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1
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Edwards-Glenn JM, Fontes MT, Waigi EW, Costa TJ, Maiseyeu A, Webb RC, McCarthy CG, Wenceslau CF. Specialized Pro-resolving Mediator Improves Vascular Relaxation via Formyl Peptide Receptor-2. Am J Hypertens 2023; 36:542-550. [PMID: 37439351 PMCID: PMC10502783 DOI: 10.1093/ajh/hpad062] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 06/29/2023] [Accepted: 07/11/2023] [Indexed: 07/14/2023] Open
Abstract
BACKGROUND The resolution of inflammation is an active phenomenon important for switching off inflammatory processes once the harmful stimuli are removed and facilitate the return to homeostasis. Specialized pro-resolving mediators (SPMs), such as lipoxin A4, resolvin D1, and resolvin E1, derived from ω-3 or ω-6 polyunsaturated fatty acids, are crucial for the resolution of inflammation. We hypothesized that SPMs are decreased in hypertension which contributes to the acetylcholine-induced contraction in resistance arteries, which are well known to be mediated by leukotrienes and prostaglandins. Moreover, treatment with SPMs will decrease this contraction via formyl peptide receptor-2 (FPR-2) in resistance arteries from spontaneously hypertensive rats (SHR). METHODS AND RESULTS We performed a comprehensive eicosanoid lipid panel analysis, and our data showed for the first time that precursors of SPMs are decreased in SHR, limiting the production of SPMs and resolution of inflammation in vivo. This phenomenon was associated with an increase in lipid peroxidation in resistance arteries. Although SPMs did not abolish acetylcholine-induced contraction, these lipid mediators improved endothelial function in arteries from SHR via FPR-2 activation at nanomolar concentrations. SPMs also buffered TNF-α-induced reactive oxygen species generation in endothelial cells from C57Bl/6 mice. CONCLUSIONS We suggest that FPR-2 and SPMs could be revealed as a new target or therapeutic agent to improve vascular function in arteries from hypertensive rats.
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Affiliation(s)
- Jonnelle M Edwards-Glenn
- Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
| | - Milene T Fontes
- Cardiovascular Translational Research Center, Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina, USA
| | - Emily W Waigi
- Cardiovascular Translational Research Center, Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina, USA
| | - Tiago J Costa
- Cardiovascular Translational Research Center, Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina, USA
| | - Andrei Maiseyeu
- Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
| | - R Clinton Webb
- Cardiovascular Translational Research Center, Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina, USA
- Biomedical Engineering Program, College of Engineering and Computing, University of South Carolina, Columbia, South Carolina, USA
| | - Cameron G McCarthy
- Cardiovascular Translational Research Center, Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina, USA
- Biomedical Engineering Program, College of Engineering and Computing, University of South Carolina, Columbia, South Carolina, USA
| | - Camilla F Wenceslau
- Cardiovascular Translational Research Center, Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina, USA
- Biomedical Engineering Program, College of Engineering and Computing, University of South Carolina, Columbia, South Carolina, USA
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2
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Classes of Lipid Mediators and Their Effects on Vascular Inflammation in Atherosclerosis. Int J Mol Sci 2023; 24:ijms24021637. [PMID: 36675152 PMCID: PMC9863938 DOI: 10.3390/ijms24021637] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 01/06/2023] [Accepted: 01/08/2023] [Indexed: 01/18/2023] Open
Abstract
It is commonly believed that the inactivation of inflammation is mainly due to the decay or cessation of inducers. In reality, in connection with the development of atherosclerosis, spontaneous decay of inducers is not observed. It is now known that lipid mediators originating from polyunsaturated fatty acids (PUFAs), which are important constituents of all cell membranes, can act in the inflamed tissue and bring it to resolution. In fact, PUFAs, such as arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), are precursors to both pro-inflammatory and anti-inflammatory compounds. In this review, we describe the lipid mediators of vascular inflammation and resolution, and their biochemical activity. In addition, we highlight data from the literature that often show a worsening of atherosclerotic disease in subjects deficient in lipid mediators of inflammation resolution, and we also report on the anti-proteasic and anti-thrombotic properties of these same lipid mediators. It should be noted that despite promising data observed in both animal and in vitro studies, contradictory clinical results have been observed for omega-3 PUFAs. Many further studies will be required in order to clarify the observed conflicts, although lifestyle habits such as smoking or other biochemical factors may often influence the normal synthesis of lipid mediators of inflammation resolution.
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3
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Sachdeva S, Saluja H, Mani A, Phadnaik MB, Mani S. Lipoxins in inflammation. Clin Hemorheol Microcirc 2022; 82:201-216. [PMID: 35147530 DOI: 10.3233/ch-211346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Lipoxins and ATL appear to be the first recognized members of a new class of endogenous mediator that are anti-inflammatory or serve for the "pro-resolution" of inflammation. PGE2 can and may display anti-inflammatory properties in certain settings, but in most cases, it enhances inflammation in vivo. This is likely the result of numerous receptor isoforms and differential coupled mechanisms for PGE2 and its diverse role in human physiology. Since the integrated response of the host is essential to health and disease, it is important to achieve a more complete understanding of the molecular and cellular events governing the formation and actions of endogenous mediators of resolution that appear to control the magnitude and duration of inflammation. In view of the present body of evidence, it is not surprising that a protective action for inhibition of COX-2 was found in cardiovascular disease. Characterizing useful experimental systems with clinically relevant endpoints will also take a multidisciplinary approach and require a shift in our current thinking about inflammation and the role of lipid mediators.
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Affiliation(s)
- Shivani Sachdeva
- Department of Periodontology, Pravara Institute of Medical Sciences, Rdc, Loni, Maharashtra, India
| | - Harish Saluja
- Department of Oral and Maxillofacial Surgery, Pravara Institute of Medical Sciences, Rdc, Loni, Maharashtra, India
| | - Ameet Mani
- Department of Periodontology, Pravara Institute of Medical Sciences, Rdc, Loni, Maharashtra, India
| | - M B Phadnaik
- Department of Periodontology, #Government Dental College Nagpur, Maharashtra, India
| | - Shubhangi Mani
- Department of Orthodontics, Pravara Institute of Medical Sciences, Rdc, Loni, Maharashtra, India
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4
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Hasturk H, Schulte F, Martins M, Sherzai H, Floros C, Cugini M, Chiu CJ, Hardt M, Van Dyke T. Safety and Preliminary Efficacy of a Novel Host-Modulatory Therapy for Reducing Gingival Inflammation. Front Immunol 2021; 12:704163. [PMID: 34589083 PMCID: PMC8475270 DOI: 10.3389/fimmu.2021.704163] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Accepted: 08/23/2021] [Indexed: 12/22/2022] Open
Abstract
Background Periodontal disease is among the sixth most common inflammatory diseases worldwide with high risk to promote complications from other inflammatory diseases including diabetes, cardiovascular disease and Alzheimer’s Disease. Failure of active resolution of inflammation pathways is implicated in pathogenesis of periodontal diseases, including gingivitis. Lipoxin A4 (LXA4), a member of the specialized pro-resolving lipid mediators (SPMs) that drive resolution of inflammation via GPC-receptor mediated pathways, offered therapeutic advantages in preclinical models of periodontitis. Methods We conducted a randomized, placebo-controlled, parallel-group Phase 1 clinical trial to determine the safety and preliminary efficacy of an LXA4 analog in patients with gingival inflammation. One hundred twenty-seven (127) individuals were randomized to daily use of an oral rinse containing a LXA4 mimetic, methyl ester-benzo-lipoxin A4 (BLXA4), placebo rinse or a no-rinse control group for 28 days. Treatment emergent adverse events (TEAEs) were assessed for safety, the primary outcome. Secondary outcomes included the change in the level of gingival inflammation and periodontal pocket depth (PD). Serum SPMs were monitored using targeted lipid mediator lipidomics to assess potential systemic impact of BLXA4. Results The frequency of TEAEs was similar in BLXA4 and placebo-treated groups with no study-related SAEs. Once-daily rinsing with BLXA4 for 28-days resulted in a greater decrease in gingival inflammation compared to placebo rinse and no-rinse control groups (mean change: 0.26 GI unit vs 0.21 and 0.17, respectively). PD reduction was also greater with BLXA4 oral rinse compared to placebo and no-rinse groups (mean reduction: 1.23 mm vs. 0.71 mm and 0.46 mm, respectively). Topical application of BLXA4 increased serum levels of SPMs. Conclusion Treatment with BLXA4 reduces local inflammation, and increases abundance of pro-resolution molecules systemically, which may dampen inflammation that can mediate progression and course of inflammatory diseases beyond periodontitis. Clinical Trial Registration ClinicalTrials.gov, identifier (NCT02342691).
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Affiliation(s)
- Hatice Hasturk
- Center for Clinical and Translational Research, The Forsyth Institute, Cambridge, MA, United States.,Department of Applied Oral Sciences, The Forsyth Institute, Cambridge, MA, United States
| | - Fabian Schulte
- Department of Applied Oral Sciences, The Forsyth Institute, Cambridge, MA, United States.,Center for Salivary Diagnostics, The Forsyth Institute, Cambridge, MA, United States.,Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, United States
| | - Melissa Martins
- Center for Clinical and Translational Research, The Forsyth Institute, Cambridge, MA, United States.,Department of Applied Oral Sciences, The Forsyth Institute, Cambridge, MA, United States
| | - Homa Sherzai
- Center for Clinical and Translational Research, The Forsyth Institute, Cambridge, MA, United States.,Department of Applied Oral Sciences, The Forsyth Institute, Cambridge, MA, United States
| | - Constantinos Floros
- Center for Clinical and Translational Research, The Forsyth Institute, Cambridge, MA, United States.,Department of Applied Oral Sciences, The Forsyth Institute, Cambridge, MA, United States
| | - MaryAnn Cugini
- Center for Clinical and Translational Research, The Forsyth Institute, Cambridge, MA, United States.,Department of Applied Oral Sciences, The Forsyth Institute, Cambridge, MA, United States
| | - Chung-Jung Chiu
- Epidemiology and Biostatistics, The Forsyth Institute, Cambridge, MA, United States
| | - Markus Hardt
- Department of Applied Oral Sciences, The Forsyth Institute, Cambridge, MA, United States.,Center for Salivary Diagnostics, The Forsyth Institute, Cambridge, MA, United States.,Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, United States
| | - Thomas Van Dyke
- Center for Clinical and Translational Research, The Forsyth Institute, Cambridge, MA, United States.,Department of Applied Oral Sciences, The Forsyth Institute, Cambridge, MA, United States.,Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, United States
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5
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Chen YC, Chen YY, Yeh HW, Yeh TY, Huang JY, Liao PL, Yeh LT, Yang SF, Chou MC, Yeh CB. Association Between Aspirin Use and Decreased Risk of Pneumonia in Patients With Cardio-Cerebra-Vascular Ischemic Disease: A Population-Based Cohort Study. Front Public Health 2021; 9:625834. [PMID: 33816418 PMCID: PMC8013718 DOI: 10.3389/fpubh.2021.625834] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 02/25/2021] [Indexed: 11/13/2022] Open
Abstract
This study evaluated the association between long-term low-dose aspirin use and decreased risk of pneumonia in patients with cardio-cerebra-vascular ischemic diseases (CCVDs). This retrospective cohort study used records from Taiwan's National Health Insurance Research Database of claims made between 1997 and 2013. After propensity score matching (PSM), patients who took a low dose of aspirin for more than 90 days within 1 year of diagnosis with CCVDs were identified as the exposure group (n = 15,784). A matched total of 15,784 individuals without aspirin use were selected for the non-aspirin group. The main outcome was the development of pneumonia after the index date. Multivariable Cox regression analysis and Kaplan-Meier survival analysis were performed to estimate the adjusted hazard ratio (aHR) and cumulative probability of pneumonia. The result after PSM indicated a lower hazard ratio for pneumonia in aspirin users (aHR = 0.890, 95% confidence interval = 0.837-0.945). Therefore, patients with CCVDs who took aspirin had a lower risk of developing pneumonia than those who did not. In conclusion, this population-based cohort study demonstrated that long-term low-dose aspirin use is associated with a slightly decreased risk of pneumonia in patients with CCVDs.
