|
1
|
Abstract
Despite an increase in the rates of survival in patients suffering myocardial infarction, as yet there is no therapy specifically targeting ischaemia and reperfusion injury of the myocardium. With a greater understanding of immune activation during infarction, more potential treatment targets are now being identified. The innate immune system is believed to play an important role in the myocardium after ischaemia-driven cardiomyocyte death. The release of intracellular contents including DNA into the extracellular space during necrosis and cell rupture is now believed to create a pro-inflammatory milieu which propagates the inflammatory process. DNA and DNA fragments have been shown to activate the innate immune system by acting as Danger-Associated Molecular Patterns (DAMPs), which act as ligands on toll-like receptors (TLRs). Stimulation of TLRs, in turn, can activate intracellular cell death pathways such as pyroptosis. Here, we review the role of DNA fragments during ischaemia and reperfusion, and assess their potential as a target in the quest to preserve cardiomyocyte viability following myocardial infarction.
Collapse
Affiliation(s)
- Mohammed Shah
- The Hatter Cardiovascular Institute, 67 Chenies Mews, London, WC1E 6HX, UK
| | - Derek M Yellon
- The Hatter Cardiovascular Institute, 67 Chenies Mews, London, WC1E 6HX, UK
| | - Sean M Davidson
- The Hatter Cardiovascular Institute, 67 Chenies Mews, London, WC1E 6HX, UK.
| |
Collapse
|
|
2
|
Bromage DI, Pickard JMJ, Rossello X, Ziff OJ, Burke N, Yellon DM, Davidson SM. Remote ischaemic conditioning reduces infarct size in animal in vivo models of ischaemia-reperfusion injury: a systematic review and meta-analysis. Cardiovasc Res 2017; 113:288-297. [PMID: 28028069 PMCID: PMC5408955 DOI: 10.1093/cvr/cvw219] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Accepted: 09/22/2016] [Indexed: 12/15/2022] Open
Abstract
Aims The potential of remote ischaemic conditioning (RIC) to ameliorate myocardial ischaemia-reperfusion injury (IRI) remains controversial. We aimed to analyse the pre-clinical evidence base to ascertain the overall effect and variability of RIC in animal in vivo models of myocardial IRI. Furthermore, we aimed to investigate the impact of different study protocols on the protective utility of RIC in animal models and identify gaps in our understanding of this promising therapeutic strategy. Methods and results Our primary outcome measure was the difference in mean infarct size between RIC and control groups in in vivo models of myocardial IRI. A systematic review returned 31 reports, from which we made 22 controlled comparisons of remote ischaemic preconditioning (RIPreC) and 21 of remote ischaemic perconditioning and postconditioning (RIPerC/RIPostC) in a pooled random-effects meta-analysis. In total, our analysis includes data from 280 control animals and 373 animals subject to RIC. Overall, RIPreC reduced infarct size as a percentage of area at risk by 22.8% (95% CI 18.8–26.9%), when compared with untreated controls (P < 0.001). Similarly, RIPerC/RIPostC reduced infarct size by 22.2% (95% CI 17.1–25.3%; P < 0.001). Interestingly, we observed significant heterogeneity in effect size (T2 = 92.9% and I2 = 99.4%; P < 0.001) that could not be explained by any of the experimental variables analysed by meta-regression. However, few reports have systematically characterized RIC protocols, and few of the included in vivo studies satisfactorily met study quality requirements, particularly with respect to blinding and randomization. Conclusions RIC significantly reduces infarct size in in vivo models of myocardial IRI. Heterogeneity between studies could not be explained by the experimental variables tested, but studies are limited in number and lack consistency in quality and study design. There is therefore a clear need for more well-performed in vivo studies with particular emphasis on detailed characterization of RIC protocols and investigating the potential impact of gender. Finally, more studies investigating the potential benefit of RIC in larger species are required before translation to humans.
