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Vorobjeva NV, Chelombitko MA, Sud’ina GF, Zinovkin RA, Chernyak BV. Role of Mitochondria in the Regulation of Effector Functions of Granulocytes. Cells 2023; 12:2210. [PMID: 37759432 PMCID: PMC10526294 DOI: 10.3390/cells12182210] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Revised: 09/03/2023] [Accepted: 09/04/2023] [Indexed: 09/29/2023] Open
Abstract
Granulocytes (neutrophils, eosinophils, and basophils) are the most abundant circulating cells in the innate immune system. Circulating granulocytes, primarily neutrophils, can cross the endothelial barrier and activate various effector mechanisms to combat invasive pathogens. Eosinophils and basophils also play an important role in allergic reactions and antiparasitic defense. Granulocytes also regulate the immune response, wound healing, and tissue repair by releasing of various cytokines and lipid mediators. The effector mechanisms of granulocytes include the production of reactive oxygen species (ROS), degranulation, phagocytosis, and the formation of DNA-containing extracellular traps. Although all granulocytes are primarily glycolytic and have only a small number of mitochondria, a growing body of evidence suggests that mitochondria are involved in all effector functions as well as in the production of cytokines and lipid mediators and in apoptosis. It has been shown that the production of mitochondrial ROS controls signaling pathways that mediate the activation of granulocytes by various stimuli. In this review, we will briefly discuss the data on the role of mitochondria in the regulation of effector and other functions of granulocytes.
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Affiliation(s)
- Nina V. Vorobjeva
- Department Immunology, Biology Faculty, Lomonosov Moscow State University, 119234 Moscow, Russia;
| | - Maria A. Chelombitko
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia; (M.A.C.); (R.A.Z.)
- The Russian Clinical Research Center for Gerontology, Ministry of Healthcare of the Russian Federation, Pirogov Russian National Research Medical University, 129226 Moscow, Russia
| | - Galina F. Sud’ina
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia; (M.A.C.); (R.A.Z.)
| | - Roman A. Zinovkin
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia; (M.A.C.); (R.A.Z.)
- The Russian Clinical Research Center for Gerontology, Ministry of Healthcare of the Russian Federation, Pirogov Russian National Research Medical University, 129226 Moscow, Russia
| | - Boris V. Chernyak
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia; (M.A.C.); (R.A.Z.)
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Enhancing Mesenchymal Stromal Cell Immunomodulation for Treating Conditions Influenced by the Immune System. Stem Cells Int 2019; 2019:7219297. [PMID: 31467564 PMCID: PMC6701346 DOI: 10.1155/2019/7219297] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Accepted: 05/13/2019] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stromal cells (MSCs), formerly known as mesenchymal stem cells, are nonhematopoietic multipotent cells and are emerging worldwide as the most clinically used and promising source for allogeneic cell therapy. MSCs, initially obtained from bone marrow, can be derived from several other tissues, such as adipose tissue, placenta, and umbilical cord. Diversity in tissue sourcing and manufacturing procedures has significant effects on MSC products. However, in 2006, a minimal set of standard criteria has been issued by the International Society of Cellular Therapy for defining derived MSCs. These include adherence to plastic in conventional culture conditions, particular phenotype, and multilineage differentiation capacity in vitro. Moreover, MSCs have trophic capabilities, a high in vitro self-renewal ability, and immunomodulatory characteristics. Thus, immunosuppressive treatment with MSCs has been proposed as a potential therapeutic alternative for conditions in which the immune system cells influence outcomes, such as inflammatory and autoimmune diseases. The precise mechanism by which MSCs affect functions of most immune effector cells is not completely understood but involves direct contact with immune cells, soluble mediators, and local microenvironmental factors. Recently, it has been shown that their homeostatic resting state requires activation, which can be achieved in vitro with various cytokines, including interferon-γ. In the present review, we focus on the suppressive effect that MSCs exert on the immune system and highlight the significance of in vitro preconditioning and its use in preclinical studies. We discuss the clinical aspects of using MSCs as an immunomodulatory treatment. Finally, we comment on the risk of interfering with the immune system in regard to cancer formation and development.
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Reactive oxygen species production and antioxidant enzyme activity during epididymal sperm maturation in Corynorhinus mexicanus bats. Reprod Biol 2016; 16:78-86. [DOI: 10.1016/j.repbio.2016.01.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2015] [Revised: 01/08/2016] [Accepted: 01/10/2016] [Indexed: 11/23/2022]
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Glenn JD, Whartenby KA. Mesenchymal stem cells: Emerging mechanisms of immunomodulation and therapy. World J Stem Cells 2014; 6:526-539. [PMID: 25426250 PMCID: PMC4178253 DOI: 10.4252/wjsc.v6.i5.526] [Citation(s) in RCA: 299] [Impact Index Per Article: 27.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 09/09/2014] [Accepted: 09/17/2014] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are a pleiotropic population of cells that are self-renewing and capable of differentiating into canonical cells of the mesenchyme, including adipocytes, chondrocytes, and osteocytes. They employ multi-faceted approaches to maintain bone marrow niche homeostasis and promote wound healing during injury. Biomedical research has long sought to exploit their pleiotropic properties as a basis for cell therapy for a variety of diseases and to facilitate hematopoietic stem cell establishment and stromal reconstruction in bone marrow transplantation. Early results demonstrated their usage as safe, and there was little host response to these cells. The discovery of their immunosuppressive functions ushered in a new interest in MSCs as a promising therapeutic tool to suppress inflammation and down-regulate pathogenic immune responses in graft-versus-host and autoimmune diseases such as multiple sclerosis, autoimmune diabetes, and rheumatoid arthritis. MSCs produce a large number of soluble and membrane-bound factors, some of which inhibit immune responses. However, the full range of MSC-mediated immune-modulation remains incompletely understood, as emerging reports also reveal that MSCs can adopt an immunogenic phenotype, stimulate immune cells, and yield seemingly contradictory results in experimental animal models of inflammatory disease. The present review describes the large body of literature that has been accumulated on the fascinating biology of MSCs and their complex effects on immune responses.
