Sanjay Mehta
- Centre for Critical Illness Research, Lawson Health Research Institute, Division of Respirology, University of Western Ontario, London, Ontario, Canada.
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Mitsuhashi H, Ikeuchi H, Yamashita S, Kuroiwa T, Kaneko Y, Hiromura K, Ueki K, Nojima Y. Increased levels of serum sulfite in patients with acute pneumonia. Shock 2004; 21:99-102. [PMID: 14752280 DOI: 10.1097/01.shk.0000105501.75189.85] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Sulfite, a common air pollutant, is toxic for humans, causing hypersensitivity or chronic airway diseases. We previously reported that sulfite is actively produced from neutrophils by stimulation with bacterial endotoxin, lipopolysaccharide (LPS). We also found that the serum sulfite concentration is increased in a rat model of sepsis induced by systemic injection of LPS. However, information on sulfite metabolism in human inflammatory conditions is limited. In the current study, the serum concentration of sulfite was determined in 25 patients with acute pneumonia. Serum sulfite concentration in pneumonia patients was significantly higher than that in control subjects (3.75 +/- 0.88 vs. 1.23 +/- 0.48 microM, respectively, P < 0.05). Among 20 patients, serum sulfite was serially determined before and after antibiotic therapy. The levels of serum sulfite were significantly reduced during the recovery phase compared with those during the acute phase (1.34 +/- 0.56 vs. 3.65 +/- 0.92 microM, respectively, P < 0.05). Moreover, neutrophils obtained from three patients during the acute phase of pneumonia spontaneously produced higher amounts of sulfite in vitro than those obtained after recovery. There was a close positive correlation (r = 0.71, P < 0.05) between serum sulfite and C-reactive protein (CRP) in patients with pneumonia. Taken together, the current findings suggest that serum sulfite increases during systemic inflammation in humans. Activated neutrophils might be responsible, at least in part, for the up-regulation of sulfite. Given various biological effects reported previously, sulfite may act as a mediator in inflammation.
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Affiliation(s)
- Hideki Mitsuhashi
- Department of Medicine and Clinical Science, Gunma Graduate School of Medicine, Maebashi, Japan
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34
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Clark IA, Alleva LM, Mills AC, Cowden WB. Pathogenesis of malaria and clinically similar conditions. Clin Microbiol Rev 2004; 17:509-39, table of contents. [PMID: 15258091 PMCID: PMC452556 DOI: 10.1128/cmr.17.3.509-539.2004] [Citation(s) in RCA: 129] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
There is now wide acceptance of the concept that the similarity between many acute infectious diseases, be they viral, bacterial, or parasitic in origin, is caused by the overproduction of inflammatory cytokines initiated when the organism interacts with the innate immune system. This is also true of certain noninfectious states, such as the tissue injury syndromes. This review discusses the historical origins of these ideas, which began with tumor necrosis factor (TNF) and spread from their origins in malaria research to other fields. As well the more established proinflammatory mediators, such as TNF, interleukin-1, and lymphotoxin, the roles of nitric oxide and carbon monoxide, which are chiefly inhibitory, are discussed. The established and potential roles of two more recently recognized contributors, overactivity of the enzyme poly(ADP-ribose) polymerase 1 (PARP-1) and the escape of high-mobility-group box 1 (HMGB1) protein from its normal location into the circulation, are also put in context. The pathogenesis of the disease caused by falciparum malaria is then considered in the light of what has been learned about the roles of these mediators in these other diseases, as well as in malaria itself.
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Affiliation(s)
- Ian A Clark
- School of Biochemistry and Molecular Biology, Australian National University, Canberra, ACT 0200, Australia.
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Prondzinsky R, Werdan K, Buerke M. [Cardiogenic shock: pathophysiology, clinics, therapeutical options and perspectives]. Internist (Berl) 2004; 45:284-95. [PMID: 14997307 DOI: 10.1007/s00108-003-1139-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Documented mortality from myocardial infarction (MI) has significantly decreased from around 30% in the 1960s to 6-7% currently, following the introduction of intensive care treatment, thrombolysis, effective antithrombotic therapy and coronary angioplasty. However, the approximate mortality of 70-80% of patients with cardiogenic shock following acute MI has hardly improved despite the introduction of modern treatment strategies. The major cause of in-hospital MI mortality remains myocardial failure with consecutive cardiogenic shock and multi-organ failure. Prompt coronary revascularisation by "facilitated" or "adjunctive" percutaneous coronary intervention (PCI), is currently considered the best method to reduce the high mortality in these patients. Facilitated PCI includes administration of glycoproteine receptor antagonists, mechanical circulation support strategies, such as, intraaortic balloon counterpulsation and potentially prehospital thrombolysis.