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Affiliation(s)
- Ying-Cheng Chen
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Surgery, Changhua Christian Hospital, Changhua, Taiwan
| | - Yin-Yang Chen
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Han Wei Yeh
- School of Medicine, Chang Gung University, Taoyuan City, Taiwan
| | - Tung-Ying Yeh
- Graduate School of Dentistry, School of Dentistry, Chung Shan Medical University, Taichung, Taiwan.,Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Jing-Yang Huang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Pei-Lun Liao
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Liang-Tsai Yeh
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Anesthesiology, Changhua Christian Hospital, Changhua, Taiwan
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Ming-Chih Chou
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Chao-Bin Yeh
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Emergency Medicine, School of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Emergency Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan
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6
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Yamamoto M, Aizawa R. Maintaining a protective state for human periodontal tissue. Periodontol 2000 2021; 86:142-156. [PMID: 33690927 DOI: 10.1111/prd.12367] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Periodontitis, caused by infection with periodontal pathogens, is primarily characterized by inflammatory bone resorption and destruction of connective tissue. Simply describing periodontitis as a specific bacterial infection cannot completely explain the various periodontal tissue destruction patterns observed. Periodontal tissue damage is thought to be caused by various factors. In recent years, research goals for periodontal pathogens have shifted from searching for specific pathogens to investigating mechanisms that damage periodontal tissues. Bacteria interact directly with the host in several ways, influencing expression and activity of molecules that evade host defenses, and destroying local tissues and inhibiting their repair. The host's innate and acquired immune systems are important defense mechanisms that protect periodontal tissues from attack and invasion of periodontal pathogens, thus preventing infection. Innate and acquired immunity have evolved to confront the microbial challenge, forming a seamless defense network in periodontal tissues. In the innate immune response, host cells quickly detect, via specialized receptors, macromolecules and nucleic acids present on bacterial cell walls, and this triggers a protective, inflammatory response. The work of this subsystem of host immunity is performed mainly by phagocytes, beta-defensin, and the complement system. In addition, the first line of defense in oral innate immunity is the junctional epithelium, which acts as a physical barrier to the entry of oral bacteria and other nonself substances. In the presence of a normal flora, junctional epithelial cells differentiate actively and proliferate apically, with concomitant increase in chemotactic factor expression recruiting neutrophils. These immune cells play an important role in maintaining homeostasis and the protective state in periodontal tissue because they eliminate unwanted bacteria over time. Previous studies indicate a mechanism for attracting immune cells to periodontal tissue with the purpose of maintaining a protective state; although this mechanism can function without bacteria, it is enhanced by the normal flora. A better understanding of the relationship between the protective state and its disruption in periodontal disease could lead to the development of new treatment strategies for periodontal disease.
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Affiliation(s)
- Matsuo Yamamoto
- Department of Periodontology, School of Dentistry, Showa University, Tokyo, Japan
| | - Ryo Aizawa
- Department of Periodontology, School of Dentistry, Showa University, Tokyo, Japan
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7
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Burstein S. Molecular Mechanisms for the Inflammation-Resolving Actions of Lenabasum. Mol Pharmacol 2021; 99:125-132. [PMID: 33239333 DOI: 10.1124/molpharm.120.000083] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 11/19/2020] [Indexed: 12/31/2022] Open
Abstract
A first-in-class cannabinoid analog called lenabasum that is a CB2 agonist is being developed as an inflammation-resolving drug candidate. Thus far, specific therapeutic targets include scleroderma, cystic fibrosis, dermatomyositis, and lupus, all of which represent unmet medical needs. Two somewhat-independent molecular mechanisms for this type of action are here proposed. Both pathways initially involve the release of free arachidonic acid after activation of the CB2 receptor and phospholipase A2 by lenabasum. The pathways then diverge into a cyclooxygenase 2-mediated and a lipoxygenase-mediated route. The former leads to increased levels of the cyclopentenone prostaglandin 15-deoxy-Δ12,14-prostaglandin-J2 that can activate the NLPR3 inflammasome, which in turn releases caspase-3, leading to apoptosis and the resolution of chronic inflammation. The lipoxygenase-mediated pathway stimulates the production of lipoxin A4 as well as other signaling molecules called specialized proresolving mediators. These also have inflammation-resolving actions. It is not well understood under which conditions each of these mechanisms operates and whether there is crosstalk between them. Thus, much remains to be learned about the mechanisms describing the actions of lenabasum. SIGNIFICANCE STATEMENT: The resolution of chronic inflammation is a major unmet medical need. The synthetic nonpsychoactive cannabinoid lenabasum could provide a safe and effective drug for this purpose. Two putative molecular mechanisms are suggested to better understand how lenabasum produces this action. In both, different metabolites of arachidonic acid act as mediators.
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Affiliation(s)
- Sumner Burstein
- Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts
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8
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Edwards JM, McCarthy CG, Wenceslau CF. The Obligatory Role of the Acetylcholine-Induced Endothelium-Dependent Contraction in Hypertension: Can Arachidonic Acid Resolve this Inflammation? Curr Pharm Des 2020; 26:3723-3732. [PMID: 32303165 PMCID: PMC7542659 DOI: 10.2174/1381612826666200417150121] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Accepted: 04/10/2020] [Indexed: 02/07/2023]
Abstract
The endothelium produces many substances that can regulate vascular tone. Acetylcholine is a widely used pharmacological tool to assess endothelial function. In general, acetylcholine binds to G-protein coupled muscarinic receptors that mediate a transient elevation in intracellular, free calcium. This intracellular rise in calcium is responsible for triggering several cellular responses, including the synthesis of nitric oxide, endothelium- derived hyperpolarizing factor, and eicosanoids derived from arachidonic acid. Endothelial arachidonic acid metabolism is also an important signaling pathway for mediating inflammation. Therefore, in conditions with sustained and excessive inflammation such as hypertension, arachidonic acid serves as a substrate for the synthesis of several vasoconstrictive metabolites, predominantly via the cyclooxygenase and lipoxygenase enzymes. Cyclooxygenase and lipoxygenase products can then activate G-protein coupled receptors expressed on vascular smooth muscle cells to causes contractile responses. As a result, acetylcholine-induced contraction due to arachidonic acid is a commonly observed feature of endothelial dysfunction and vascular inflammation in hypertension. In this review, we will critically analyze the literature supporting this concept, as well as address the potential underlying mechanisms, including the possibility that arachidonic acid signaling is diverted away from the synthesis of pro-resolving metabolites in conditions such as hypertension.
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Affiliation(s)
- Jonnelle M. Edwards
- Center for Hypertension and Precision Medicine, Department of Physiology and Pharmacology, University of Toledo College of Medicine & Life Sciences, Toledo, OH, USA
| | - Cameron G. McCarthy
- Center for Hypertension and Precision Medicine, Department of Physiology and Pharmacology, University of Toledo College of Medicine & Life Sciences, Toledo, OH, USA
| | - Camilla F. Wenceslau
- Center for Hypertension and Precision Medicine, Department of Physiology and Pharmacology, University of Toledo College of Medicine & Life Sciences, Toledo, OH, USA
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9
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15-epi-lipoxin A4 inhibits TNF-α-induced tissue factor expression via the PI3K/AKT/ NF-κB axis in human umbilical vein endothelial cells. Biomed Pharmacother 2019; 117:109099. [DOI: 10.1016/j.biopha.2019.109099] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 06/04/2019] [Accepted: 06/04/2019] [Indexed: 01/03/2023] Open
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10
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Cheng Y, Rong J. Pro-resolving lipid mediators as therapeutic leads for cardiovascular diseases. Expert Opin Ther Targets 2019; 23:423-436. [PMID: 30917700 DOI: 10.1080/14728222.2019.1599360] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Yuanyuan Cheng
- School of Pharmaceutical Sciences, Guangzhou Univ Chinese Med, Guangzhou, China
| | - Jianhui Rong
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, China
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11
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Hoxha M. A systematic review on the role of eicosanoid pathways in rheumatoid arthritis. Adv Med Sci 2018; 63:22-29. [PMID: 28818745 DOI: 10.1016/j.advms.2017.06.004] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Revised: 06/05/2017] [Accepted: 06/18/2017] [Indexed: 11/29/2022]
Abstract
BACKGROUND Rheumatoid arthritis is characterized by the production of eicosanoids, cytokines, adhesion molecules, infiltration of T and B lymphocytes in the synovium and oxygen reduction accompanied by the cartilage degradation. Eicosanoids are responsible for the progressive destruction of cartilage and bone, however neither steroids, nor the non steroidal anti-inflammatory drugs (NSAIDs), cannot slow down cartilage and bone destruction providing only symptomatic improvement. The current rheumatoid arthritis treatment options include mainly the use of disease-modifying anti-rheumatic drugs, the corticosteroids, the NSAIDs and biological agents. METHODS PubMed, Cochrane, and Embase electronic database were used as the main sources for extracting several articles, reviews, original papers in English for further review and analysis on the implication of arachidonic acid metabolites with rheumatoid arthritis and different strategies of targeting arachidonic acid metabolites, different enzymes or receptors for improving the treatment of rheumatoid arthritis patients. RESULTS We first focused on the role of individual prostaglandins and leukotrienes, in the inflammatory process of arthritis, concluding with an outline of the current clinical situation of rheumatoid arthritis and novel treatment strategies targeting the arachidonic acid pathway. CONCLUSIONS Extended research is necessary for the development of these novel compounds targeting the eicosanoid pathway, by increasing the levels of anti-inflammatory eicosanoids (PGD2,15dPGJ2), by inhibiting the production of pro-inflammatory eicosanoids (PGE2, LTB4, PGI2) involved in rheumatoid arthritis or also by developing dual compounds displaying both the COX-2 inhibitor/TP antagonist activity within a single compound.