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Ekyalongo RC, Nakayama H, Kina K, Kaga N, Iwabuchi K. Organization and functions of glycolipid-enriched microdomains in phagocytes. Biochim Biophys Acta Mol Cell Biol Lipids 2014; 1851:90-7. [PMID: 24968752 DOI: 10.1016/j.bbalip.2014.06.009] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2014] [Revised: 06/03/2014] [Accepted: 06/17/2014] [Indexed: 11/26/2022]
Abstract
Populations of glycolipids change markedly during leukocyte differentiation, suggesting that these molecules are involved in biological functions. About 70% of the glycosphingolipids in human neutrophils are lactosylceramide, a molecule also expressed on monocytes and dendritic cells, but not on lymphocytes. In contrast, phosphatidylglucoside is mainly expressed on neutrophils. STED microscopic analysis showed that phosphatidylglucoside and lactosylceramide form different domains on plasma membranes of neutrophils, with phosphatidylglucoside preferentially expressed along the neutrophil differentiation pathway. Phosphatidylglucoside was found to mediate the differentiation of HL-60 cells into the neutrophilic lineage, and to be involved in FAS-dependent neutrophil apoptosis. In contrast, lactosylceramide was only expressed on mature neutrophils. Complexes of lactosylceramide and the Src family kinase Lyn form membrane microdomains. LacCer-enriched membrane microdomains mediate neutrophil innate immune responses; e.g. chemotaxis, phagocytosis, and superoxide generation. C24 fatty acid chains of LacCer are indispensable for the formation of LacCer-Lyn complexes and for LacCer-dependent functions. Moreover, Lyn-coupled LacCer-enriched microdomains serve as signal transduction platforms for αMβ2 integrin-mediated phagocytosis. This review describes the organization and potential functions of glycolipids in phagocytes, as well as the roles of both phosphatidylglucoside and lactosylceramide in neutrophils. This article is part of a Special Issue entitled Linking transcription to physiology in lipidomics.
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Affiliation(s)
- Roudy C Ekyalongo
- Institute for Environmental and Gender-specific Medicine, Juntendo University Graduate School of Medicine, Japan
| | - Hitoshi Nakayama
- Institute for Environmental and Gender-specific Medicine, Juntendo University Graduate School of Medicine, Japan; Laboratory of Biochemistry, Juntendo University School of Health Care and Nursing, Japan
| | - Katsunari Kina
- Institute for Environmental and Gender-specific Medicine, Juntendo University Graduate School of Medicine, Japan
| | - Naoko Kaga
- Division of Proteomics and Biomolecular Science, BioMedical Research Center, Juntendo University Graduate School of Medicine, Japan
| | - Kazuhisa Iwabuchi
- Institute for Environmental and Gender-specific Medicine, Juntendo University Graduate School of Medicine, Japan; Laboratory of Biochemistry, Juntendo University School of Health Care and Nursing, Japan; Infection Control Nursing, Juntendo University Graduate School of Health Care and Nursing, Japan.
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Cohen G, Raupachova J, Borchhardt K, Hörl WH. Cinacalcet effect on polymorphonuclear leucocytes of kidney transplant patients. Eur J Clin Invest 2013; 43:476-82. [PMID: 23521420 DOI: 10.1111/eci.12075] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2012] [Accepted: 02/26/2013] [Indexed: 11/28/2022]
Abstract
BACKGROUND Polymorphonuclear leucocytes (PMNLs) play a key role in the nonspecific immune defence. Cinacalcet reduces serum calcium levels in kidney transplant recipients with mineral bone disorder associated with chronic kidney disease. We investigated essential functions of PMNLs of kidney transplant recipients with and without hypercalcaemia and with and without cinacalcet therapy. SUBJECTS AND METHODS Oxidative burst, phagocytosis, apoptosis and intracellular calcium concentrations of PMNLs from normocalcaemic kidney transplant patients without (KT-NC) or with cinacalcet intake (KT-NC/CI), hypercalcaemic kidney transplant patients (KT-HC) and healthy subjects (HS) were investigated. RESULTS Stimulation of oxidative burst of PMNLs from KT-HC patients by phorbol-12-myristate-13-acetate or Escherichia coli was significantly attenuated compared with PMNLs from KT-NC, KT-NC/CI and HS. Apoptosis of PMNLs from KT-HC patients was significantly decreased compared with cells from KT-NC, KT-NC/CI and HS. Apoptosis correlated significantly with serum calcium concentrations. Intracellular calcium concentrations and phagocytosis of PMNLs did not differ between groups. CONCLUSIONS Our data indicate that stimulation of PMNL oxidative burst and apoptosis is significantly diminished in kidney transplant patients with hypercalcaemia, while kidney transplant patients with serum calcium levels normalized by cinacalcet have normal PMNL functions despite immunosuppressive therapy.
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Affiliation(s)
- Gerald Cohen
- Division of Nephrology and Dialysis, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
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El Kebir D, Filep JG. Modulation of Neutrophil Apoptosis and the Resolution of Inflammation through β2 Integrins. Front Immunol 2013; 4:60. [PMID: 23508943 PMCID: PMC3589696 DOI: 10.3389/fimmu.2013.00060] [Citation(s) in RCA: 94] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2012] [Accepted: 02/21/2013] [Indexed: 01/13/2023] Open
Abstract
Precise control of the neutrophil death program provides a balance between their defense functions and safe clearance, whereas impaired regulation of neutrophil death is thought to contribute to a wide range of inflammatory pathologies. Apoptosis is essential for neutrophil functional shutdown, removal of emigrated neutrophils, and timely resolution of inflammation. Neutrophils receive survival and pro-apoptosis cues from the inflammatory microenvironment and integrate these signals through surface receptors and common downstream mechanisms. Among these receptors are the leukocyte-specific membrane receptors β2 integrins that are best known for regulating adhesion and phagocytosis. Accumulating evidence indicate that outside-in signaling through the β2 integrin Mac-1 can generate contrasting cues in neutrophils, leading to promotion of their survival or apoptosis. Binding of Mac-1 to its ligands ICAM-1, fibrinogen, or the azurophilic granule enzyme myeloperoxidase suppresses apoptosis, whereas Mac-1-mediated phagocytosis of bacteria evokes apoptotic cell death. Mac-1 signaling is also target for the anti-inflammatory, pro-resolving mediators, including lipoxin A4, aspirin-triggered lipoxin A4, and resolvin E1. This review focuses on molecular mechanisms underlying Mac-1 regulation of neutrophil apoptosis and highlights recent advances how hierarchy of survival and pro-apoptosis signals can be harnessed to facilitate neutrophil apoptosis and the resolution of inflammation.