Collapse
Affiliation(s)
| | | | | | | | | | - Derek M. Yellon
- Corresponding author. Tel: +44 203 447 9591; fax: +44 203 447 9818, E-mail:
| | | |
Collapse
|
|
3
|
Meštrović J, Pogorelić Z, Drmić-Hofman I, Vilović K, Todorić D, Popović M. Protective effect of urapidil on testicular torsion–detorsion injury in rats. Surg Today 2016; 47:393-398. [DOI: 10.1007/s00595-016-1388-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Accepted: 06/23/2016] [Indexed: 11/24/2022]
|
|
4
|
Ogawa T, Shimizu S, Shimizu T. The effect of heparin on antigen-induced mucus hypersecretion in the nasal epithelium of sensitized rats. Allergol Int 2013; 62:77-83. [PMID: 23000727 DOI: 10.2332/allergolint.12-oa-0438] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2012] [Accepted: 06/09/2012] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Heparin is a potential anti-inflammatory drug for allergic airway inflammation. To elucidate the effects of heparin on allergic inflammation, we examined the in vivo effects of heparin on antigen-induced mucus hypersecretion and infiltration of eosinophils and neutrophils in the nasal epithelium of sensitized rats. METHODS We induced hypertrophic and metaplastic changes of goblet cells in the nasal epithelium of ovalbumin (OVA)-sensitized rats by intranasal challenge with OVA. The effects of intranasal instillation with low molecular weight heparin (LMWH; 1-1000IU/0.1ml) on mucus production and eosinophil/neutrophil infiltration were examined. RESULTS Intranasal instillation with low-dose LMWH (1-10IU/0.1ml) at 30 minutes before OVA instillation stimulated OVA-induced mucus production in the nasal epithelium of sensitized rats, whereas treatment with 100IU/0.1ml LMWH showed no effect. Intranasal instillation with high-dose LMWH (1000IU/0.1ml) significantly inhibited OVA-induced mucus production. Intranasal instillation with LMWH (1-1000IU/0.1ml) dose-dependently inhibited eosinophil and neutrophil infiltration into the rat nasal mucosa. CONCLUSIONS These results indicate that heparin inhibits mucus hypersecretion and infiltration of eosinophils and neutrophils in allergic inflammation, though the inhibitory effect against mucus production is obtained in high-dose heparin. Intranasal instillation with high-dose heparin may provide a new therapeutic strategy for the treatment of nasal allergic inflammation.
Collapse
Affiliation(s)
- Takao Ogawa
- Department of Otorhinolaryngology, Shiga University of Medical Science, Shiga, Japan. −med.ac.jp
| | | | | |
Collapse
|
|
5
|
Abstract
It was nearly 100 years since heparin was discovered, but the role of this widely used anticoagulant is still remarkably thought provoking now. During pathological processes such as atherosclerosis, inflammation, cancer and infection, phenomena of cell adhesion are ubiquitous and complicated. Heparin exerts anti-adhesion activity appearing as a common mechanism of its potential polypharmacology in those diseases. Furthermore, heparin can bind a variety of signalling molecules such as growth factors, cell surface proteins of pathogens and most notably, cell adhesion molecules. These signalling molecules are involved in cell communication, acting as ligands, receptors and second messengers. Considering that heparan sulphate glycosaminoglycan is increasingly recognized as a key mediator in many cellular processes, the structural similarity with heparan sulphate suggests that heparin is a multifunctional intervenor in cell communication.
Collapse
Affiliation(s)
- Xianxiang Xu
- Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China
| | | |
Collapse
|
|
6
|
Mocco J, Shelton CE, Sergot P, Ducruet AF, Komotar RJ, Otten ML, Sosunov SA, MacArthur RB, Kennedy TP, Connolly ES. O-DESULFATED HEPARIN IMPROVES OUTCOME AFTER RAT CEREBRAL ISCHEMIA/REPERFUSION INJURY. Neurosurgery 2007; 61:1297-303; discussion 1303-4. [DOI: 10.1227/01.neu.0000306109.55174.e6] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Affiliation(s)
- J Mocco
- Department of Neurological Surgery, Columbia University, New York, New York
| | - Corbett E. Shelton
- Department of Neurological Surgery, Columbia University, New York, New York
| | - Paulina Sergot
- Department of Neurological Surgery, Columbia University, New York, New York
| | - Andrew F. Ducruet
- Department of Neurological Surgery, Columbia University, New York, New York
| | - Ricardo J. Komotar
- Department of Neurological Surgery, Columbia University, New York, New York
| | - Marc L. Otten
- Department of Neurological Surgery, Columbia University, New York, New York
| | - Sergei A. Sosunov
- Department of Neurological Surgery, Columbia University, New York, New York
| | | | - Thomas P. Kennedy
- Department of Internal Medicine, University of Utah, Salt Lake City, Utah
| | | |
Collapse
|
|
7
|
Young E. The anti-inflammatory effects of heparin and related compounds. Thromb Res 2007; 122:743-52. [PMID: 17727922 DOI: 10.1016/j.thromres.2006.10.026] [Citation(s) in RCA: 289] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2006] [Revised: 10/26/2006] [Accepted: 10/26/2006] [Indexed: 01/09/2023]
Abstract
Heparin is a glycosaminoglycan well known for its anticoagulant properties. In addition, heparin possesses anti-inflammatory effects. Although the mechanisms responsible for the anticoagulant effects of heparin are well understood, those underlying its anti-inflammatory effects are not. This review presents some of the evidence from clinical and animal studies supporting an anti-inflammatory role for heparin and heparin-related derivatives. Potential mechanisms by which heparin can exert its anti-inflammatory effects are discussed. The clinical use of heparin as an anti-inflammatory agent has been held back by the fear of bleeding. Development of nonanticoagulant heparins or heparin derivatives should mitigate this concern.