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Affiliation(s)
- Malvina Hoxha
- Department of Chemical-Toxicological and Pharmacological Evaluation of Drugs, Catholic University Our Lady of Good Counsel, Tirana, Albania; Department of Pharmacological and Biomolecular Sciences, Università degli studi di Milano, Milan, Italy.
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12
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Balta MG, Loos BG, Nicu EA. Emerging Concepts in the Resolution of Periodontal Inflammation: A Role for Resolvin E1. Front Immunol 2017; 8:1682. [PMID: 29312286 PMCID: PMC5735081 DOI: 10.3389/fimmu.2017.01682] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Accepted: 11/15/2017] [Indexed: 02/02/2023] Open
Abstract
Inflammatory response is a protective biological process intended to eliminate the harmful effect of the insulting influx. Resolution of inflammation constitutes an active sequence of overlapping events mediated by specialized proresolving mediators, such as lipoxins, resolvins, protectins, and maresins, which originate from the enzymatic conversion of polyunsaturated fatty acids (PUFAs). An unresolved acute inflammatory response results in chronic inflammation, which is a leading cause of several common pathological conditions. Periodontitis is a biofilm-induced chronic inflammatory disease, which results in loss of periodontal connective tissue and alveolar bone support around the teeth, leading to tooth exfoliation. An inadequate proresolving host response may constitute a mechanism explaining the pathogenesis of periodontal disease. An emerging body of clinical and experimental evidence has focused on the underlying molecular mechanisms of resolvins and particularly Resolvin E1 (RvE1) in periodontitis. Recently, RvE1 has been directly correlated with the resolution of inflammation in periodontal disease. Herein, we provide a comprehensive overview of the literature regarding the role and possible mechanisms of action of RvE1 on different cell populations recruited in periodontal inflammation as well as its potential therapeutic implications. Along with recent data on the benefits of PUFAs supplementation in periodontal clinical parameters, we touch upon suggested future directions for research.
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Affiliation(s)
- Maria G Balta
- Department of Periodontology, Academic Centre for Dentistry Amsterdam, Amsterdam, Netherlands
| | - Bruno G Loos
- Department of Periodontology, Academic Centre for Dentistry Amsterdam, Amsterdam, Netherlands
| | - Elena A Nicu
- Department of Periodontology, Academic Centre for Dentistry Amsterdam, Amsterdam, Netherlands.,Opris Dent SRL, Sibiu, Romania
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13
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Whittington RA, Planel E, Terrando N. Impaired Resolution of Inflammation in Alzheimer's Disease: A Review. Front Immunol 2017; 8:1464. [PMID: 29163531 PMCID: PMC5681480 DOI: 10.3389/fimmu.2017.01464] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2017] [Accepted: 10/19/2017] [Indexed: 12/31/2022] Open
Abstract
Alzheimer’s disease (AD) remains the leading cause of dementia worldwide, and over the last several decades, the role of inflammation in the pathogenesis of this neurodegenerative disorder has been increasingly elucidated. The initiation of the acute inflammatory response is counterbalanced by an active process termed resolution. This process is designed to restore homeostasis and promote tissue healing by the activation of neutrophilic apoptosis, promotion of neutrophil clearance by macrophages, and increasing anti-inflammatory cytokine levels, while concurrently leading to a diminution in pro-inflammatory mediators. The switch from the initiation to the resolution phase of inflammation is initially characterized by increased production of arachidonic acid-derived pro-resolving lipoxins and decreases in pro-inflammatory prostaglandin and leukotriene levels, subsequently followed by increases in specialized pro-resolving lipid mediators derived from omega-3 fatty acids (ω-3 FAs). There is mounting evidence that in AD, the resolution of inflammation is impaired, resulting in chronic inflammation and the exacerbation of the AD-related pathology. In this review, we examine preclinical and clinical evidence supporting the hypothesis that AD is a neurodegenerative disorder where the impairment or failure of resolution contributes to the disease process. Moreover, we review the literature supporting the potential therapeutic role of ω-3 FAs and specialized pro-resolving lipid mediators in the management of the disease. Lastly, we highlight areas that could strengthen the association of failed resolution to AD and should, therefore, be the focus of future scientific investigations in this research field.
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Affiliation(s)
- Robert A Whittington
- Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, NY, United States
| | - Emmanuel Planel
- Faculté de Médecine, Département de Psychiatrie et Neurosciences, Université Laval, Québec City, QC, Canada.,Centre de Recherche du CHU de Quebec, Centre Hospitalier de l'Université Laval, Neurosciences, Québec City, QC, Canada
| | - Niccolò Terrando
- Department of Anesthesiology, Duke University, Durham, NC, United States
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Quantifying the Effects of Prior Acetyl-Salicylic Acid on Sepsis-Related Deaths: An Individual Patient Data Meta-Analysis Using Propensity Matching. Crit Care Med 2017; 45:1871-1879. [PMID: 28799949 DOI: 10.1097/ccm.0000000000002654] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
OBJECTIVE The primary objective was to conduct a meta-analysis on published observational cohort data describing the association between acetyl-salicylic acid (aspirin) use prior to the onset of sepsis and mortality in hospitalized patients. STUDY SELECTION Studies that reported mortality in patients on aspirin with sepsis with a comparison group of patients with sepsis not on prior aspirin therapy were included. DATA SOURCES Fifteen studies described hospital-based cohorts (n = 17,065), whereas one was a large insurance-based database (n = 683,421). Individual-level patient data were incorporated from all selected studies. DATA EXTRACTION Propensity analyses with 1:1 propensity score matching at the study level were performed, using the most consistently available covariates judged to be associated with aspirin. Meta-analyses were performed to estimate the pooled average treatment effect of aspirin on sepsis-related mortality. DATA SYNTHESIS Use of aspirin was associated with a 7% (95% CI, 2-12%; p = 0.005) reduction in the risk of death as shown by meta-analysis with considerable statistical heterogeneity (I = 61.6%). CONCLUSIONS These results are consistent with effects ranging from a 2% to 12% reduction in mortality risk in patients taking aspirin prior to sepsis onset. This association anticipates results of definitive studies of the use of low-dose aspirin as a strategy for reduction of deaths in patients with sepsis.
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Sodin-Semrl S, Spagnolo A, Mikus R, Barbaro B, Varga J, Fiore S. Opposing Regulation of Interleukin-8 and NF-kB Responses by Lipoxin A4 and Serum Amyloid a via the Common Lipoxin a Receptor. Int J Immunopathol Pharmacol 2017; 17:145-56. [PMID: 15171815 DOI: 10.1177/039463200401700206] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Lipoxin A4 (LXA4) is a potent eicosanoid that inhibits IL-1β-induced activation of human fibroblast-like synoviocytes (FLS) via the LXA4 receptor (ALXR). Serum amyloid A (SAA) is an acute phase reactant with cytokine-like properties. SAA has been shown to bind the same seven transmembrane G protein-coupled receptor ligated by LXA4. Here we compared the inflammatory responses of lipid (LXA4) and peptide (SAA) ligands in human FLS via the shared ALX and characterized their downstream signaling. LXA4 induced stimulation of tissue inhibitors of metalloproteinase-2, whereas SAA induced interleukin-8 and matrix metalloproteinase-3 production. SAA up-regulated NF-kB and AP-1 DNA binding activity, while LXA4 markedly inhibited these responses after IL-1β stimulation. A human IL-8 promoter luciferase construct was transfected into CHO cells stably expressing ALXR in order to determine the role of NF-kB and/or AP-1 in the regulation of IL-8 gene expression. The NF-kB pathway proved to be the preeminent for the biological responses elicited by both ligands. These findings suggest that two endogenous molecules, targeting a common receptor, could participate in the pathogenesis of inflammatory arthritis by differentially regulating inflammatory responses in tissues expressing the ALXR.
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Affiliation(s)
- S Sodin-Semrl
- Section of Rheumatology, Dept Med, COM, University of Illinois, Chicago, IL 60607-7171, USA
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16
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The comparative efficacy and safety of topical non-steroidal anti-inflammatory drugs for the treatment of anterior chamber inflammation after cataract surgery: a systematic review and network meta-analysis. Graefes Arch Clin Exp Ophthalmol 2017; 255:639-649. [DOI: 10.1007/s00417-017-3599-8] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Revised: 01/11/2017] [Accepted: 01/17/2017] [Indexed: 01/01/2023] Open
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17
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Eisen DP, Moore EM, Leder K, Lockery J, McBryde ES, McNeil JJ, Pilcher D, Wolfe R, Woods RL. AspiriN To Inhibit SEPSIS (ANTISEPSIS) randomised controlled trial protocol. BMJ Open 2017; 7:e013636. [PMID: 28110287 PMCID: PMC5253551 DOI: 10.1136/bmjopen-2016-013636] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
INTRODUCTION Sepsis is a leading global cause of morbidity and mortality, and is more common at the extremes of age. Moreover, the cost of in-hospital care for elderly patients with sepsis is significant. There are indications from experimental and observational studies that aspirin may reduce inflammation associated with infection. This paper describes the rationale and design of the AspiriN To Inhibit SEPSIS (ANTISEPSIS) trial, a substudy of ASPirin in Reducing Events in the Elderly (ASPREE). ANTISEPSIS primarily aims to determine whether low-dose aspirin reduces sepsis-related deaths in older people. Additionally, it will assess whether low-dose aspirin reduces sepsis-related hospitalisations and sepsis-related Intensive Care Unit (ICU) admissions. METHODS AND ANALYSIS ASPREE is a double-blinded, randomised, placebo-controlled primary prevention trial that will determine whether daily low-dose aspirin extends disability-free longevity in 19 000 healthy older people recruited in Australia and the USA. The ANTISEPSIS substudy involves additional ASPREE trial data collection to assess the impact of daily low-dose aspirin on sepsis-related events in the 16 703 ASPREE participants aged 70 years and over, recruited in Australia. The intervention is a daily 100 mg dose of enteric-coated aspirin versus matching placebo, with 1:1 randomisation. The primary outcome for the ANTISEPSIS substudy is the incidence of sepsis-related death in eligible patients. The incidence of sepsis-related hospital and ICU admissions are secondary outcomes. ANTISEPSIS is to be conducted between 2012 and 2018. DISCUSSION This substudy will determine whether aspirin, an inexpensive and accessible therapy, safely reduces sepsis-related deaths and hospitalisations in older Australians. If shown to be the case, this would have profound effects on the health of older Australians. TRIAL REGISTRATION NUMBER Pre-results, ACTRN12613000349741.