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Affiliation(s)
- Driss El Kebir
- Department of Pathology and Cell Biology, University of Montreal and Research Center, Maisonneuve-Rosemont Hospital Montreal, QC, Canada
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Sarkar A, Aga E, Bussmeyer U, Bhattacharyya A, Möller S, Hellberg L, Behnen M, Solbach W, Laskay T. Infection of neutrophil granulocytes with Leishmania major activates ERK 1/2 and modulates multiple apoptotic pathways to inhibit apoptosis. Med Microbiol Immunol 2012; 202:25-35. [PMID: 22661217 DOI: 10.1007/s00430-012-0246-1] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2012] [Accepted: 05/09/2012] [Indexed: 12/28/2022]
Abstract
Neutrophil granulocytes provide the first line of defense against bacterial, fungal, and parasitic infections. They phagocytose and kill many invading pathogens. Certain pathogenic microorganisms such as the intracellular protozoan parasite Leishmania major (L. major) can survive inside neutrophils. Mature neutrophils have a very short life span due to spontaneous apoptosis. Previously, we have reported that infections with L. major are able to delay spontaneous apoptosis. In the present study, we addressed the underlying mechanisms of regulation of both extrinsic and intrinsic apoptosis. We show that interaction with L. major transiently activates ERK1/2 phosphorylation. Pharmacological inhibition of ERK1/2 phosphorylation reversed the apoptosis delay. Moreover, infection leads to the enhanced and sustainable expression of the anti-apoptotic proteins Bcl-2 and Bfl-1, respectively. As downstream events, the release of cytochrome c from mitochondria and processing of caspase-6 were inhibited. We also confirm that infection with L. major results in reduced FAS expression on the surface of neutrophils. The presented data indicate that infection with L. major affects both intrinsic as well as extrinsic pathways of neutrophil apoptosis. Enhanced life span of host neutrophils enables the parasite to survive within neutrophils.
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Affiliation(s)
- Arup Sarkar
- Institute for Medical Microbiology and Hygiene, University of Lübeck, Lübeck, Germany
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Barros MP, Marin DP, Bolin AP, de Cássia Santos Macedo R, Campoio TR, Fineto C, Guerra BA, Polotow TG, Vardaris C, Mattei R, Otton R. Combined astaxanthin and fish oil supplementation improves glutathione-based redox balance in rat plasma and neutrophils. Chem Biol Interact 2012; 197:58-67. [PMID: 22465178 DOI: 10.1016/j.cbi.2012.03.005] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2011] [Revised: 03/09/2012] [Accepted: 03/10/2012] [Indexed: 12/30/2022]
Abstract
The present study aimed to investigate the effects of daily (45 days) intake of fish oil (FO; 10mg EPA/kg body weight (BW) and 7 mg DHA/kg BW) and/or natural ASTA (1mg ASTA/kg BW) on oxidative stress and functional indexes of neutrophils isolated from Wistar rats by monitoring superoxide (O(2)(-)), hydrogen peroxide (H(2)O(2)), and nitric oxide (NO()) production compared to the progression of auto-induced lipid peroxidation and Ca(2+) release in activated neutrophils. Furthermore, phagocytic capacity, antioxidant enzyme activities, glutathione-recycling system, and biomarkers of lipid and protein oxidation in neutrophils were compared to the redox status. Our results show evidence of the beneficial effects of FO+ASTA supplementation for immune competence based on the redox balance in plasma (significant increase in GSH-dependent reducing power), non-activated neutrophils (increased activity of the glutathione-recycling enzymes GPx and GR) and PMA-activated neutrophils (lower O(2)(-), H(2)O(2), and NO() generation, reduced membrane oxidation, but higher phagocytic activity). Combined application of ASTA and FO promoted hypolipidemic/hypocholesterolemic effects in plasma and resulted in increased phagocytic activity of activated neutrophils when compared with ASTA or FO applied alone. In PMA-activated neutrophils, ASTA was superior to FO in exerting antioxidant effects. The bulk of data reinforces the hypothesis that habitual consumption of marine fish (e.g. salmon, which is a natural source of both astaxanthin and fish oil) is beneficial to human health, in particular by improving immune response and lowering the risk of vascular and infectious diseases.
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Affiliation(s)
- Marcelo Paes Barros
- Human Movement Sciences, Institute of Physical Activity and Sport Sciences (ICAFE), Universidade Cruzeiro do Sul, São Paulo, SP, Brazil
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Neutrophil Function and Apoptosis in Patients with Chronic Hepatitis C Treated with Pegylated Interferon α and Ribavirin. Arch Immunol Ther Exp (Warsz) 2011; 60:61-8. [DOI: 10.1007/s00005-011-0153-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2011] [Accepted: 07/01/2011] [Indexed: 12/11/2022]
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Kina K, Masuda H, Nakayama H, Nagatsuka Y, Nabetani T, Hirabayashi Y, Takahashi Y, Shimada K, Daida H, Ogawa H, Takamori K, Iwabuchi K. The Novel Neutrophil Differentiation Marker Phosphatidylglucoside Mediates Neutrophil Apoptosis. THE JOURNAL OF IMMUNOLOGY 2011; 186:5323-32. [DOI: 10.4049/jimmunol.1002100] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
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Volk APD, Barber BM, Goss KL, Ruff JG, Heise CK, Hook JS, Moreland JG. Priming of neutrophils and differentiated PLB-985 cells by pathophysiological concentrations of TNF-α is partially oxygen dependent. J Innate Immun 2010; 3:298-314. [PMID: 21088376 PMCID: PMC3128147 DOI: 10.1159/000321439] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2010] [Accepted: 09/25/2010] [Indexed: 02/01/2023] Open
Abstract
Activation of polymorphonuclear leukocytes (PMN) can be modulated to intermediate 'primed' states characterized by enhanced responsiveness to subsequent stimuli. We studied priming in response to TNF-α in human PMN and PLB-985 cells, a myeloid cell line differentiated to a neutrophilic phenotype (PLB-D). PMN generated reactive oxygen species (ROS) in response to TNF-α alone, and NADPH oxidase activity increased in response to stimulation with formyl-Met-Leu-Phe after priming. PLB-D cells also demonstrated priming of NADPH oxidase activity. Similar to priming by endotoxin, priming of the respiratory burst by TNF-α was predominantly oxygen dependent, with marked attenuation of ROS generation if primed anaerobically. Both PMN and PLB-D cells displayed significant increases in cell surface CD11b and gp91(phox) expression after TNF-α priming and PMN displayed activation of MAPK. In response to TNF-α priming, neither mobilization of intracellular proteins nor activation of MAPK pathways was NADPH oxidase dependent. Priming of PMN and PLB-D cells by low TNF-α concentrations enhanced chemotaxis. These data demonstrate that pathophysiological concentrations of TNF-α elicit NADPH oxidase-derived ROS and prime cells for enhanced surface protein expression, activation of p38 and ERK1/2 MAPK pathways, and increased chemotaxis. Furthermore, PLB-D cells undergo TNF-α priming and provide a genetically modifiable model to study priming mechanisms.