Collapse
Affiliation(s)
- Edward Young
- Department of Pathology and Molecular Medicine and Henderson Research Center, McMaster University, Hamilton, Ontario, Canada.
| |
Collapse
|
|
8
|
Dwyer KM, Deaglio S, Crikis S, Gao W, Enjyoji K, Strom TB, Cowan PJ, d'Apice AJ, Robson SC. Salutary roles of CD39 in transplantation. Transplant Rev (Orlando) 2007. [DOI: 10.1016/j.trre.2007.01.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
|
|
9
|
Paparella D, Al Radi OO, Meng QH, Venner T, Teoh K, Young E. The effects of high-dose heparin on inflammatory and coagulation parameters following cardiopulmonary bypass. Blood Coagul Fibrinolysis 2006; 16:323-8. [PMID: 15970715 DOI: 10.1097/01.mbc.0000172328.58506.4a] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Systemic inflammation and the activation of the coagulation system following cardiopulmonary bypass (CPB) may contribute to postoperative complications. In vitro studies have demonstrated that heparin possesses anti-inflammatory properties. To ascertain the relative benefits of high versus low heparin doses, we studied the impact of varying heparin doses on the inflammatory response and coagulation system during and following CPB. Forty patients scheduled for elective coronary artery bypass surgery requiring CPB were randomized to either a low dose (300 U/kg) (Group L) or a high dose of unfractionated heparin (600 U/kg) (Group H). To evaluate the inflammatory response, proinflammatory cytokines [tumor necrosis factor-alpha and interleukin-6 (IL-6)] were measured at four different times: before CPB (T0), 30 min after the institution of CPB (T1), 30 min after cross-clamp release (T2), and 4 h after the end of CPB (T3). Thrombin-antithrombin complex, platelet factor 4 and anti-activated factor X heparin concentrations were also measured. Patients in Group H received greater heparin (44.934 U versus 27.741 U, P<0.001) and protamine (P=0.003) doses. Postoperative blood loss and blood products transfusions were not significantly different in the groups. At T1, mean heparin plasma concentration was higher in Group H (P<0.001). IL-6 was significantly lower in Group H compared with Group L (P=0.01) only at T1. Using a mixed-effects statistical model, tumor necrosis factor-alpha and IL-6 levels were comparable regardless of the heparin dose. Thrombin-antithrombin complex levels were lower in Group H (P=0.04) and platelet factor 4 levels were significantly lower in Group H at T2 (P=0.04). Higher heparin doses were associated with higher heparin concentrations during CPB. A high heparin dose achieved a better preservation of the coagulation system with less thrombin formation and platelet activation. The heparin dose had small influence on proinflammatory cytokines release.
Collapse
Affiliation(s)
- Domenico Paparella
- Henderson Research Centre, McMaster University, Hamilton, Ontario, Canada.
| | | | | | | | | | | |
Collapse
|
|
10
|
Becker RC. The vulnerable endothelium: priming the vascular endothelium for thrombosis with unfractionated heparin: biologic plausibility for observations from the Superior Yield of the New Strategy of Enoxaparin, Revascularization and GlYcoprotein IIb/IIIa Inhibitors (SYNERGY) trial. Am Heart J 2005; 150:189-92. [PMID: 16086916 DOI: 10.1016/j.ahj.2005.04.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2004] [Accepted: 04/05/2005] [Indexed: 11/21/2022]
|
|
11
|
Gori AM, Attanasio M, Gazzini A, Rossi L, Lucarini L, Miletti S, Chini J, Manoni M, Abbate R, Gensini GF. Cytokine gene expression and production by human LPS-stimulated mononuclear cells are inhibited by sulfated heparin-like semi-synthetic derivatives. J Thromb Haemost 2004; 2:1657-62. [PMID: 15333044 DOI: 10.1111/j.1538-7836.2004.00866.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
BACKGROUND The K5 polysaccharide obtained from Escherichia coli strain 010:K5:H4 is a polymer of the disaccharidic unit formed by D-glucuronic acid and N-acetylglucosamine. This structure is akin to N-acetylheparosan, the precursory polymer of heparin and of heparan sulfate. This structural affinity with N-acetylated heparin and with de-sulfated heparin makes the K5 polysaccharide extremely useful for the preparation of sulfated heparin-like semi-synthetic derivatives. It has been demonstrated that heparins are able to inhibit tissue factor and cytokine production and expression by human monocytes. OBJECTIVE The aim of this study was to evaluate the effects of four different heparin-like semi-synthetic derivatives on inflammatory cytokine production and expression by human mononuclear cells. RESULTS The simultaneous addition of lipopolysaccharide (LPS; 0.2 and 10 micro g mL(-1)) and the K5 polysaccharide did not inhibit interleukin (IL)-1beta, IL-6 or tumor necrosis factor (TNF)-alpha production by stimulated mononuclear cells. IL-1beta, IL-6 and TNF-alpha concentrations in supernatants of LPS-stimulated mononuclear cells were not influenced by the addition of N,O-sulfated K5 polysaccharide (K5-N, OS) and epimerized N-sulfated K5 polysaccharide (K5 NS epi) at 5 and 10 microg mL(-1), whereas the addition of epimerized N,O-sulfated K5 polysaccharide (K5-N, OS epi) (5 and 10 microg mL(-1)) and O-sulfated K5 polysaccharide (K5-OS) (5 and 10 microg mL(-1)) to LPS-stimulated cells caused a significant dose-dependent inhibition of IL-1beta, IL-6 and TNF-alpha. All sulfated heparin-like semi-synthetic derivatives did not influence the IL-10 production by LPS-stimulated mononuclear cells. In LPS-stimulated cells (0.2 and 10 microg mL(-1)), K5-OS or K5-N, OS epi at 5 and 10 microg mL(-1) markedly decreased TNF-alpha mRNA expression. CONCLUSIONS These results indicate that the sulfated heparin-like semi-synthetic derivatives K5-OS and K5-N, OS epi are able to inhibit both expression and production of inflammatory cytokines, whereas they do not influence the anti-inflammatory cytokine IL-10, suggesting a potential role for these products as modulators of inflammatory reactions.