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Affiliation(s)
- Damon P Eisen
- Townsville Hospital and Health Service, Townsville, Queensland, Australia
- Division of Tropical Health and Medicine, College of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia
- Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
| | - Elizabeth M Moore
- Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
| | - Karin Leder
- Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
- Victorian Infectious Diseases Service at the Peter Doherty Institute, Royal Melbourne Hospital, Melbourne, Victoria, Australia
| | - Jessica Lockery
- Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
| | - Emma S McBryde
- Division of Tropical Health and Medicine, Australian Institute of Tropical Health and Medicine, James Cook University, Townsville, Queensland, Australia
| | - John J McNeil
- Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
| | - David Pilcher
- Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
- Department of Intensive Care, The Alfred Hospital, Melbourne, Victoria, Australia
- The Australian and New Zealand Intensive Care Society (ANZICS) Centre for Outcome and Resource Evaluation (CORE), Melbourne, Victoria, Australia
| | - Rory Wolfe
- Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
| | - Robyn L Woods
- Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
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18
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Freire MO, Dalli J, Serhan CN, Van Dyke TE. Neutrophil Resolvin E1 Receptor Expression and Function in Type 2 Diabetes. THE JOURNAL OF IMMUNOLOGY 2016; 198:718-728. [PMID: 27994073 DOI: 10.4049/jimmunol.1601543] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 09/08/2016] [Accepted: 11/15/2016] [Indexed: 12/31/2022]
Abstract
Unresolved inflammation is key in linking metabolic dysregulation and the immune system in type 2 diabetes. Successful regulation of acute inflammation requires biosynthesis of specialized proresolving lipid mediators, such as E-series resolvin (RvE) 1, and activation of cognate G protein-coupled receptors. RvE1 binds to leukotriene B4 (BLT-1) on neutrophils and to ERV-1/ChemR23 on monocyte/macrophages. We show novel actions of RvE1 and expression patterns of neutrophil receptors in type 2 diabetes. Neutrophils from healthy subjects express functional BLT-1, low levels of minimally functional ERV-1, and inversed coexpression when compared to neutrophils from type 2 diabetes subjects. Stimulation with TNF-α or LPS increased the expression of ERV-1 by healthy and diabetic neutrophils. RvE1 counteracted LPS and TNF-α induction of ERV-1 overexpression and endogenous diabetic overexpression, activating phagocytosis and resolution signals. Functional ERV-1 was determined by phosphorylation of the signaling protein ribosomal S6. Receptor-antagonism experiments revealed that the increase in phosphorylation of ribosomal S6 was mediated by BLT-1 in healthy subject neutrophils and by ERV-1 in diabetes. Metabololipidomics reveal a proinflammatory profile in diabetic serum. Cell phagocytosis is impaired in type 2 diabetes and requires RvE1 for activation. The dose of RvE1 required to activate resolution signals in type 2 diabetic neutrophils was significantly higher than in healthy controls. RvE1 rescues the dysregulation seen on neutrophil receptor profile and, following a therapeutic dosage, activates phagocytosis and resolution signals in type 2 diabetes. These findings reveal the importance of resolution receptors in health, disease, and dysregulation of inflammation in type 2 diabetes.
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Affiliation(s)
- Marcelo O Freire
- Department of Applied Oral Sciences, Center for Periodontology, The Forsyth Institute, Cambridge, MA 02142.,Department of Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115; and
| | - Jesmond Dalli
- Department of Anesthesiology, Perioperative and Pain Medicine, Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115
| | - Charles N Serhan
- Department of Anesthesiology, Perioperative and Pain Medicine, Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115
| | - Thomas E Van Dyke
- Department of Applied Oral Sciences, Center for Periodontology, The Forsyth Institute, Cambridge, MA 02142; .,Department of Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115; and
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Dakin SG, Martinez FO, Yapp C, Wells G, Oppermann U, Dean BJF, Smith RDJ, Wheway K, Watkins B, Roche L, Carr AJ. Inflammation activation and resolution in human tendon disease. Sci Transl Med 2016; 7:311ra173. [PMID: 26511510 DOI: 10.1126/scitranslmed.aac4269] [Citation(s) in RCA: 184] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Improved understanding of the role of inflammation in tendon disease is required to facilitate therapeutic target discovery. We studied supraspinatus tendons from patients experiencing pain before and after surgical subacromial decompression treatment. Tendons were classified as having early, intermediate, or advanced disease, and inflammation was characterized through activation of pathways mediated by interferon (IFN), nuclear factor κB (NF-κB), glucocorticoid receptor, and signal transducer and activator of transcription 6 (STAT-6). Inflammation signatures revealed expression of genes and proteins induced by IFN and NF-κB in early-stage disease and genes and proteins induced by STAT-6 and glucocorticoid receptor activation in advanced-stage disease. The proresolving proteins FPR2/ALX and ChemR23 were increased in early-stage disease compared to intermediate- to advanced-stage disease. Patients who were pain-free after treatment had tendons with increased expression of CD206 and ALOX15 mRNA compared to tendons from patients who continued to experience pain after treatment, suggesting that these genes and their pathways may moderate tendon pain. Stromal cells from diseased tendons cultured in vitro showed increased expression of NF-κB and IFN target genes after treatment with lipopolysaccharide or IFNγ compared to stromal cells derived from healthy tendons. We identified 15-epi lipoxin A4, a stable lipoxin isoform derived from aspirin treatment, as potentially beneficial in the resolution of tendon inflammation.
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Affiliation(s)
- Stephanie G Dakin
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Nuffield Orthopaedic Centre, Headington OX3 7LD, UK. NIHR Oxford Biomedical Research Unit, Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK
| | - Fernando O Martinez
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Nuffield Orthopaedic Centre, Headington OX3 7LD, UK
| | - Clarence Yapp
- Structural Genomics Consortium, University of Oxford, Old Road Campus, Headington OX3 7DQ, UK
| | - Graham Wells
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Nuffield Orthopaedic Centre, Headington OX3 7LD, UK
| | - Udo Oppermann
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Nuffield Orthopaedic Centre, Headington OX3 7LD, UK. Structural Genomics Consortium, University of Oxford, Old Road Campus, Headington OX3 7DQ, UK
| | - Benjamin J F Dean
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Nuffield Orthopaedic Centre, Headington OX3 7LD, UK. NIHR Oxford Biomedical Research Unit, Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK
| | - Richard D J Smith
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Nuffield Orthopaedic Centre, Headington OX3 7LD, UK. NIHR Oxford Biomedical Research Unit, Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK
| | - Kim Wheway
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Nuffield Orthopaedic Centre, Headington OX3 7LD, UK. NIHR Oxford Biomedical Research Unit, Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK
| | - Bridget Watkins
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Nuffield Orthopaedic Centre, Headington OX3 7LD, UK. NIHR Oxford Biomedical Research Unit, Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK
| | - Lucy Roche
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Nuffield Orthopaedic Centre, Headington OX3 7LD, UK. NIHR Oxford Biomedical Research Unit, Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK
| | - Andrew J Carr
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Nuffield Orthopaedic Centre, Headington OX3 7LD, UK. NIHR Oxford Biomedical Research Unit, Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK
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20
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Dakin SG. A review of the healing processes in equine superficial digital flexor tendinopathy. EQUINE VET EDUC 2016. [DOI: 10.1111/eve.12572] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- S. G. Dakin
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences; Botnar Research Centre; Nuffield Orthopaedic Centre; University of Oxford; UK
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21
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Abstract
Inflammation is a protective response essential for maintaining human health and for fighting disease. As an active innate immune reaction to challenge, inflammation gives rise to clinical cardinal signs: rubor, calor, dolor, tumor and functio laesa. Termination of acute inflammation was previously recognized as a passive process; a natural decay of pro-inflammatory signals. We now understand that the natural resolution of inflammation involves well-integrated, active, biochemical programs that return tissues to homeostasis. This review focuses on recent advances in the understanding of the role of endogenous lipid mediators that modulate cellular fate and inflammation. Biosynthesis of eicosanoids and other lipids in exudates coincides with changes in the types of inflammatory cells. Resolution of inflammation is initiated by an active class switch in lipid mediators, such as classic prostaglandins and leukotrienes, to the production of proresolution mediators. Endogenous pro-resolving lipid mediators, including arachidonic acid-derived lipoxins, aspirin-triggered lipoxins, ω3-eicosapentaenoic acid-derived resolvins of the E-series, docosahexaenoic acid-derived resolvins of the D-series, protectins and maresins, are biosynthesized during the resolution phase of acute inflammation. Depending on the type of injury and the type of tissue, the initial cells that respond are polymorphonuclear leukocytes, monocytes/macrophages, epithelial cells or endothelial cells. The selective interaction of specific lipid mediators with G protein-coupled receptors expressed on innate immune cells (e.g. G protein-coupled receptor 32, lipoxin A4 receptor/formyl peptide receptor2, chemokine-like receptor 1, leukotriene B4 receptor type 1 and cabannoid receptor 2) induces cessation of leukocyte infiltration; vascular permeability/edema returns to normal with polymorphonuclear neutrophil death (mostly via apoptosis), the nonphlogistic infiltration of monocyte/macrophages and the removal (by macrophages) of apoptotic polymorphonuclear neutrophils, foreign agents (bacteria) and necrotic debris from the site. While an acute inflammatory response that is resolved in a timely manner prevents tissue injury, inadequate resolution and failure to return tissue to homeostasis results in neutrophil-mediated destruction and chronic inflammation. A better understanding of the complex mechanisms of lipid agonist mediators, cell targets and actions allows us to exploit and develop novel therapeutic strategies to treat human inflammatory diseases, including periodontal diseases.
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22
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Wang ZF, Li Q, Liu SB, Mi WL, Hu S, Zhao J, Tian Y, Mao-Ying QL, Jiang JW, Ma HJ, Wang YQ, Wu GC. Aspirin-triggered Lipoxin A4 attenuates mechanical allodynia in association with inhibiting spinal JAK2/STAT3 signaling in neuropathic pain in rats. Neuroscience 2014; 273:65-78. [PMID: 24836854 DOI: 10.1016/j.neuroscience.2014.04.052] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2013] [Revised: 04/21/2014] [Accepted: 04/21/2014] [Indexed: 12/13/2022]
Abstract
Aspirin-triggered Lipoxin A4 (ATL), as a Lipoxin A4 (LXA4) epimer, is endogenously produced by aspirin-acetylated cycloxygenase-2 (COX-2) and plays a vital role in endogenous anti-inflammation via the LXA4 receptor (ALX). Recent investigations have indicated that spinal neuroinflammation and the activation of the Janus Kinase 2 (JAK2)/Signal Transducers and Transcription Activators 3 (STAT3) signaling pathway are involved in neuropathic pain states. However, the effect of ATL on neuroinflammation and JAK2/STAT3 signaling in chronic constriction injury (CCI)-induced neuropathic pain in rats has not been well-studied. The present study demonstrated the anti-inflammatory and analgesic effect of ATL on neuropathic pain and assessed the role of spinal JAK2/STAT3 signaling on the effect of ATL. Intrathecal administration of ATL significantly attenuated mechanical allodynia via spinal ALX and inhibited the upregulation of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) on day 7 of CCI surgery. In addition, ATL markedly suppressed the upregulation of p-STAT3 induced by the neuropathic pain. Blockade of JAK2-STAT3 signaling with intrathecal administration of the JAK2 inhibitor AG490 or the STAT3 inhibitor S3I-201 clearly reduced mechanical allodynia and the upregulation of pro-inflammatory cytokines in CCI rats. Interestingly, inhibition of JAK2/STAT3 signaling via ATL or the specific signaling inhibitor (AG49, S3I-201) further promoted the increased expression of suppressor of cytokine signaling 3 (SOCS3) mRNA in the spinal cord induced by CCI surgery. Taken together, our results suggested that the analgesic effect of ATL was mediated by inhibiting spinal JAK2/STAT3 signaling and hence the spinal neuroinflammation in CCI rats.