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Affiliation(s)
| | | | | | | | | | | | - Jessica G. Moreland
- Division of Critical Care, Department of Pediatrics, Inflammation Program, University of Iowa and Veterans Affairs Medical Center, Iowa City, Iowa, USA
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Protective effects of propolis and related polyphenolic/flavonoid compounds against toxicity induced by irinotecan. Med Oncol 2009; 27:1346-58. [PMID: 20013318 DOI: 10.1007/s12032-009-9387-5] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2009] [Accepted: 12/02/2009] [Indexed: 10/20/2022]
Abstract
Despite the excellent chemotherapeutic effect of irinotecan, its cytotoxicity and genotoxicity in normal cells remains a major problem in chemotherapy. This study was carried out to find whether propolis preparations and related flavonoids (quercetin, naringin) might enhance irinotecan-induced cytotoxicity to tumor cells in mice bearing Ehrlich ascites tumors (EAT) while protecting normal blood, liver, and kidney cells. The preparation of propolis and their flavonoids were given to mice intraperitoneally at a dose of 100 mg kg(-1) body weight for three consecutive days before the ip injection of EAT cells (2×10(6)). Irinotecan was administered ip at dose of 50 mg kg(-1) on days 3, 4, and 5 after tumor cell inoculation. The combination treatment resulted in substantial inhibition of the growth of EAT cells as well as treatment with quercetin or irinotecan alone, whereas other treatment by itself showed little effect. However, when mice were pre-treated with test components prior to irinotecan, the frequencies of irinotecan-induced micronuclei (MN) was decreased but in mice bearing tumor QU and EEP increased number of micronucleated cells. Propolis preparation and related flavonoids were found to exhibit an important immunomodulatory effect and could decrease irinotecan-induced toxic and genotoxic effects to normal cells without effecting irinotecan cytotoxicity in EAT cells.
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Graham FD, Erlemann KR, Gravel S, Rokach J, Powell WS. Oxidative stress-induced changes in pyridine nucleotides and chemoattractant 5-lipoxygenase products in aging neutrophils. Free Radic Biol Med 2009; 47:62-71. [PMID: 19376220 PMCID: PMC2891157 DOI: 10.1016/j.freeradbiomed.2009.04.016] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2009] [Revised: 03/26/2009] [Accepted: 04/01/2009] [Indexed: 01/08/2023]
Abstract
Neutrophils spontaneously undergo apoptosis, which is associated with increased oxidative stress. We found that there is a dramatic shift in the formation of 5-lipoxygenase products during this process. Freshly isolated neutrophils rapidly convert leukotriene B(4) (LTB(4)) and 5-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE) to their biologically inactive omega-oxidation products. However, omega-oxidation is impaired in neutrophils cultured for 24 h, when only 25% of the cells are nonapoptotic, resulting in the persistence of LTB(4) and a dramatic shift in 5-HETE metabolism to the potent granulocyte chemoattractant 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE). The reduced omega-oxidation activity seems to be due to a reduction in LTB(4) 20-hydroxylase activity, whereas the increased 5-oxo-ETE formation is caused by a dramatic increase in the 5-hydroxyeicosanoid dehydrogenase cofactor NADP(+). NAD(+), but not NADPH, also increased, as did the GSSG/GSH ratio, indicative of oxidative stress. The changes in 5-HETE metabolism and pyridine nucleotides were inhibited by antiapoptotic agents (GM-CSF, forskolin) and antioxidants (diphenylene iodonium, catalase, deferoxamine), suggesting the involvement of H(2)O(2) and possibly other reactive oxygen species. These results suggest that in severe inflammation, aging neutrophils that have evaded rapid uptake by macrophages may produce increased amounts of the chemoattractants 5-oxo-ETE and LTB(4), resulting in delayed resolution or exacerbation of the inflammatory process.
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Affiliation(s)
- François D. Graham
- Meakins-Christie Laboratories, McGill University, Montreal, QC, Canada H2X 2P2
| | | | - Sylvie Gravel
- Meakins-Christie Laboratories, McGill University, Montreal, QC, Canada H2X 2P2
| | - Joshua Rokach
- Claude Pepper Institute and Department of Chemistry, Florida Institute of Technology, Melbourne, FL 32901−6982, USA
| | - William S. Powell
- Meakins-Christie Laboratories, McGill University, Montreal, QC, Canada H2X 2P2
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Webb CB, Falkowski L. Oxidative stress and innate immunity in feline patients with diabetes mellitus: the role of nutrition. J Feline Med Surg 2009; 11:271-6. [PMID: 18783975 PMCID: PMC10911470 DOI: 10.1016/j.jfms.2008.07.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/01/2008] [Indexed: 11/16/2022]
Abstract
This study was undertaken to test the hypothesis that oxidative stress is increased and neutrophil function is decreased in cats with diabetes mellitus (DM). Measures of oxidative stress and neutrophil function were evaluated in 20 control and 15 diabetic cats. Cats were then fed a diet designed specifically for feline diabetics (Purina DM Dietetic Management Feline Formula) for 8 weeks, after which all assays were repeated. Cats with DM had significantly less plasma superoxide dismutase (SOD) than control cats, consistent with a greater degree of oxidative stress in the DM group. Following 8 weeks of consuming a diabetes-specific diet glutathione peroxidase, an antioxidant enzyme increased significantly in both groups. Other parameters of oxidative stress, as well as neutrophil function, were similar between groups and did not change following dietary intervention. The DM cats were significantly older and heavier than the control cats, which may have contributed to differences in parameters of oxidative stress and levels of antioxidant enzymes between these groups, but the decreased level of SOD enzyme in the diabetic group would appear to support the continued development of targeted antioxidant supplementation for this cats with this disease.