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Affiliation(s)
- R Prondzinsky
- Universitätsklinik und Poliklinik für Innere Medizin III, Martin-Luther-Universität Halle-Wittenberg, Halle/Saale.
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36
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Clark IA, Awburn MM, Harper CG, Liomba NG, Molyneux ME. Induction of HO-1 in tissue macrophages and monocytes in fatal falciparum malaria and sepsis. Malar J 2003; 2:41. [PMID: 14624702 PMCID: PMC317345 DOI: 10.1186/1475-2875-2-41] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2003] [Accepted: 11/19/2003] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND: As well as being inducible by haem, haemoxygenase -1 (HO-1) is also induced by interleukin-10 and an anti-inflammatory prostaglandin, 15d PGJ2, the carbon monoxide thus produced mediating the anti-inflammatory effects of these molecules. The cellular distribution of HO-1, by immunohistochemistry, in brain, lung and liver in fatal falciparum malaria, and in sepsis, is reported. METHODS: Wax sections were stained, at a 1:1000 dilution of primary antibody, for HO-1 in tissues collected during paediatric autopsies in Blantyre, Malawi. These comprised 37 acutely ill comatose patients, 32 of whom were diagnosed clinically as cerebral malaria and the other 5 as bacterial diseases with coma. Another 3 died unexpectedly from an alert state. Other control tissues were from Australian adults. RESULTS: Apart from its presence in splenic red pulp macrophages and microhaemorrhages, staining for HO-1 was confined to intravascular monocytes and certain tissue macrophages. Of the 32 clinically diagnosed cerebral malaria cases, 11 (category A) cases had negligible histological change in the brain and absence of or scanty intravascular sequestration of parasitized erythrocytes. Of these 11 cases, eight proved at autopsy to have other pathological changes as well, and none of these eight showed HO-1 staining within the brain apart from isolated moderate staining in one case. Two of the three without another pathological diagnosis showed moderate staining of scattered monocytes in brain vessels. Six of these 11 (category A) cases exhibited strong lung staining, and the Kupffer cells of nine of them were intensely stained. Of the seven (category B) cases with no histological changes in the brain, but appreciable sequestered parasitised erythrocytes present, one was without staining, and the other six showed strongly staining, rare or scattered monocytes in cerebral vessels. All six lung sections not obscured by neutrophils showed strong staining of monocytes and alveolar macrophages, and all six available liver sections showed moderate or strong staining of Kupffer cells. Of the 14 (category C) cases, in which brains showed micro-haemorrhages and intravascular mononuclear cell accumulations, plus sequestered parasitised erythrocytes, all exhibited strong monocyte HO-1 staining in cells forming accumulations and scattered singly within cerebral blood vessels. Eleven of the available and readable 13 lung sections showed strongly staining monocytes and alveolar macrophages, and one stained moderately. All of the 14 livers had strongly stained Kupffer cells. Of five cases of comatose culture-defined bacterial infection, three showed a scattering of stained monocytes in vessels within the brain parenchyma, three had stained cells in lung sections, and all five demonstrated moderately or strongly staining Kupffer cells. Brain sections from all three African controls, lung sections from two of them, and liver from one, showed no staining for HO-1, and other control lung and liver sections showed few, palely stained cells only. Australian-origin adult brains exhibited no staining, whether the patients had died from coronary artery disease or from non-infectious, non-cerebral conditions CONCLUSIONS: Clinically diagnosed 'cerebral malaria' in children includes some cases in whom malaria is not the only diagnosis with the hindsight afforded by autopsy. In these patients there is widespread systemic inflammation, judged by HO-1 induction, at the time of death, but minimal intracerebral inflammation. In other cases with no pathological diagnosis except malaria, there is evidence of widespread inflammatory responses both in the brain and in other major organs. The relative contributions of intracerebral and systemic host inflammatory responses in the pathogenesis of coma and death in malaria deserve further investigation.
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Affiliation(s)
- Ian A Clark
- Dept of Biochemistry, Australian National University, Canberra, Australia
| | - Melissa M Awburn
- Dept of Biochemistry, Australian National University, Canberra, Australia
| | | | - N George Liomba
- Dept of Histopathology, College of Medicine, University of Malawi, Blantyre, Malawi
| | - Malcolm E Molyneux
- Wellcome Trust Laboratories and Malaria Project, College of Medicine, University of Malawi
- School of Tropical Medicine, University of Liverpool, UK
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