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Affiliation(s)
- Z F Wang
- Department of Integrative Medicine and Neurobiology, Institute of Acupuncture Research, School of Basic Medical Sciences, Fudan University, Shanghai, China; State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Fudan University, Shanghai, China; Department of Anatomy, Integrative Medicine College, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, China.
| | - Q Li
- Department of Integrative Medicine and Neurobiology, Institute of Acupuncture Research, School of Basic Medical Sciences, Fudan University, Shanghai, China; State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Fudan University, Shanghai, China.
| | - S B Liu
- Department of Integrative Medicine and Neurobiology, Institute of Acupuncture Research, School of Basic Medical Sciences, Fudan University, Shanghai, China; State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Fudan University, Shanghai, China.
| | - W-L Mi
- Department of Integrative Medicine and Neurobiology, Institute of Acupuncture Research, School of Basic Medical Sciences, Fudan University, Shanghai, China; State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Fudan University, Shanghai, China.
| | - S Hu
- Department of Integrative Medicine and Neurobiology, Institute of Acupuncture Research, School of Basic Medical Sciences, Fudan University, Shanghai, China; State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Fudan University, Shanghai, China.
| | - J Zhao
- Department of Integrative Medicine and Neurobiology, Institute of Acupuncture Research, School of Basic Medical Sciences, Fudan University, Shanghai, China; State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Fudan University, Shanghai, China.
| | - Y Tian
- Department of Integrative Medicine and Neurobiology, Institute of Acupuncture Research, School of Basic Medical Sciences, Fudan University, Shanghai, China; State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Fudan University, Shanghai, China.
| | - Q L Mao-Ying
- Department of Integrative Medicine and Neurobiology, Institute of Acupuncture Research, School of Basic Medical Sciences, Fudan University, Shanghai, China; State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Fudan University, Shanghai, China.
| | - J W Jiang
- Department of Integrative Medicine and Neurobiology, Institute of Acupuncture Research, School of Basic Medical Sciences, Fudan University, Shanghai, China; State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Fudan University, Shanghai, China.
| | - H J Ma
- Department of Integrative Medicine and Neurobiology, Institute of Acupuncture Research, School of Basic Medical Sciences, Fudan University, Shanghai, China; State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Fudan University, Shanghai, China.
| | - Y Q Wang
- Department of Integrative Medicine and Neurobiology, Institute of Acupuncture Research, School of Basic Medical Sciences, Fudan University, Shanghai, China; State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Fudan University, Shanghai, China.
| | - G C Wu
- Department of Integrative Medicine and Neurobiology, Institute of Acupuncture Research, School of Basic Medical Sciences, Fudan University, Shanghai, China; State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Fudan University, Shanghai, China.
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Kojima F, Kapoor M, Kawai S, Crofford LJ. New insights into eicosanoid biosynthetic pathways: implications for arthritis. Expert Rev Clin Immunol 2014; 2:277-91. [DOI: 10.1586/1744666x.2.2.277] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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Lambeth JD, Neish AS. Nox enzymes and new thinking on reactive oxygen: a double-edged sword revisited. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2013; 9:119-45. [PMID: 24050626 DOI: 10.1146/annurev-pathol-012513-104651] [Citation(s) in RCA: 375] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Reactive oxygen species (ROS) are a chemical class of molecules that have generally been conceptualized as deleterious entities, albeit ones whose destructive properties could be harnessed as antimicrobial effector functions to benefit the whole organism. This appealingly simplistic notion has been turned on its head in recent years with the discovery of the NADPH oxidases, or Noxes, a family of enzymes dedicated to the production of ROS in a variety of cells and tissues. The Nox-dependent, physiological generation of ROS is highly conserved across virtually all multicellular life, often as a generalized response to microbes and/or other exogenous stressors. This review discusses the current knowledge of the role of physiologically generated ROS and the enzymes that form them in both normal biology and disease.
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Affiliation(s)
- J David Lambeth
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322;
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25
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Wu B, Walker JA, Temmermand D, Mian K, Spur B, Rodriguez A, Stein TP, Banerjee P, Yin K. Lipoxin A(4) promotes more complete inflammation resolution in sepsis compared to stable lipoxin A(4) analog. Prostaglandins Leukot Essent Fatty Acids 2013; 89:47-53. [PMID: 23688707 DOI: 10.1016/j.plefa.2013.04.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2013] [Revised: 04/06/2013] [Accepted: 04/09/2013] [Indexed: 12/23/2022]
Abstract
In sepsis, excessive inflammation may lead to organ injury or a paradoxical immunosuppressed state where the host is unable to clear preexisting infection. Resolution of inflammation is the process which restores tissue homeostasis and ensures that a chronic cycle of infection/inflammation does not occur. Lipoxin A4 (LXA4) is one of a family of lipid mediators with novel inflammation resolution activity. We compared the actions of LXA4 to the stable 15-epi-16-(para-fluorophenoxy)-lipoxin A4 methyl ester (LXA4 analog) in the cecal ligation and puncture (CLP) model of sepsis. Both LXA4 compounds (at 7 μg/kg; i.v.) reduced plasma TNFα and IL-6 concentrations compared to rats given vehicle saline. Neither treatment altered plasma IL-10 compared to CLP given saline, but LXA4 analog, increased plasma IL-10 concentrations compared to rats given LXA4. LXA4 reduced blood bacterial load but the LXA4 analog did not. LXA4 increased 8 day survival and the LXA4 analog did not have a significant effect. To examine possible mechanisms for the differences, we investigated peritoneal leukocyte gene expression of iNOS and macrophage phagocytic ability. Only LXA4 increased the percentage of phagocytic peritoneal macrophages. LXA4 reduced neutrophil gene expression of iNOS compared to CLP rats given vehicle, while the LXA4 analog did not. Our results suggest that at doses which reduced systemic inflammation, only LXA4 inhibited bacterial spread and increased survival. This difference may be due to the shorter-lived compound being able to increase macrophage phagocytosis and reduce neutrophil iNOS expression.
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Affiliation(s)
- B Wu
- Department of Cell Biology, University of Medicine and Dentistry, New Jersey School of Osteopathic Medicine, NJ, USA
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Dakin SG, Dudhia J, Smith RKW. Science in brief: Resolving tendon inflammation. A new perspective. Equine Vet J 2013; 45:398-400. [DOI: 10.1111/evj.12030] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Affiliation(s)
- S. G. Dakin
- Department of Veterinary Clinical Sciences; Royal Veterinary College; UK
| | - J. Dudhia
- Department of Veterinary Clinical Sciences; Royal Veterinary College; UK
| | - R. K. W. Smith
- Department of Veterinary Clinical Sciences; Royal Veterinary College; UK
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Kodela R, Chattopadhyay M, Goswami S, Gan ZY, Rao PPN, Nia KV, Velázquez-Martínez CA, Kashfi K. Positional isomers of aspirin are equally potent in inhibiting colon cancer cell growth: differences in mode of cyclooxygenase inhibition. J Pharmacol Exp Ther 2013; 345:85-94. [PMID: 23349335 PMCID: PMC3608450 DOI: 10.1124/jpet.112.201970] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2012] [Accepted: 01/08/2013] [Indexed: 01/05/2023] Open
Abstract
We compared the differential effects of positional isomers of acetylsalicylic acid (o-ASA, m-ASA, and p-ASA) on cyclooxygenase (COX) inhibition, gastric prostaglandin E2 (PGE2), malondialdehyde, tumor necrosis factor-alpha (TNF-α) levels, superoxide dismutase (SOD) activity, human adenocarcinoma colon cancer cell growth inhibition, cell proliferation, apoptosis, and cell-cycle progression. We also evaluated the gastric toxicity exerted by ASA isomers. All ASA isomers inhibit COX enzymes, but only the o-ASA exerted an irreversible inhibitory profile. We did not observe a significant difference between ASA isomers in their ability to decrease the in vivo synthesis of PGE2 and SOD activity. Furthermore, all isomers increased the levels of gastric and TNF-α when administered orally at equimolar doses. We observed a dose-dependent cell growth inhibitory effect; the order of potency was p-ASA > m-ASA ≈ o-ASA. There was a dose-dependent decrease in cell proliferation and an increase in apoptosis, with a concomitant Go/G1 arrest. The ulcerogenic profile of the three ASA isomers showed a significant difference between o-ASA (aspirin) and its two positional isomers when administered orally at equimolar doses (1 mmol/kg); the ulcer index (UI) for o-ASA indicated extensive mucosal injury (UI = 38), whereas m-ASA and p-ASA produced a significantly decreased toxic response (UI = 12 and 8, respectively) under the same experimental conditions. These results suggest that the three positional isomers of ASA exert practically the same biologic profile in vitro and in vivo but showed different safety profiles. The mechanism of gastric ulcer formation exerted by aspirin and its two isomers warrants a more detailed and thorough investigation.
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Affiliation(s)
- Ravinder Kodela
- Department of Physiology, Pharmacology, and Neuroscience, Sophie Davis School of Biomedical Education, City University of New York Medical School, New York, New York 10031, USA
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Brennan EP, Nolan KA, Börgeson E, Gough OS, McEvoy CM, Docherty NG, Higgins DF, Murphy M, Sadlier DM, Ali-Shah ST, Guiry PJ, Savage DA, Maxwell AP, Martin F, Godson C. Lipoxins attenuate renal fibrosis by inducing let-7c and suppressing TGFβR1. J Am Soc Nephrol 2013; 24:627-37. [PMID: 23520204 DOI: 10.1681/asn.2012060550] [Citation(s) in RCA: 132] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Lipoxins, which are endogenously produced lipid mediators, promote the resolution of inflammation, and may inhibit fibrosis, suggesting a possible role in modulating renal disease. Here, lipoxin A4 (LXA4) attenuated TGF-β1-induced expression of fibronectin, N-cadherin, thrombospondin, and the notch ligand jagged-1 in cultured human proximal tubular epithelial (HK-2) cells through a mechanism involving upregulation of the microRNA let-7c. Conversely, TGF-β1 suppressed expression of let-7c. In cells pretreated with LXA4, upregulation of let-7c persisted despite subsequent stimulation with TGF-β1. In the unilateral ureteral obstruction model of renal fibrosis, let-7c upregulation was induced by administering an LXA4 analog. Bioinformatic analysis suggested that targets of let-7c include several members of the TGF-β1 signaling pathway, including the TGF-β receptor type 1. Consistent with this, LXA4-induced upregulation of let-7c inhibited both the expression of TGF-β receptor type 1 and the response to TGF-β1. Overexpression of let-7c mimicked the antifibrotic effects of LXA4 in renal epithelia; conversely, anti-miR directed against let-7c attenuated the effects of LXA4. Finally, we observed that several let-7c target genes were upregulated in fibrotic human renal biopsies compared with controls. In conclusion, these results suggest that LXA4-mediated upregulation of let-7c suppresses TGF-β1-induced fibrosis and that expression of let-7c targets is dysregulated in human renal fibrosis.