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Affiliation(s)
- Craig B Webb
- Clinical Sciences Department, Colorado State University, Fort Collins, CO 80523, USA.
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Webb CB, McCord KW, Twedt DC. Assessment of oxidative stress in leukocytes and granulocyte function following oral administration of a silibinin-phosphatidylcholine complex in cats. Am J Vet Res 2009; 70:57-62. [DOI: 10.2460/ajvr.70.1.57] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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17
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Khymenets O, Covas MI, Farré M, Langohr K, Fitó M, de la Torre R. Role of sex and time of blood sampling in SOD1 and SOD2 expression variability. Clin Biochem 2008; 41:1348-54. [DOI: 10.1016/j.clinbiochem.2008.08.064] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2008] [Revised: 07/10/2008] [Accepted: 08/06/2008] [Indexed: 11/26/2022]
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18
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Anti-interleukin-8 autoantibody:interleukin-8 immune complexes in acute lung injury/acute respiratory distress syndrome. Clin Sci (Lond) 2008; 114:403-12. [DOI: 10.1042/cs20070272] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
ALI/ARDS (acute lung injury/acute respiratory distress syndrome) is a severe inflammatory lung disease associated with very high mortality. Importantly, no effective therapy has been developed to date for ALI/ARDS. Neutrophils have been implicated in the pathogenesis of ALI/ARDS, and IL-8 (interleukin-8) has been identified as the main chemotactic factor for neutrophils in lung fluids of patients with ALI/ARDS. Significantly, studies from our laboratory have revealed the presence of anti-IL-8 autoantibody:IL-8 immune complexes in lung fluids from patients with ALI/ARDS. Autoantibodies to several cytokines, including IL-8, have been found in human plasma and other tissues. The function of anticytokine autoantibodies is far from clear; however, in some instances, it has been suggested that such autoantibodies may contribute to the pathogenesis of variety of human diseases. In addition, many of these autoantibodies can form immune complexes with target cytokines. Furthermore, immune complexes consisting of anti-IL-8 autoantibodies and IL-8 are very stable due to the high affinity of autoantibodies against IL-8. These complexes are present in various human tissues, including the lung, as they have been detected in lung fluids from patients with ALI/ARDS. In this review, the significance of the latter findings are explored, and the possible involvement of anti-IL-8 autoantibody:IL-8 immune complexes in pathogenesis of ALI/ARDS is discussed.
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Raffaghello L, Bianchi G, Bertolotto M, Montecucco F, Busca A, Dallegri F, Ottonello L, Pistoia V. Human mesenchymal stem cells inhibit neutrophil apoptosis: a model for neutrophil preservation in the bone marrow niche. Stem Cells 2008; 26:151-162. [PMID: 17932421 DOI: 10.1634/stemcells.2007-0416] [Citation(s) in RCA: 348] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Mesenchymal stem cells (MSC) establish close interactions with bone marrow sinusoids in a putative perivascular niche. These vessels contain a large storage pool of mature nonproliferating neutrophils. Here, we have investigated the effects of human bone marrow MSC on neutrophil survival and effector functions. MSC from healthy donors, at very low MSC:neutrophil ratios (up to 1:500), significantly inhibited apoptosis of resting and interleukin (IL)-8-activated neutrophils and dampened N-formyl-l-methionin-l-leucyl-l-phenylalanine (f-MLP)-induced respiratory burst. The antiapoptotic activity of MSC did not require cell-to-cell contact, as shown by transwell experiments. Antibody neutralization experiments demonstrated that the key MSC-derived soluble factor responsible for neutrophil protection from apoptosis was IL-6, which signaled by activating STAT-3 transcription factor. Furthermore, IL-6 expression was detected in MSC by real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. Finally, recombinant IL-6 was found to protect neutrophils from apoptosis in a dose-dependent manner. MSC had no effect on neutrophil phagocytosis, expression of adhesion molecules, and chemotaxis in response to IL-8, f-MLP, or C5a. These results support the following conclusions: (a) in the bone marrow niche, MSC likely protect neutrophils of the storage pool from apoptosis, preserving their effector functions and preventing the excessive or inappropriate activation of the oxidative metabolism, and (b) a novel mechanism whereby the inflammatory potential of activated neutrophils is harnessed by inhibition of apoptosis and reactive oxygen species production without impairing phagocytosis and chemotaxis has been identified.
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20
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Hydrogen peroxide activates calcium influx in human neutrophils. Mol Cell Biochem 2007; 309:151-6. [PMID: 18008137 DOI: 10.1007/s11010-007-9653-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2007] [Accepted: 10/31/2007] [Indexed: 01/23/2023]
Abstract
The correlation between an increased production of reactive oxygen species (ROS) and an enhanced calcium entry in primed neutrophils stimulated with fMLP suggests that endogenous ROS could serve as an agonist to reinforce calcium signaling by positive feedback. This work shows that exogenous H2O2 produced a rapid influx of Mn2+ and an increase of intracellular calcium. The H2O2 was insufficient to produce significant changes in the absence of extracellular calcium but addition of Ca2+ to H2O2-treated cells suspended in a free Ca2+/EGTA buffer resulted in a great increase in [Ca2+]i reflecting influx of Ca2+ across the cell membrane. The increase of intracellular calcium was inhibited by Ni2+, La3+, and hyperosmotic solutions of mannitol and other osmolytes. This raises the possibility that the secretion of H2O2 by activated neutrophils could act as an autocrine regulator of neutrophil function through the activation of calcium entry.