Collapse
Affiliation(s)
- A M Gori
- Department of Medical and Surgical Critical Care, Section of Clinical Medicine and Cardiology, University of Florence, Florence, Italy.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
12
|
Elsayed E, Becker RC. The impact of heparin compounds on cellular inflammatory responses: a construct for future investigation and pharmaceutical development. J Thromb Thrombolysis 2004; 15:11-8. [PMID: 14574071 DOI: 10.1023/a:1026184100030] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Atherosclerotic disease is recognized as a chronic inflammatory disorder with intermittent and widely variable phases of cellular proliferation and heightened thrombotic activity. The multi-tiered links between inflammation, atherogenesis and thrombogenesis provide a unique opportunity for research and development of pharmaceuticals which target one or more critical pathobiologic steps (Fig. 1). The purpose of the following review on heparin compounds is to comprehensively examine the multi-cellular, pleuripotential effects of a commonly used anticoagulant drug in the context of normal and disease-altered vascular responses and illustrate possible constructs for avenues of subsequent investigation in the field of atherothrombosis. The overview is divided into five integrated parts; antiinflammatory properties of the normal vessel wall, the relationship between glycosaminoglycans and inflammation, heparin-mediated effects on cellular inflammatory responses, association between molecular weight and antiinflammatory capabilities, and oral heparin compounds for achieving prolonged cell-based inhibition.
Collapse
Affiliation(s)
- Essam Elsayed
- Department of Medicine, UMass-Memorial Medical Center, Cardiovascular Thrombosis Research Center, University of Massachusetts Medical School, Worcester, MA, USA
| | | |
Collapse
|
|
13
|
Rodríguez-Sinovas A, Bis J, Anivarro I, de la Torre J, Bayés-Genís A, Cinca J. Coronary smooth muscle reactivity to muscarinic stimulation after ischemia-reperfusion in porcine myocardial infarction. J Appl Physiol (1985) 2003; 95:81-8. [PMID: 12626485 DOI: 10.1152/japplphysiol.00119.2003] [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: 11/22/2022] Open
Abstract
This study tested whether ischemia-reperfusion alters coronary smooth muscle reactivity to vasoconstrictor stimuli such as those elicited by an adventitial stimulation with methacholine. In vitro studies were performed to assess the reactivity of endothelium-denuded infarct-related coronary arteries to methacholine (n = 18). In addition, the vasoconstrictor effects of adventitial application of methacholine to left anterior descending (LAD) coronary artery was assessed in vivo in pigs submitted to 2 h of LAD occlusion followed by reperfusion (n = 12), LAD deendothelization (n = 11), or a sham operation (n = 6). Endothelial-dependent vasodilator capacity of infarct-related LAD was assessed by intracoronary injection of bradykinin (n = 13). In vitro, smooth muscle reactivity to methacholine was unaffected by ischemia-reperfusion. In vivo, baseline methacholine administration induced a transient and reversible drop in coronary blood flow (9.6 +/- 4.6 to 1.9 +/- 2.6 ml/min, P < 0.01), accompanied by severe left ventricular dysfunction. After ischemia-reperfusion, methacholine induced a prolonged and severe coronary blood flow drop (9.7 +/- 7.0 to 3.4 +/- 3.9 ml/min), with a significant delay in recovery (P < 0.001). Endothelial denudation mimics in part the effects of methacholine after ischemia-reperfusion, and intracoronary bradykinin confirmed the existence of endothelial dysfunction. Infarct-related epicardial coronary artery shows a delayed recovery after vasoconstrictor stimuli, because of appropriate smooth muscle reactivity and impairment of endothelial-dependent vasodilator capacity.