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Affiliation(s)
- Eoin P Brennan
- Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland
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29
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Dakin SG, Dudhia J, Werling NJ, Werling D, Abayasekara DRE, Smith RKW. Inflamm-aging and arachadonic acid metabolite differences with stage of tendon disease. PLoS One 2012; 7:e48978. [PMID: 23155437 PMCID: PMC3498370 DOI: 10.1371/journal.pone.0048978] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2012] [Accepted: 10/01/2012] [Indexed: 01/01/2023] Open
Abstract
The contribution of inflammation to the pathogenesis of tendinopathy and high prevalence of re-injury is not well established, although recent evidence suggests involvement of prostaglandins. We investigated the roles of prostaglandins and inflammation-resolving mediators in naturally occurring equine tendon injury with disease stage and age. Levels of prostaglandins E2 (PGE2), F2α (PGF2α), lipoxin A4 (LXA4) and its receptor FPR2/ALX were analysed in extracts of normal, sub-acute and chronic injured tendons. To assess whether potential changes were associated with altered PGE2 metabolism, microsomal prostaglandin E synthase-1 (mPGES-1), prostaglandin dehydrogenase (PGDH), COX-2 and EP4 receptor expression were investigated. The ability of tendons to resolve inflammation was determined by assessing FPR2/ALX expression in natural injury and IL-1β stimulated tendon explants. Alterations in the profile of lipid mediators during sub-acute injury included low PGE2 and elevated LXA4 levels compared to normal and chronic injuries. In contrast, PGF2α levels remained unchanged and were three-fold lower than PGE2. The synthetic capacity of PGE2 as measured by the ratio of mPGES-1:PGDH was elevated in sub-acute injury, suggesting aberrations in tendon prostaglandin metabolism, whilst COX-2 and EP4 receptor were unchanged. Paradoxically low tendon PGE2 levels in early injury may be attributed to increased local clearance via PGDH or the class switching of lipid mediators from the prostaglandin to the lipoxin axis. PGE2 is therefore implicated in the development of tendon inflammation and its ensuing resolution. Whilst there was no relationship between age and tendon LXA4 levels, there was an age-associated decline in FPR2/ALX receptor expression with concurrent increased PGE2 levels in injury. Furthermore, uninjured tendon explants from younger (<10 years) but not older horses (≥10 years) treated with IL-1β responded by increasing FPR2/ALX suggesting aged individuals exhibit a reduced capacity to resolve inflammation via FPR2/ALX, which may present a potential mechanism for development of chronic tendinopathy and re-injury.
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Affiliation(s)
- Stephanie Georgina Dakin
- Department of Veterinary Clinical Sciences, Royal Veterinary College, University of London, Hatfield, United Kingdom.
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Jones RM, Mercante JW, Neish AS. Reactive oxygen production induced by the gut microbiota: pharmacotherapeutic implications. Curr Med Chem 2012; 19:1519-29. [PMID: 22360484 DOI: 10.2174/092986712799828283] [Citation(s) in RCA: 175] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2011] [Revised: 12/22/2011] [Accepted: 12/26/2011] [Indexed: 12/18/2022]
Abstract
The resident prokaryotic microbiota of the mammalian intestine influences diverse homeostatic functions, including regulation of cellular growth, maintenance of barrier function, and modulation of immune responses. However, it is unknown how commensal prokaryotic organisms mechanistically influence eukaryotic signaling networks. Recent data has demonstrated that gut epithelia contacted by enteric commensal bacteria rapidly generate reactive oxygen species (ROS). While the induced generation of ROS via stimulation of formyl peptide receptors is a cardinal feature of the cellular response of phagocytes to pathogenic or commensal bacteria, evidence is accumulating that ROS are also similarly elicited in other cell types, including intestinal epithelia, in response to microbial signals. Additionally, ROS have been shown to serve as critical second messengers in multiple signal transduction pathways stimulated by proinflammatory cytokines and growth factors. This physiologically-generated ROS is known to participate in cellular signaling via the rapid and transient oxidative inactivation of a defined class of sensor proteins bearing oxidant-sensitive thiol groups. These proteins include tyrosine phosphatases that serve as regulators of MAP kinase pathways, cytoskeletal dynamics, as well as components involved in control of ubiquitination-mediated NF-κB activation. Consistently, microbial-elicited ROS has been shown to mediate increased cellular proliferation and motility and to modulate innate immune signaling. These results demonstrate how enteric microbiota influence regulatory networks of the mammalian intestinal epithelia. We hypothesize that many of the known effects of the normal microbiota on intestinal physiology, and potential beneficial effects of candidate probiotic bacteria, may be at least partially mediated by this ROS-dependent mechanism.
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Affiliation(s)
- R M Jones
- Emory University School of Medicine, Atlanta, GA 30322, USA
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Dakin SG, Werling D, Hibbert A, Abayasekara DRE, Young NJ, Smith RKW, Dudhia J. Macrophage sub-populations and the lipoxin A4 receptor implicate active inflammation during equine tendon repair. PLoS One 2012; 7:e32333. [PMID: 22384219 PMCID: PMC3284560 DOI: 10.1371/journal.pone.0032333] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2011] [Accepted: 01/25/2012] [Indexed: 01/15/2023] Open
Abstract
Macrophages (Mϕ) orchestrate inflammatory and reparatory processes in injured connective tissues but their role during different phases of tendon healing is not known. We investigated the contribution of different Mϕ subsets in an equine model of naturally occurring tendon injury. Post mortem tissues were harvested from normal (uninjured), sub-acute (3–6 weeks post injury) and chronically injured (>3 months post injury) superficial digital flexor tendons. To determine if inflammation was present in injured tendons, Mϕ sub-populations were quantified based on surface antigen expression of CD172a (pan Mϕ), CD14highCD206low (pro-inflammatory M1Mϕ), and CD206high (anti-inflammatory M2Mϕ) to assess potential polarised phenotypes. In addition, the Lipoxin A4 receptor (FPR2/ALX) was used as marker for resolving inflammation. Normal tendons were negative for both Mϕ and FPR2/ALX. In contrast, M1Mϕ predominated in sub-acute injury, whereas a potential phenotype-switch to M2Mϕ polarity was seen in chronic injury. Furthermore, FPR2/ALX expression by tenocytes was significantly upregulated in sub-acute but not chronic injury. Expression of the FPR2/ALX ligand Annexin A1 was also significantly increased in sub-acute and chronic injuries in contrast to low level expression in normal tendons. The combination of reduced FPR2/ALX expression and persistence of the M2Mϕ phenotype in chronic injury suggests a potential mechanism for incomplete resolution of inflammation after tendon injury. To investigate the effect of pro-inflammatory mediators on lipoxin A4 (LXA4) production and FPR2/ALX expression in vitro, normal tendon explants were stimulated with interleukin-1 beta and prostaglandin E2. Stimulation with either mediator induced LXA4 release and maximal upregulation of FPR2/ALX expression after 72 hours. Taken together, our data suggests that although tenocytes are capable of mounting a protective mechanism to counteract inflammatory stimuli, this appears to be of insufficient duration and magnitude in natural tendon injury, which may potentiate chronic inflammation and fibrotic repair, as indicated by the presence of M2Mϕ.
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Affiliation(s)
- Stephanie Georgina Dakin
- Department of Veterinary Clinical Sciences, Royal Veterinary College, University of London, Hatfield, United Kingdom.
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Das UN. A defect in the activities of Δ and Δ desaturases and pro-resolution bioactive lipids in the pathobiology of non-alcoholic fatty liver disease. World J Diabetes 2011; 2:176-88. [PMID: 22087354 PMCID: PMC3215767 DOI: 10.4239/wjd.v2.i11.176] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2011] [Revised: 09/28/2011] [Accepted: 10/31/2011] [Indexed: 02/05/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a low-grade systemic inflammatory condition, since liver and adipose tissue tumor necrosis factor-α (TNF-α) and TNF receptor 1 transcripts and serum TNF-α levels are increased and IL-6(-/-) mice are less prone to NAFLD. Fatty liver damage caused by high-fat diets is associated with the generation of pro-inflammatory prostaglandin E(2) (PGE(2)). A decrease in the levels of arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and the usefulness of EPA and DHA both in the prevention and management of NAFLD has been reported. AA, EPA and DHA and their anti-inflammatory products lipoxins (LXs), resolvins and protectins suppress IL-6 and TNF-α and PGE(2) production. These results suggest that the activities of Δ(6) and Δ(5) desaturases are reduced in NAFLD and hence, the dietary essential fatty acids, linoleic acid (LA) and α-linolenic acid (ALA) are not metabolized to their long-chain products AA, EPA and DHA, the precursors of anti-inflammatory molecules, LXs, resolvins and protectins that could pre vent NAFLD. This suggests that an imbalance between pro- and anti-inflammatory bioactive lipids contribute to NAFLD. Hence, it is proposed that plasma and tissue levels of AA, EPA, DHA and LXs, resolvins and protectins could be used as predictors and prognostic biomarkers of NAFLD. It is suggested that the synthesis and use of more stable analogues of LXs, resolvins and protectins need to be explored in the prevention and management of NAFLD.
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Affiliation(s)
- Undurti N Das
- Undurti N Das, UND Life Sciences, 13800 Fairhill Road, 321, Shaker Heights, OH 44120, United States
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Navarrete CM, Pérez M, de Vinuesa AG, Collado JA, Fiebich BL, Calzado MA, Muñoz E. Endogenous N-acyl-dopamines induce COX-2 expression in brain endothelial cells by stabilizing mRNA through a p38 dependent pathway. Biochem Pharmacol 2010; 79:1805-14. [PMID: 20206142 DOI: 10.1016/j.bcp.2010.02.014] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2009] [Revised: 02/23/2010] [Accepted: 02/24/2010] [Indexed: 01/31/2023]
Abstract
Cerebral microvascular endothelial cells play an active role in maintaining cerebral blood flow, microvascular tone and blood brain barrier (BBB) functions. Endogenous N-acyl-dopamines like N-arachidonoyl-dopamine (NADA) and N-oleoyl-dopamine (OLDA) have been recently identified as a new class of brain neurotransmitters sharing endocannabinoid and endovanilloid biological activities. Endocannabinoids are released in response to pathogenic insults and may play an important role in neuroprotection. In this study we demonstrate that NADA differentially regulates the release of PGE(2) and PGD(2) in the microvascular brain endothelial cell line, b.end5. We found that NADA activates a redox-sensitive p38 MAPK pathway that stabilizes COX-2 mRNA resulting in the accumulation of the COX-2 protein, which depends on the dopamine moiety of the molecule and that is independent of CB(1) and TRPV1 activation. In addition, NADA inhibits the expression of mPGES-1 and the release of PGE(2) and upregulates the expression of L-PGD synthase enhancing PGD(2) release. Hence, NADA and other molecules of the same family might be included in the group of lipid mediators that could prevent the BBB injury under inflammatory conditions and our findings provide new mechanistic insights into the anti-inflammatory activities of NADA in the central nervous system and its potential to design novel therapeutic strategies to manage neuroinflammatory diseases.