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21
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Moreland JG, Davis AP, Matsuda JJ, Hook JS, Bailey G, Nauseef WM, Lamb FS. Endotoxin priming of neutrophils requires NADPH oxidase-generated oxidants and is regulated by the anion transporter ClC-3. J Biol Chem 2007; 282:33958-67. [PMID: 17908687 DOI: 10.1074/jbc.m705289200] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Several soluble mediators, including endotoxin, prime neutrophils for an enhanced respiratory burst in response to subsequent stimulation. Priming of neutrophils occurs in vitro, and primed neutrophils are found in vivo. We previously localized the anion transporter ClC-3 to polymorphonuclear leukocytes (PMN) secretory vesicles and demonstrated that it is required for normal NADPH oxidase activation in response to both particulate and soluble stimuli. We now explore the contribution of the NADPH oxidase and ClC-3 to endotoxin-mediated priming. Lipooligosaccharide (LOS) from Neisseria meningitidis enhances the respiratory burst in response to formyl-Met-Leu-Phe, an effect that was impaired in PMNs lacking functional ClC-3 and under anaerobic conditions. Mobilization of receptors to the cell surface and phosphorylation of p38 MAPK by LOS were both impaired in PMN with the NADPH oxidase chemically inhibited or genetically absent and in cells lacking functional ClC-3. Furthermore, inhibition of the NADPH oxidase or ClC-3 in otherwise unstimulated cells elicited a phenotype similar to that seen after endotoxin priming, suggesting that basal oxidant production helps to maintain cellular quiescence. In summary, NADPH oxidase activation was required for LOS-mediated priming, but basal oxidants kept unstimulated cells from becoming primed. ClC-3 contributes to both of these processes.
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Affiliation(s)
- Jessica G Moreland
- Division of Critical Care, Department of Pediatrics, The Inflammation Program, University of Iowa and Veterans Affairs Medical Center, Iowa City, IA 52242, USA.
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22
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Kapiszewska M, Cierniak A, Elas M, Lankoff A. Lifespan of etoposide-treated human neutrophils is affected by antioxidant ability of quercetin. Toxicol In Vitro 2007; 21:1020-30. [PMID: 17467952 DOI: 10.1016/j.tiv.2007.03.005] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2006] [Revised: 03/06/2007] [Accepted: 03/12/2007] [Indexed: 11/29/2022]
Abstract
Neutropenia is the primary dose-limiting effect of etoposide toxicity resulting in a decreased efficiency of cancer treatment. Hence, the protection of neutrophils has important clinical implications. We investigated whether quercetin, due to its antioxidant properties, is able to modulate the damaging activity of etoposide. DNA damage, evaluated by the comet assay, and apoptosis, determined by FACScan flow cytometry using Annexin/PI, increased with etoposide doses. The intracellular level of reactive oxygen species (ROS) was enhanced in resting neutrophils incubated with etoposide at concentrations up to 25 microM; above this concentration etoposide revealed antioxidant properties. Only in latex-activated neutrophils, i.e. with latex-stimulated respiratory burst was the ROS production inhibited, as assessed by the luminol amplified chemiluminescence. The characteristic electron spin resonance (ESR) signal of etoposide phenoxyl radical, which occurs in the presence of myeloperoxidase, H2O2 and etoposide, was quenched by quercetin in a dose-dependent manner (0.1-0.5 microM). Quercetin also inhibited DNA damage induced by etoposide and enhanced the inhibitory action of etoposide on the ROS formation in neutrophils. However, quercetin (1 microM) lowered early and late apoptosis/necrosis only when apoptosis was induced by 25 microM etoposide; at higher etoposide concentration apoptosis was enhanced. Summing up, antioxidant adjuvant therapy using quercetin can be beneficial in prolonging neutrophils' lifespan in peripheral blood only when etoposide plasma concentration is low.
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Affiliation(s)
- Maria Kapiszewska
- Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland.
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Arruda MA, Barcellos-de-Souza P, Sampaio ALF, Rossi AG, Graça-Souza AV, Barja-Fidalgo C. NADPH oxidase-derived ROS: key modulators of heme-induced mitochondrial stability in human neutrophils. Exp Cell Res 2006; 312:3939-48. [PMID: 17010337 DOI: 10.1016/j.yexcr.2006.08.022] [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: 03/21/2006] [Revised: 08/24/2006] [Accepted: 08/26/2006] [Indexed: 11/19/2022]
Abstract
Heme is a proinflammatory molecule able to cause a profound delay of constitutive apoptosis of human neutrophils, an effect that likely contributes to chronic inflammation associated with hemolytic diseases. Herein we show that heme-induced delay of neutrophil apoptosis correlates with the prevention of mitochondrial potential (Deltapsi(m)) dissipation by a mechanism dependent on NADPH oxidase (NADPHox)-generated reactive oxygen species (ROS) and NF-kappaB. Deltapsi(m) maintenance is accompanied by inhibition of Bax insertion into mitochondria and by a decrease in the Bad/Bcl-X(L) ratio. Heme induces Bad degradation in a completely ROS-dependent manner, as well as Bcl-X(L) synthesis, a phenomenon that also requires NF-kappaB activation. These data indicate that heme-induced preservation of mitochondrial integrity is a critical checkpoint controlled by NADPH oxidase generated-ROS and redox-sensitive NF-kappaB activation.
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Affiliation(s)
- Maria Augusta Arruda
- Departamento de Farmacologia, Instituto de Biologia, Universidade do Estado do Rio de Janeiro, Av. 28 de setembro 87-Vila Izabel, Rio de Janeiro, RJ, 20551-030 Brazil
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24
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Arenas-Ríos E, León-Galván MA, Mercado PE, Rosado A. Superoxide dismutase, catalase, and glutathione peroxidase during epididymal maturation and prolonged storage of spermatozoa in the Mexican big-eared bat (Corynorhinus mexicanus). CAN J ZOOL 2005. [DOI: 10.1139/z05-152] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
We studied the activities of reactive oxygen species (ROS) scavenging enzymes during epididymal spermatozoon maturation and storage in Corynorhinus mexicanus (G.M. Allen, 1916), a vespertilionid bat that stores spermatozoa in the epididymides for several months after regression of the testes. Depending on the phase of the epididymal reproductive cycle, two different patterns of antioxidant enzyme activities were observed in C. mexicanus. Catalase activity is clearly present in both caput and cauda epididymides throughout the entire annual reproductive cycle, being particularly high during the post-testicular phase of epididymal function. Superoxide dismutase (SOD) activity, present during the testicular phase of epididymal transport and maturation of spermatozoa, is almost completely absent or inhibited in both epididymal segments during the post-testicular epididymal storage period. GPx activity is low during the testicular phase of epididymal spermatozoon maturation and is high in both epididymal segments during the storage phase of epididymal function. From our results, we postulate that (i) the pattern of epididymal antioxidant enzyme activities in C. mexicanus is significantly different from the pattern that is proposed to be unique for mammals; (ii) epididymal function in these species of bats can be clearly divided into two phases, a testicular-dependent phase that is related to the spermatozoon maturation function of the epididymides and a testicular-independent phase that is related to the long-term spermatozoon storage function observed in these mammals; (iii) the study of the regulation of the redox potential of the microenvironment, associated with mammalian spermatozoa as they transit through the epididymides, must be particularly focused on the anatomical region where ROS generation scavenging and spermatozoon maturation storage processes take place.