Collapse
Affiliation(s)
- Antonio Rodríguez-Sinovas
- Laboratory of Cardiovascular Physiology, Vall d'Hebron Hospitals and Cardiology Service, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, 08025 Barcelona, Spain
| | | | | | | | | | | |
Collapse
|
|
14
|
Shen XD, Ke B, Zhai Y, Gao F, Anselmo D, Lassman CR, Busuttil RW, Kupiec-Weglinski JW. Stat4 and Stat6 signaling in hepatic ischemia/reperfusion injury in mice: HO-1 dependence of Stat4 disruption-mediated cytoprotection. Hepatology 2003; 37:296-303. [PMID: 12540779 DOI: 10.1053/jhep.2003.50066] [Citation(s) in RCA: 94] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Ischemia/reperfusion (I/R) injury remains an important problem in clinical organ transplantation. There is growing evidence that T lymphocytes, and activated CD4+ T cells in particular, play a key role in hepatic I/R injury. This study analyzes the role of signal transducer and activator of transcription 4 (Stat4) and Stat6 signaling in liver I/R injury. Using a partial lobar warm ischemia model, groups of wild-type (WT), T cell-deficient, Stat4-/Stat6-deficient knockout (KO) mice were assessed for the extent/severity of I/R injury. Ninety minutes of warm ischemia followed by 6 hours of reperfusion induced a fulminant liver failure in WT and Stat6 KO mice, as assessed by hepatocellular damage (serum alanine aminotransferase [sALT] levels), neutrophil accumulation (myeloperoxidase [MPO] activity) and histology (Suzuki scores). In contrast, T cell deficiency (nu/nu mice) or disruption of Stat4 signaling (Stat4 KO mice) reduced I/R insult. Unlike adoptive transfer of WT or Stat6-deficient T cells, infusion of Stat4-deficient T cells failed to restore hepatic I/R injury and prevented tumor necrosis factor alpha (TNF-alpha) production in nu/nu mice. Diminished TNF-alpha/Th1-type cytokine messenger RNA (mRNA)/protein elaborations patterns, along with overexpression of heme oxygenase-1 (HO-1)-accompanied hepatic cytoprotection in Stat4 KO recipients. In contrast, HO-1 depression restored hepatic injury in otherwise I/R resistant Stat4 KOs. In conclusion, Stat4 signaling is required for, whereas Stat4 disruption protects against, warm hepatic I/R injury in mice. The cytoprotection rendered by Stat4 disruption remains HO-1-dependent.
Collapse
Affiliation(s)
- Xiu-Da Shen
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, Los Angeles, CA 90095, USA
| | | | | | | | | | | | | | | |
Collapse
|
|
15
|
Zhou T, Chen JL, Song W, Wang F, Zhang MJ, Ni PH, Geng JG. Effect of N-desulfated heparin on hepatic/renal ischemia reperfusion injury in rats. World J Gastroenterol 2002; 8:897-900. [PMID: 12378638 PMCID: PMC4656583 DOI: 10.3748/wjg.v8.i5.897] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of N-desulfated heparin on hepatic/renal ischemia and reperfusion injury in rats.
METHODS: Using rat models of 60 min hepatic or renal ischemia followed by 1 h, 3 h, 6 h and 24 h reperfusion, animals were randomly divided into following groups, the sham operated controls, ischemic group receiving only normal saline, and treated group receiving N-desulfated heparin at a dose of 12 mg/kg at 5 min before reperfusion. P-selectin expression was detected in hepatic/renal tissues with immunohistochemistry method.
RESULTS: P-selectin expression, serum ALT, AST, BUN and Cr levels were significantly increased during 60 minute ischemia and 1 h, 3 h, 6 h and 24 h reperfusion, while the increment was significantly inhibited, and hepatic/renal pathology observed by light microscopy was remarkably improved by treatment with the N-desulfated heparin. Furthermore, the heparin was found no effects on PT and KPTT.
CONCLUSION: P-selectin might mediate neutrophil infiltration and contribute to hepatic/renal ischemia and reperfusion. The N-desulfated heparin might prevent hepatic/renal damage induced by ischemia and reperfusion injury without significant anticoagulant activity.