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Affiliation(s)
- Carmen M Navarrete
- Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba. Facultad de Medicina. Avda de Menéndez Pidal s/n, 14004 Córdoba, Spain.
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Karim MJ, Bhattacherjee P, Biswas S, Paterson CA. Anti-Inflammatory Effects of Lipoxins on Lipopolysaccharide-Induced Uveitis in Rats. J Ocul Pharmacol Ther 2009; 25:483-6. [DOI: 10.1089/jop.2008.0134] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Affiliation(s)
- Md. Jahurul Karim
- Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, Kentucky
| | - Parimal Bhattacherjee
- Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, Kentucky
| | - Sumana Biswas
- Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, Kentucky
| | - Christopher A. Paterson
- Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, Kentucky
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Schultz H, Weiss JP. The bactericidal/permeability-increasing protein (BPI) in infection and inflammatory disease. Clin Chim Acta 2007; 384:12-23. [PMID: 17678885 PMCID: PMC2695927 DOI: 10.1016/j.cca.2007.07.005] [Citation(s) in RCA: 86] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2007] [Revised: 05/23/2007] [Accepted: 07/03/2007] [Indexed: 11/28/2022]
Abstract
Gram-negative bacteria (GNB) and their endotoxin present a constant environmental challenge. Endotoxins can potently signal mobilization of host defenses against invading GNB but also potentially induce severe pathophysiology, necessitating controlled initiation and resolution of endotoxin-induced inflammation to maintain host integrity. The bactericidal/permeability-increasing protein (BPI) is a pluripotent protein expressed, in humans, mainly neutrophils. BPI exhibits strong antimicrobial activity against GNB and potent endotoxin-neutralizing activity. BPI mobilized with neutrophils in response to invading GNB can promote intracellular and extracellular bacterial killing, endotoxin neutralization and clearance, and delivery of GNB outer membrane antigens to dendritic cells. Tissue expression by dermal fibroblasts and epithelia could further amplify local levels of BPI and local interaction with GNB and endotoxin, helping to constrain local tissue infection and inflammation and prevent systemic infection and systemic inflammation. This review article focuses on the structural and functional properties of BPI with respect to its contribution to host defense during GNB infections and endotoxin-induced inflammation and the genesis of autoantibodies against BPI that can blunt BPI activity and potentially contribute to chronic inflammatory disease.
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Affiliation(s)
- Hendrik Schultz
- Division of Infectious Diseases, University of Iowa, and Iowa City VAMC, USA, Iowa City, Iowa 52242, USA.
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36
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Kowal-Bielecka O, Kowal K, Distler O, Rojewska J, Bodzenta-Lukaszyk A, Michel BA, Gay RE, Gay S, Sierakowski S. Cyclooxygenase- and lipoxygenase-derived eicosanoids in bronchoalveolar lavage fluid from patients with scleroderma lung disease: an imbalance between proinflammatory and antiinflammatory lipid mediators. ACTA ACUST UNITED AC 2006; 52:3783-91. [PMID: 16320329 DOI: 10.1002/art.21432] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Eicosanoids play a key role in the regulation of inflammation and fibrosis. Recently we showed that levels of 5-lipoxygenase (5-LOX)-derived proinflammatory/profibrotic leukotrienes are elevated in bronchoalveolar lavage (BAL) fluid from patients with scleroderma lung disease (SLD). The present study was undertaken to investigate whether increased levels of leukotrienes are balanced by the antiinflammatory/antifibrotic cyclooxygenase (COX)- and 15-LOX-derived eicosanoids in the lungs of patients with SLD. METHODS Levels of 5-LOX-derived leukotriene B(4) (LTB(4)), COX-derived prostaglandin E(2) (PGE(2)), and 15-LOX-derived 15-hydroxyeicosatetraenoic acid (15-HETE) and lipoxin A(4) (LXA(4)) in BAL fluid from systemic sclerosis (SSc) patients with SLD (n = 32) and without SLD (n = 16) and from healthy individuals (n = 12) were measured by enzyme-linked immunosorbent assay. RESULTS Levels of LTB(4) (mean +/- SEM 248 +/- 29 pg/ml) and PGE(2) (51 +/- 10 pg/ml) in SSc patients with SLD were significantly higher compared with patients without SLD (LTB(4) 119 +/- 35 pg/ml, PGE(2) 17 +/- 3 pg/ml; P < 0.05 for both) and with healthy controls (85 +/- 12 pg/ml and 19 +/- 2 pg/ml, respectively; P < 0.05 for both). Accordingly, the mean +/- SEM PGE(2):LTB(4) ratio was similar in SSc patients with SLD (0.30 +/- 0.05), SSc patients without SLD (0.29 +/- 0.07), and controls (0.31 +/- 0.07). In contrast, levels of 15-HETE and LXA(4) in patients with SLD did not differ significantly from levels in patients without SLD or in controls. The ratio of LXA(4):LTB(4) in SLD patients (0.16 +/- 0.03) was significantly lower (P < 0.05) than that in patients without SLD (0.40 +/- 0.10) or controls (0.34 +/- 0.08). CONCLUSION Increased production of LTB(4) in the lungs of patients with SLD is not balanced by an up-regulation of 15-LOX-derived antiinflammatory/antifibrotic eicosanoids such as 15-HETE or LXA(4). Targeting the 5-LOX/15-LOX balance may be of practical value in the treatment of SLD.
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Mangino MJ, Brounts L, Harms B, Heise C. Lipoxin biosynthesis in inflammatory bowel disease. Prostaglandins Other Lipid Mediat 2005; 79:84-92. [PMID: 16516812 DOI: 10.1016/j.prostaglandins.2005.10.004] [Citation(s) in RCA: 82] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2005] [Revised: 10/28/2005] [Accepted: 10/28/2005] [Indexed: 12/24/2022]
Abstract
BACKGROUND AND AIMS Lipoxins are anti-inflammatory lipid mediators that are produced in gut mucosa, which serve to limit and resolve persistent inflammation. The purpose of this study was to evaluate colonic lipoxin biosynthesis in patients with ulcerative colitis (UC) to establish a possible biochemical basis for persistent inflammation in UC. METHODS Colonic mucosa from patients with UC or organ donors (controls) was placed into tissue culture for 90 min. The conditioned media was assayed (ELISA) for lipoxin A4 (LXA) and the biologically active isomer 15-epi-LXA4 (aspirin triggered lipoxin, ATL). Mucosal tissue 15-lipoxygenase protein was determined by Western blot. RESULTS Patient colonic mucosa produced significantly lower (12-fold) amounts of LXA, relative to organ donors. This occurred irregardless of patient steroid treatment. However, patient tissue responded to in vitro aspirin by synthesizing biologically active ATL. For the first time, human colonic mucosa was found to synthesize 15-lipoxygenase-2, an epithelial-derived isoenzyme used for lipoxin synthesis. These levels were significantly lower in UC patients compared to the control tissue. Finally, mice chronically treated with a putative selective 15-lipoxygenase inhibitor (PD 146176) experienced significantly worse intestinal function during experimental colitis, relative to untreated mice. CONCLUSION Colonic mucosa from UC patients demonstrated defective lipoxin biosynthesis, which may contribute to the inability of these patients to resolve persistent colonic inflammation.
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Affiliation(s)
- Martin J Mangino
- Department of Surgery, University of Wisconsin Medical School, 600 Highland Avenue, Madison, WI 53792, USA.
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Rodgers K, McMahon B, Mitchell D, Sadlier D, Godson C. Lipoxin A4 modifies platelet-derived growth factor-induced pro-fibrotic gene expression in human renal mesangial cells. THE AMERICAN JOURNAL OF PATHOLOGY 2005; 167:683-94. [PMID: 16127149 PMCID: PMC1698722 DOI: 10.1016/s0002-9440(10)62043-3] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Lipoxins (LXs), endogenously produced eicosanoids, possess potent anti-inflammatory, pro-resolution bioactivities. We investigated the potential of LXA(4) (1 to 10 nmol/L) to modify the effects of platelet-derived growth factor (PDGF)-induced gene expression in human renal mesangial cells (hMCs). Using oligonucleotide microarray analysis we profiled pro-fibrotic cytokines and matrix-associated genes induced in response to PDGF. LXA(4) modulated the expression of many PDGF-induced genes, including transforming growth factor-beta1, fibronectin, thrombospondin, matrix metalloproteinase 1, and several collagens. Analysis of both transcript and protein levels confirmed these findings. Because the activated glomerulus is frequently a source of injurious mediators that contribute to tubulointerstitial damage, we investigated the effect of hMC-secreted products on the integrity of renal proximal tubular epithelial cells using an in vitro model of progressive renal disease. Cell supernatant from PDGF-stimulated hMCs caused morphological and genetic changes in proximal tubular epithelial cells, consistent with a pro-fibrotic phenotype. Interestingly, supernatant from cells pre-exposed to LXA(4) and PDGF did not induce these effects. These results suggest a novel role for LXA(4) as a potent modulator of matrix accumulation and pro-fibrotic change and suggest a potential protective role in progressive renal disease.
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Affiliation(s)
- Karen Rodgers
- Department of Medicine and Therapeutics, The Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland
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Abstract
Endothelial cells are key regulators of the inflammatory response. Lining blood vessels, they provide in the steady state an antiinflammatory, anticoagulatory surface. However, in the case of injury or infection, endothelial cells control the adhesion and migration of inflammatory cells, as well as the exchange of fluid from the bloodstream into the damaged tissue. Thus, expression of endothelial adhesion molecules, cytokines, and changes in permeability need to be tightly regulated to allow for a controlled inflammatory response. Acute inflammation is characterized by tissue infiltration of neutrophils, followed by monocytes/macrophages. For successful tissue regeneration and healing, the acute inflammatory response needs to be actively shut down, a process called resolution of inflammation. Unsuccessful resolution may lead to excessive tissue damage and ultimately results in chronic, self-promoting inflammation. This review will summarize recent advances in the field of endothelial biology, which point to an active participation of the endothelial barrier in the resolving process.