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25
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Sulowska Z, Majewska E, Klink M, Banasik M, Tchórzewski H. Flow cytometric evaluation of human neutrophil apoptosis during nitric oxide generation in vitro: the role of exogenous antioxidants. Mediators Inflamm 2005; 2005:81-7. [PMID: 16030390 PMCID: PMC1533907 DOI: 10.1155/mi.2005.81] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Among numerous inflammatory mediators a
nitric oxide molecule is supposed to be important in the
modulation of neutrophil survival in vivo and
in vitro.
The effect of exogenous supply of NO donors such as
SNP, SIN-1, and GEA-3162 on the course of human neutrophil
apoptosis and the role of extracellular antioxidants in this
process was investigated. Isolated from
peripheral blood, neutrophils were cultured in the presence or
absence of NO donor compounds and antioxidants for 8, 12, and
20 hours. Apoptosis of neutrophils was determined
in vitro
by flow cytometric analysis of cellular DNA content and Annexin V
protein binding to the cell surface. Exposure of
human neutrophils to GEA-3162 and SIN-1 significantly
accelerates and enhances their apoptosis in vitro in a
time-dependent fashion. In the presence of SNP, intensification of
apoptosis has not been revealed until 12 hours after the culture.
The inhibition of GEA-3162- and SIN-1-mediated neutrophil
apoptosis by superoxide dismutase (SOD) but not by catalase (CAT)
was observed. Our results show that SOD and
CAT can protect neutrophils against NO-donors-induced apoptosis
and suggest that the interaction of NO and oxygen metabolites
signals may determine the destructive or protective role of NO
donor compounds during apoptotic neutrophil death.
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Affiliation(s)
- Zofia Sulowska
- Center for Medical Biology, Polish Academy of Sciences, Lodz, Poland.
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26
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Melley DD, Evans TW, Quinlan GJ. Redox regulation of neutrophil apoptosis and the systemic inflammatory response syndrome. Clin Sci (Lond) 2005; 108:413-24. [PMID: 15831090 DOI: 10.1042/cs20040228] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
SIRS (systemic inflammatory response syndrome) may result from a wide variety of non-infective insults. Surgery is a recognized cause of SIRS, the onset of which can have adverse prognostic significance. Neutrophil activation is a key histopathological feature of SIRS, and neutrophil clearance through programmed cell death or apoptosis is an essential step in its resolution. Increasingly, it is recognized that ROS (reactive oxygen species), such as those generated by activated neutrophils during cardiac surgery, may have a regulatory role, influencing neutrophil lifespan and thus inflammation. In this review, we discuss the continuing importance of SIRS as a herald of inflammation and the role of neutrophil longevity in the resolution of inflammation, and we consider recent evidence for the regulation of neutrophil apoptosis by ROS.
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Affiliation(s)
- Daniel D Melley
- Department of Critical Care Medicine, Imperial College, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK
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27
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Arruda MA, Rossi AG, de Freitas MS, Barja-Fidalgo C, Graça-Souza AV. Heme inhibits human neutrophil apoptosis: involvement of phosphoinositide 3-kinase, MAPK, and NF-kappaB. THE JOURNAL OF IMMUNOLOGY 2004; 173:2023-30. [PMID: 15265937 DOI: 10.4049/jimmunol.173.3.2023] [Citation(s) in RCA: 121] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
High levels of free heme are found in pathological states of increased hemolysis, such as sickle cell disease, malaria, and ischemia reperfusion. The hemolytic events are often associated with an inflammatory response that usually turns into chronic inflammation. We recently reported that heme is a proinflammatory molecule, able to induce neutrophil migration, reactive oxygen species generation, and IL-8 expression. In this study, we show that heme (1-50 microM) delays human neutrophil spontaneous apoptosis in vitro. This effect requires heme oxygenase activity, and depends on reactive oxygen species production and on de novo protein synthesis. Inhibition of ERK and PI3K pathways abolished heme-protective effects upon human neutrophils, suggesting the involvement of the Ras/Raf/MAPK and PI3K pathway on this effect. Confirming the involvement of these pathways in the modulation of the antiapoptotic effect, heme induces Akt phosphorylation and ERK-2 nuclear translocation in neutrophils. Futhermore, inhibition of NF-kappa B translocation reversed heme antiapoptotic effect. NF-kappa B (p65 subunit) nuclear translocation and I kappa B degradation were also observed in heme-treated cells, indicating that free heme may regulate neutrophil life span modulating signaling pathways involved in cell survival. Our data suggest that free heme associated with hemolytic episodes might play an important role in the development of chronic inflammation by interfering with the longevity of neutrophils.