Collapse
Affiliation(s)
- Tong Zhou
- Department of Nephrology, Ruijin Hospital, Shanghai Second Medical University, Shanghai 200025,China.
| | | | | | | | | | | | | |
Collapse
|
|
16
|
Iràculis E, Cequier A, Gómez-Hospital JA, Sabaté M, Mauri J, Fernández-Nofrerias E, García del Blanco B, Jara F, Esplugas E. Early dysfunction and long-term improvement in endothelium-dependent vasodilation in the infarct-related artery after thrombolysis. J Am Coll Cardiol 2002; 40:257-65. [PMID: 12106929 DOI: 10.1016/s0735-1097(02)01953-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
OBJECTIVES This study assessed the degree of endothelial dysfunction in post-acute myocardial infarction (AMI) and its subsequent status in the infarct-related artery (IRA) in patients treated with thrombolysis. BACKGROUND Coronary flow reserve alterations in the IRA after thrombolysis have been described, but the endothelium-dependent vasomotion has not been investigated, to date. METHODS Endothelial function in patients after thrombolysis was assessed by infusion of acetylcholine (ACh) at increasing doses in the IRA. Diameter changes in the distal segments were evaluated using quantitative coronary angiography. Patients with coronary atherosclerosis constituted the control group. Clinical variables, electrocardiography and biochemical markers were used to determine the timing of reperfusion and the extent of the infarct. Patients in the AMI group were re-evaluated one year later. RESULTS In the initial assessment, 16 patients showed a vasoconstriction response to ACh in the IRA compared to the control group (-20 +/- 21% vs. 4 +/- 4%; p < 0.01). Significant correlations between the degree of vasoconstriction and maximum value of the creatine kinase-MB fraction and number of new Q waves were observed. Of the 12 patients re-evaluated, 4 had complete occlusion of the IRA. In the remaining eight patients with patent artery, an improvement in response to ACh was observed relative to the initial study (+3 +/- 11%, vs. -19 +/- 15%, p < 0.05). CONCLUSIONS In patients with AMI treated with thrombolysis, severe endothelial dysfunction in the IRA is observed early. In patients who retain patency of the IRA, the endothelial dysfunction improves during the follow-up and suggests a component of stunned endothelium in the first few days post-AMI.
Collapse
Affiliation(s)
- Emili Iràculis
- Servei de Cardiologia, Hospital de Bellvitge, Universitat de Barcelona, C/Feixa Llarga s/n, L'Hospitalet de Llobregat, 08907 Barcelona, Spain
| | | | | | | | | | | | | | | | | |
Collapse
|
|
17
|
Nakamura T, Vollmar B, Winning J, Ueda M, Menger MD, Schäfers HJ. Heparin and the nonanticoagulant N-acetyl heparin attenuate capillary no-reflow after normothermic ischemia of the lung. Ann Thorac Surg 2001; 72:1183-8; discussion 1188-9. [PMID: 11603434 DOI: 10.1016/s0003-4975(01)02959-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Ischemia-reperfusion injury of the lung frequently occurs after cardiopulmonary bypass, after pulmonary thromboendarterectomy, and especially after lung transplantation. Heparin is known to be protective in ischemia-reperfusion injury, but the risk for bleeding disorders may restrict its use in a variety of diseased conditions. Therefore, we tested the efficiency of nonanticoagulant N-acetyl (NA) heparin to protect from postischemic reperfusion injury of the lung. METHODS Pentobarbital-anesthetized, mechanically ventilated Lewis rats were heparinized (100 IU/kg) before insertion of catheters. Additionally, animals received either heparin (200 IU/kg; n = 7), NA heparin (1.1 mg/kg; n = 7), or saline (control, n = 7) before ischemia. After normothermic ischemia for 50 minutes, the left lung was reperfused for 120 minutes, or until the death of the animal. The nonischemic right lung was excluded after 10 minutes of reperfusion. RESULTS Survival rate at 120 minutes of reperfusion was 7 of 7 and 6 of 7 in the heparin and the NA-heparin group, but 0 in 7 in the control group (p < 0.01). At 30 minutes of reperfusion, PaO2, blood flow through the ascending aorta and mean systemic blood pressure were also significantly higher in the heparin and the NA-heparin group when compared with the control group (p < 0.05). Pulmonary vascular resistance was significantly lower in the heparin and the NA-heparin groups, and histologic examination of the lungs from these groups confirmed reperfusion of nutritive alveolar capillaries by the presence of red blood cells. Lack of red blood cells in the alveolar capillaries of lung specimens from the control group indicated failure of capillary reperfusion. CONCLUSIONS Heparin and NA heparin exert similar protection against capillary no-reflow after normothermic ischemia of the lung. This implies that the protective effect of heparin is mediated by properties different from its anticoagulant activity. Thus the nonanticoagulant N-acetyl heparin may pose a safe new therapeutic approach in lung ischemia-reperfusion injury without increasing the risk of hemorrhagic complications.
Collapse
Affiliation(s)
- T Nakamura
- Department of Thoracic and Cardiovascular Surgery and Institute for Clinical and Experimental Surgery, University of Saarland, Homburg/Saar, Germany
| | | | | | | | | | | |
Collapse
|
|
18
|
Geng JG. Directional migration of leukocytes: their pathological roles in inflammation and strategies for development of anti-inflammatory therapies. Cell Res 2001; 11:85-8. [PMID: 11453550 DOI: 10.1038/sj.cr.7290071] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Directional migration of leukocytes is indispensable to innate immunity for host defense. However, recruitment of leukocytes to a site of tissue injury also constitutes a leading cause for inflammatory responses. Mechanistically, it involves a cascade of cellular events precisely regulated by temporal and spatial presentation of a repertoire of molecules in the migrating leukocytes and their surroundings (microenvironments). Here I will summarize the emerging evidence that has shed lights on the underlying molecular mechanism for directional migration of leukocytes, which has guided the therapeutical development for innovative anti-inflammatory medicines.