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Affiliation(s)
- Alexandra Kadl
- Cardiovascular Research Center and Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA
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40
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Fiore S, Antico G, Aloman M, Sodin-Semrl S. Lipoxin A4 biology in the human synovium. Role of the ALX signaling pathways in modulation of inflammatory arthritis. Prostaglandins Leukot Essent Fatty Acids 2005; 73:189-96. [PMID: 16125377 DOI: 10.1016/j.plefa.2005.05.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- S Fiore
- Section of Rheumatology, Department of Medicine, COM, University of Illinois, Chicago, IL 60607, USA
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Schmelzer KR, Kubala L, Newman JW, Kim IH, Eiserich JP, Hammock BD. Soluble epoxide hydrolase is a therapeutic target for acute inflammation. Proc Natl Acad Sci U S A 2005; 102:9772-7. [PMID: 15994227 PMCID: PMC1168955 DOI: 10.1073/pnas.0503279102] [Citation(s) in RCA: 378] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
As of 2004, >73 million people were prescribed antiinflammatory medication. Despite the extensive number of current products, many people still suffer from their diseases or the pharmacological properties (side effects) of the medications. Therefore, developing therapeutic strategies to treat inflammation remains an important endeavor. Here, we demonstrate that the soluble epoxide hydrolase (sEH) is a key pharmacologic target for treating acute systemic inflammation. Lipopolysaccharide-induced mortality, systemic hypotension, and histologically evaluated tissue injury were substantially diminished by administration of urea-based, small-molecule inhibitors of sEH to C57BL/6 mice. Moreover, sEH inhibitors decreased plasma levels of proinflammatory cytokines and nitric oxide metabolites while promoting the formation of lipoxins, thus supporting inflammatory resolution. These data suggest that sEH inhibitors have therapeutic efficacy in the treatment and management of acute inflammatory diseases.
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Affiliation(s)
- Kara R Schmelzer
- Department of Entomology, University of California-Davis, One Shields Avenue, Davis, CA 95616, USA
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Liang X, Wu L, Hand T, Andreasson K. Prostaglandin D2 mediates neuronal protection via the DP1 receptor. J Neurochem 2005; 92:477-86. [PMID: 15659218 DOI: 10.1111/j.1471-4159.2004.02870.x] [Citation(s) in RCA: 135] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Cyclo-oxygenases (COXs) catalyze the first committed step in the synthesis of the prostaglandins PGE(2), PGD(2), PGF(2alpha), PGI(2) and thomboxane A(2). Expression and enzymatic activity of COX-2, the inducible isoform of COX, are observed in several neurological diseases and result in significant neuronal injury. The neurotoxic effect of COX-2 is believed to occur through downstream effects of its prostaglandin products. In this study, we examined the function of PGD(2) and its two receptors DP1 and chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) (DP2) in neuronal survival. PGD(2) is the most abundant prostaglandin in brain and regulates sleep, temperature and nociception. It signals through two distinct G protein-coupled receptors, DP1 and DP2, that have opposing effects on cyclic AMP (cAMP) production. Physiological concentrations of PGD(2) potently and unexpectedly rescued neurons in paradigms of glutamate toxicity in cultured hippocampal neurons and organotypic slices. This effect was mimicked by the DP1-selective agonist BW245C but not by the PGD(2) metabolite 15d-PGJ(2), suggesting that neuroprotection was mediated by the DP1 receptor. Conversely, activation of the DP2 receptor promoted neuronal loss. The protein kinase A inhibitors H89 and KT5720 reversed the protective effect of PGD(2), indicating that PGD(2)-mediated neuroprotection was dependent on cAMP signaling. These studies indicate that activation of the PGD(2) DP1 receptor protects against excitotoxic injury in a cAMP-dependent manner, consistent with recent studies of PGE(2) receptors that also suggest a neuroprotective effect of prostaglandin receptors. Taken together, these data support an emerging and paradoxical neuroprotective role of prostaglandins in the CNS.
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Affiliation(s)
- Xibin Liang
- Department of Neurology, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21205, USA
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Abstract
The inflammatory response protects the body against infection and injury but can itself become deregulated with deleterious consequences to the host. It is now clear that several endogenous biochemical pathways activated during defense reactions can counterregulate inflammation. New experimental evidence adds resolvin E1 to this group of endogenous inhibitors and provides further rationale for the beneficial effects of dietary supplementation with fish oils. It also highlights an unexpected twist in the pharmacology of aspirin.
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Bonnans C, Chanez P, Chavis C. Lipoxins in asthma: potential therapeutic mediators on bronchial inflammation? Allergy 2004; 59:1027-41. [PMID: 15355460 DOI: 10.1111/j.1398-9995.2004.00617.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Arachidonic acid metabolism represents an important source of mediators with ambivalent actions. Among these, lipoxins (LXs) are the first agents identified and recognized as anti-inflammatory endogenous lipid mediators, which are involved in the resolution of inflammation and are present in the airways of asthmatic patients. Lipoxins result mainly from the interaction between 5 and 15-lipoxygenases (LO) and their levels are modulated by the degree of bronchial inflammation as well as by the long-term glucocorticoid treatments. In the airways, LX synthesis is higher in mild asthmatics than in severe asthmatics, whereas in vitro chemokine release inhibition by LXs is more effective in cells from severe asthmatics than from mild asthmatics. LipoxinA(4) effects on interleukin (IL)-8 released by blood mononuclear cells and on calcium influx in epithelial cells are mediated by the specific receptor ALX. Lipoxin generation by lung epithelial cells depends mainly on 15-LO activity. Mild asthmatics present higher 15-LOb expression at the epithelium level than severe patients, whereas the LX deficit in severe asthma is associated with an up-regulation of the 15-LOa expressions. Therefore, bronchial epithelial cells become a target for therapeutic intervention and LXs represent a potential therapeutic solution for bronchial inflammation resolution in asthma.
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Affiliation(s)
- C Bonnans
- Inserm U454-IFR 3, Clinique des Maladies Respiratoires, CHU de Montpellier, France
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Phillips ED, Chang HF, Holmquist CR, McCauley JP. Synthesis of methyl (5S,6R,7E,9E,11Z,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-7,9,11,13-hexadecatetraenoate, an analogue of 15R-lipoxin A4. Bioorg Med Chem Lett 2003; 13:3223-6. [PMID: 12951097 DOI: 10.1016/s0960-894x(03)00667-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
We describe a method for the synthesis of methyl (5S,6R,7E,9E,11Z,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-7,9,11,13-hexadecatetraenoate, a compound that has been described as a metabolically stable analogue of 15R-lipoxin A(4).
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Affiliation(s)
- Eifion D Phillips
- Department of Chemistry, AstraZeneca R&D Wilmington, 1800 Concord Pike, Wilmington, DE 19850, USA.
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Chiang N, Takano T, Arita M, Watanabe S, Serhan CN. A novel rat lipoxin A4 receptor that is conserved in structure and function. Br J Pharmacol 2003; 139:89-98. [PMID: 12746227 PMCID: PMC1573822 DOI: 10.1038/sj.bjp.0705220] [Citation(s) in RCA: 75] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
1. Lipoxin (LX) A(4) and aspirin-triggered-LX (ATL) are endogenous lipid-derived mediators that regulate leukocyte trafficking via specific LXA(4) receptors (ALX), and are involved in endogenous anti-inflammation and resolution. Both LXA(4) and ATL are produced by rat tissues in vitro as well as in vivo. In rats, LXA(4) and ATL exhibit potent physiological and pathophysiological roles. Thus, we set out to determine whether ALX is expressed in rat tissues and its potential role in modulating leukocyte trafficking with LXA(4) and ATL. 2. In rats, a stable analog of ATL, when given intravenously with two consecutive doses at approximately 60 microg kg(-1) each injection, significantly inhibited neutrophil infiltration (approximately 43%) and protein extravasation (approximately 42%) in a casein-induced peritonitis. 3. The rat orthologue of ALX was cloned from peripheral blood leukocytes encoding a putative G protein-coupled receptor (GPCR). It gave approximately 74 and approximately 84% homology, respectively to the deduced amino-acid sequences of the human and mouse ALX. 4. Tissue distribution analysis by RNase protection revealed that this rat receptor is expressed in tissues/cells, where LXA(4) displays physiological and pathophysiological roles, namely, lung, kidney and leukocytes. 5. The rat orthologue of ALX gave specific radioligand binding with [(3)H]LXA(4) and [(125)-Tyr]-annexin 1-derived peptide with apparent K(d) values of 5 and 820 nM, respectively, that are at levels comparable to those of the human ALX. 6. Activation of rat ALX inhibited tumor necrosis factor alpha-mediated nuclear factor kappaB activity in a ligand-dependent manner utilizing a luciferase reporter gene system. 7. Together, these results are the first demonstration of a rat ALX that is conserved in both structure and function suggesting that ALX plays key roles in regulating effector immune responses from murine to human species.
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Affiliation(s)
- Nan Chiang
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, U.S.A
| | - Tomoko Takano
- Nephrology Research, McGill University, 3775 University Street, Montreal, Quebec, Canada, H3A2B4
| | - Makoto Arita
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, U.S.A
| | - Shiro Watanabe
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, U.S.A
| | - Charles N Serhan
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, U.S.A
- Author for correspondence:
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Devchand PR, Arita M, Hong S, Bannenberg G, Moussignac RL, Gronert K, Serhan CN. Human ALX receptor regulates neutrophil recruitment in transgenic mice: roles in inflammation and host defense. FASEB J 2003; 17:652-9. [PMID: 12665478 DOI: 10.1096/fj.02-0770com] [Citation(s) in RCA: 134] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Signaling pathways instrumental in the temporal and spatial progression of acute inflammation toward resolution are of wide interest. Here a transgenic mouse with myeloid-selective expression of human lipoxin A4 receptor (hALX) was prepared and used to evaluate in vivo the effect of hALX expression. hALX-transfected HEK293 cells transmitted LXA4 signals that inhibit TNFalpha-induced NFkappaB activation. Transgenic FvB mice were generated by DNA injections of a 3.8 kb transgene consisting of the full-length hALX cDNA driven by a fragment of the hCD11b promoter. When topically challenged via dermal ear skin, hALX transgenic mice gave attenuated neutrophil infiltration (approximately 80% reduction) in response to leukotriene B4 (LTB4) plus prostaglandin E2 (PGE2) as well as approximately 50% reduction in PMN infiltrates (P<0.02) to receptor-bypass inflammation evoked by phorbol ester. The hALX transgenic mice gave markedly decreased PMN infiltrates to the peritoneum with zymosan and altered the dynamics of this response. Transgenic hALX mice displayed increased sensitivity with >50% reduction in PMN infiltrates to suboptimal doses (10 ng/mouse) of the ligand lipoxin A4 stable analog compared with <10% reduction of PMN in nontransgenic littermates. Soluble mediators generated within the local inflammatory milieu of hALX mice showed diminished ability to activate the proinflammatory transcription factor NFkappaB. Analyses of the lipid-derived mediators from exudates using LC-MS tandem mass spectroscopy indicated an altered profile in hALX transgenic mice that included lower levels of LTB4 and increased amounts of lipoxin A4 compared with nontransgenic littermates. Together these results demonstrate a gain-of-function with hALX transgenic mouse and indicate that ALX is a key receptor and sensor in formation of acute exudates and their resolution.
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Affiliation(s)
- Pallavi R Devchand
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
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