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Affiliation(s)
- Maria Augusta Arruda
- Departamento de Farmacologia, Instituto de Biologia, Universidade do Estado do Rio de Janeiro, Brazil
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28
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Abstract
Redox regulated events are fundamental to our understanding of many cellular pathways and pathological processes. On the one hand, production of reactive oxygen species by mammalian spermatozoa has been associated with a loss of cell function and DNA integrity as a consequence of oxidative stress. These cells are exquisitely sensitive to such damage as a consequence of their relative lack of cytosolic antioxidant enzymes and relative abundance of polyunsaturated fatty acids. Given this susceptibility, it is surprising to discover that spermatozoa are intensely redox active cells and professional generators of reactive oxygen species. The latter are physiologically important to the spermatozoa in regulating every aspect of sperm function examined, including their movement characteristics, capacitation, sperm-zona interaction, the acrosome reaction and sperm-oocyte fusion. The molecular basis of this redox drive is still poorly understood in terms of the source of the reactive oxygen species and the mechanisms by which these reactive metabolites enhance sperm function. Recent advances include the discovery of NOX5 in the male germ line and elucidation of the role of reactive oxygen species in controlling a unique signal transduction cascade associated with sperm capacitation. Given the central importance of redox chemistry in the control of sperm function further research in this area may uncover valuable targets for contraceptive intervention.
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Affiliation(s)
- Mark A Baker
- Discipline of Biological Sciences, School of Environmental and Life Sciences and ARC Centre of Excellence in Biotechnology and Development, The University of Newcastle, Newcastle, NSW 2308, Australia
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29
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Fadeel B, Kagan VE. Apoptosis and macrophage clearance of neutrophils: regulation by reactive oxygen species. Redox Rep 2004; 8:143-50. [PMID: 12935311 DOI: 10.1179/135100003225001511] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Inflammation is a beneficial host response to foreign challenge involving numerous soluble factors and cell types, including polymorphonuclear granulocytes or neutrophils. Programmed cell death (apoptosis) of neutrophils has been documented in vitro as well as in vivo, and is thought to be important for the resolution of inflammation, as this process allows for engulfment and removal of senescent cells prior to their necrotic disintegration. Studies in recent years have begun to unravel the mechanism of macrophage clearance of apoptotic cells, and evidence has accrued for a critical role of externalization and oxidation of plasma membrane phosphatidylserine, and its subsequent recognition by macrophage receptors, in this process. Activated neutrophils generate vast amounts of reactive oxygen species for the purpose of killing ingested micro-organisms, and these reactive metabolites may also modulate the life-span, as well as the clearance, of the neutrophil itself. This review aims to address the latter topic, as well as to summarize current knowledge on the molecular mechanisms of neutrophil apoptosis and macrophage clearance of these cells at the site of inflammation.
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Affiliation(s)
- Bengt Fadeel
- Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
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30
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Abstract
Regulation of the neutrophil life span by apoptosis provides a fine balance between their function as effector cells of host defense and a safe turnover of these potentially harmful cells. Alterations of neutrophil apoptosis are associated with a number of diseases. As do other cell types, neutrophils possess components of both extrinsic and intrinsic apoptotic routes. The intrinsic pathway of apoptosis seems to be of major importance in neutrophils since they are programmed for a rapid spontaneous cell death. However, in neutrophils this mechanism of apoptosis has special features, probably due to peculiarities of neutrophil mitochondria, which are believed to be a core regulator of intrinsic cell death. A better understanding of mechanisms underlying neutrophil cell death would help to understand neutrophil physiology and contribute to the search of new approaches for handling of pathology related to disturbances in neutrophil apoptosis and also increase our knowledge of inflammation in general.
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Affiliation(s)
- N A Maianski
- Emma Children's Hospital, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
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31
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Andrews T, Sullivan KE. Infections in patients with inherited defects in phagocytic function. Clin Microbiol Rev 2003; 16:597-621. [PMID: 14557288 PMCID: PMC207096 DOI: 10.1128/cmr.16.4.597-621.2003] [Citation(s) in RCA: 123] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Patients with defects in phagocytic function are predisposed to intracellular microorganisms and typically have early dissemination of the infection. Recognition of the underlying disorder and aggressive antimicrobial therapy has been beneficial for the patients. Improved understanding of the pathophysiology has also affected patient management by allowing specific, targeted immunomodulatory intervention. The disorders described in this review are not common but have had a significant impact on our understanding of the role of phagocytic cells in host defense. Conversely, understanding the role of the neutrophil and macrophage in infection has benefited not just the patients described in this review but also other patients with similar disease processes.
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Affiliation(s)
- Timothy Andrews
- Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
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Leuzzi R, Bánhegyi G, Kardon T, Marcolongo P, Capecchi PL, Burger HJ, Benedetti A, Fulceri R. Inhibition of microsomal glucose-6-phosphate transport in human neutrophils results in apoptosis: a potential explanation for neutrophil dysfunction in glycogen storage disease type 1b. Blood 2003; 101:2381-7. [PMID: 12424192 DOI: 10.1182/blood-2002-08-2576] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Mutations in the gene of the hepatic glucose-6-phosphate transporter cause glycogen storage disease type 1b. In this disease, the altered glucose homeostasis and liver functions are accompanied by an impairment of neutrophils/monocytes. However, neither the existence of a microsomal glucose-6-phosphate transport, nor the connection between its defect and cell dysfunction has been demonstrated in neutrophils/monocytes. In this study we have characterized the microsomal glucose-6-phosphate transport of human neutrophils and differentiated HL-60 cells. The transport of glucose-6-phosphate was sensitive to the chlorogenic acid derivative S3483, N-ethylmaleimide, and 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid, known inhibitors of the hepatic microsomal glucose-6-phosphate transporter. A glucose-6-phosphate uptake was also present in microsomes from undifferentiated HL-60 and Jurkat cells, but it was insensitive to S3483. The treatment with S3484 of intact human neutrophils and differentiated HL-60 cells mimicked some leukocyte defects of glycogen storage disease type 1b patients (ie, the drug inhibited phorbol myristate acetate-induced superoxide anion production and reduced the size of endoplasmic reticulum Ca(2+) stores). Importantly, the treatment with S3484 also resulted in apoptosis of human neutrophils and differentiated HL-60 cells, while undifferentiated HL-60 and Jurkat cells were unaffected by the drug. The proapoptotic effect of S3483 was prevented by the inhibition of nicotinamide adenine dinucleotide phosphate oxidase or by antioxidant treatment. These results suggest that microsomal glucose-6-phosphate transport has a role in the antioxidant protection of neutrophils, and that the genetic defect of the transporter leads to the impairment of cellular functions and apoptosis.
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Affiliation(s)
- Rosanna Leuzzi
- Dipartimento di Fisiopatologia e Medicina Sperimentale and Istituto di Semeiotica Medica, Università di Siena, Siena, Italy
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