Collapse
Affiliation(s)
- J G Geng
- Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai.
| |
Collapse
|
|
19
|
John S, Delles C, Jacobi J, Schlaich MP, Schneider M, Schmitz G, Schmieder RE. Rapid improvement of nitric oxide bioavailability after lipid-lowering therapy with cerivastatin within two weeks. J Am Coll Cardiol 2001; 37:1351-8. [PMID: 11300446 DOI: 10.1016/s0735-1097(01)01128-7] [Citation(s) in RCA: 78] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
OBJECTIVES We investigated whether improvement of endothelial dysfunction in hypercholesterolemia can be achieved with short-term lipid-lowering therapy. BACKGROUND Impaired endothelium-dependent vasodilation plays a pivotal role in the pathogenesis of atherosclerosis and acute coronary syndromes. METHODS In a randomized, double-blind, placebo-controlled trial, we studied 37 patients (52 +/- 11 yrs) with low density lipoprotein cholesterol > or = 160 mg/dl (196 +/- 44 mg/dl) randomly assigned to either cerivastatin (0.4 mg/d) or placebo. Endothelium-dependent vasodilation of the forearm vasculature was measured by plethysmography and intra-arterial infusion of acetylcholine (ACh 12, 48 microg/min) and endothelium-independent vasodilation by intra-arterial infusion of nitroprusside (3.2, 12.8 microg/min). RESULTS Low density lipoprotein cholesterol decreased after two weeks of treatment (cerivastatin -33 +/- 4% vs. placebo + 2 +/- 4%, x +/- SEM, p < 0.001). Endothelium-dependent vasodilation improved after two weeks of therapy with cerivastatin compared with baseline (ACh 12 microg/min: + 22.3 +/- 5.2 vs. + 11.2 +/- 1.9 ml/min/100 ml, p < 0.01; ACh 48 microg/min: +31.2 +/- 6.3 vs. +19.1 +/- 3.1 ml/min/100 ml, p < 0.05). In contrast, changes in forearm blood flow to ACh were similar before and after therapy in the placebo group (ACh 12 microg/min: + 12.9 +/- 3.6 vs. + 9.0 +/- 1.9 ml/min/100 ml, NS; ACh 48 microg/min: +20.7 +/- 3.7 vs. 19.4 +/- 2.9 ml/min/100 ml, NS). Endothelium-dependent vasodilation improved in comparison with placebo (ACh 48 microg/min: +203 +/- 85% [cerivastatin] vs. -26 +/- 71% [placebo], p < 0.05). This improvement in endothelium-dependent vasodilation was no longer observed when the nitric oxide-synthase inhibitor N(G)-monomethyl-L-arginine was coinfused (ACh 48 microg/min + N(G)-monomethyl-L-arginine 4 micromol/min -48 +/- 85% [cerivastatin]). CONCLUSIONS Short-term lipid-lowering therapy with cerivastatin can improve endothelial function and NO bioavailability after two weeks in patients with hypercholesterolemia.
Collapse
Affiliation(s)
- S John
- Department of Medicine IV, University of Erlangen-Nürnberg, Klinikum Nürnberg-Süd, Nürnberg, Germany
| | | | | | | | | | | | | |
Collapse
|
|
20
|
Xie X, Rivier AS, Zakrzewicz A, Bernimoulin M, Zeng XL, Wessel HP, Schapira M, Spertini O. Inhibition of selectin-mediated cell adhesion and prevention of acute inflammation by nonanticoagulant sulfated saccharides. Studies with carboxyl-reduced and sulfated heparin and with trestatin a sulfate. J Biol Chem 2000; 275:34818-25. [PMID: 10944519 DOI: 10.1074/jbc.m001257200] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Selectins play a major role in the inflammatory reaction by initiating neutrophil attachment to activated vascular endothelium. Some heparin preparations can interact with L- and P-selectin; however, the determinants required for inhibiting selectin-mediated cell adhesion have not yet been characterized. We now report that carboxyl-reduced and sulfated heparin (prepared by chemical modifications of porcine intestinal mucosal heparin leading to the replacement of carboxylates by O-sulfate groups) and trestatin A sulfate (obtained by sulfation of trestatin A, a non-uronic pseudo-nonasaccharide extracted from Streptomyces dimorphogenes) exhibit strong anti-P-selectin and anti-L-selectin activity while lacking antithrombin-mediated anticoagulant activity. In vitro experiments revealed that both compounds inhibited P-selectin- and L-selectin-mediated cell adhesion under laminar flow conditions. Moreover, carboxyl-reduced and sulfated heparin and trestatin A sulfate were also active in vivo, as assessed by experiments showing 1) that microinfusion of trestatin A sulfate reduced by 96% leukocyte rolling along rat mesenteric postcapillary venules and 2) that both compounds inhibited (by 58-81%) neutrophil migration into thioglycollate-inflamed peritoneum of BALB/c mice. These results indicate that nonanticoagulant sulfated saccharides targeted at P-selectin and L-selectin may have therapeutic potential in inflammatory disorders.
Collapse
Affiliation(s)
- X Xie
- Division and Central Laboratory of Hematology, Centre Hospitalier Universitaire Vaudois, Bugnon 46, 1011 Lausanne, Switzerland
| | | | | | | | | | | | | | | |
Collapse
|
|
21
|
Thourani VH, Brar SS, Kennedy TP, Thornton LR, Watts JA, Ronson RS, Zhao ZQ, Sturrock AL, Hoidal JR, Vinten-Johansen J. Nonanticoagulant heparin inhibits NF-kappaB activation and attenuates myocardial reperfusion injury. Am J Physiol Heart Circ Physiol 2000; 278:H2084-93. [PMID: 10843908 DOI: 10.1152/ajpheart.2000.278.6.h2084] [Citation(s) in RCA: 61] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Heparin reduces ischemia-reperfusion injury to myocardium. This effect has been attributed to complement inhibition, but heparin also has other activities that might diminish ischemia-reperfusion. To further probe these mechanisms, we compared heparin or an o-desulfated nonanticoagulant heparin with greatly reduced anticomplement activity. When given at the time of coronary artery reperfusion in a canine model of myocardial infarction, heparin or o-desulfated heparin equally reduced neutrophil adherence to ischemic-reperfused coronary artery endothelium, influx of neutrophils into ischemic-reperfused myocardium, myocardial necrosis, and release of creatine kinase into plasma. Heparin or o-desulfated heparin also prevented dysfunction of endothelial-dependent coronary relaxation following ischemic injury. In addition, heparin and o-desulfated heparin inhibited translocation of the transcription nuclear factor-kappaB (NF-kappaB) from the cytoplasm to the nucleus in human endothelial cells and decreased NF-kappaB DNA binding in human endothelium and ischemic-reperfused rat myocardium. Thus heparin and nonanticoagulant heparin decrease ischemia-reperfusion injury by disrupting multiple levels of the inflammatory cascade, including the novel observation that heparins inhibit activation of the proinflammatory transcription factor NF-kappaB.
Collapse
Affiliation(s)
- V H Thourani
- epartment of Surgery, Emory University School of Medicine, Crawford Long Hospital, Atlanta, Georgia 30365, USA
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
22
|
Mach F, Sauty A, Iarossi AS, Sukhova GK, Neote K, Libby P, Luster AD. Differential expression of three T lymphocyte-activating CXC chemokines by human atheroma-associated cells. J Clin Invest 1999; 104:1041-50. [PMID: 10525042 PMCID: PMC408576 DOI: 10.1172/jci6993] [Citation(s) in RCA: 326] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Activated T lymphocytes accumulate early in atheroma formation and persist at sites of lesion growth and rupture, suggesting that they may play an important role in the pathogenesis of atherosclerosis. Moreover, atherosclerotic lesions contain the Th1-type cytokine IFN-gamma, a potentiator of atherosclerosis. The present study demonstrates the differential expression of the 3 IFN-gamma-inducible CXC chemokines--IFN-inducible protein 10 (IP-10), monokine induced by IFN-gamma (Mig), and IFN-inducible T-cell alpha chemoattractant (I-TAC)--by atheroma-associated cells, as well as the expression of their receptor, CXCR3, by all T lymphocytes within human atherosclerotic lesions in situ. Atheroma-associated endothelial cells (ECs), smooth muscle cells (SMCs), and macrophages (MO) all expressed IP-10, whereas Mig and I-TAC were mainly expressed in ECs and MO, as detected by double immunofluorescence staining. ECs of microvessels within lesions also expressed abundant I-TAC. In vitro experiments supported these results and showed that IL-1beta, TNF-alpha, and CD40 ligand potentiated IP-10 expression from IFN-gamma-stimulated ECs. In addition, nitric oxide (NO) treatment decreased IFN-gamma induction of IP-10. Our findings suggest that the differential expression of IP-10, Mig, and I-TAC by atheroma-associated cells plays a role in the recruitment and retention of activated T lymphocytes observed within vascular wall lesions during atherogenesis.
Collapse
Affiliation(s)
- F Mach
- Vascular Medicine and Atherosclerosis Unit, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
| | | | | | | | | | | | | |
Collapse
|