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Li Y, Chen W, Koo S, Liu H, Saiding Q, Xie A, Kong N, Cao Y, Abdi R, Serhan CN, Tao W. Innate immunity-modulating nanobiomaterials for controlling inflammation resolution. MATTER 2024; 7:3811-3844. [PMID: 40123651 PMCID: PMC11925551 DOI: 10.1016/j.matt.2024.09.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/25/2025]
Abstract
The acute inflammatory response is an inherent protective mechanism, its unsuccessful resolution can contribute to disease pathogenesis and potentially lead to death. Innate immune cells are the first line of host defenders and play a substantial role in inflammation initiation, amplification, resolution, or subsequent disease progression. As the resolution of inflammation is an active and highly regulated process, modulating innate immune cells, including neutrophils, monocytes and macrophages, and endothelial cells, and their interactions offer opportunities to control excessive inflammation. Nanobiomaterials have shown superior therapeutic potential in inflammation-related diseases by manipulating inflammatory responses because nanobiomaterials can target and interact with innate immune cells. Versatile nanobiomaterials can be designed for targeted modulation of specific innate immune responses. Nanopro-resolving medicines have been prepared both with pro-resolving lipid mediators and peptides each demonstrated to active resolution of inflammation in animal disease models. Here, we review innovative nanobiomaterials for modulating innate immunity and alleviating inflammation. We summarise the strategies converging the design of nanobiomaterials and the nano-bio interaction in modulating innate immune profiles and propelling the advancement of nanobiomaterials for inflammatory disease treatments. We also propose the future perspectives and translational challenges of nanobiomaterials that need to be overcome in this swiftly rising field.
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Affiliation(s)
- Yongjiang Li
- Center for Nanomedicine and Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- These authors contributed equally: Yongjiang Li, Wei Chen
| | - Wei Chen
- Center for Nanomedicine and Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- These authors contributed equally: Yongjiang Li, Wei Chen
| | - Seyoung Koo
- Center for Nanomedicine and Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Haijun Liu
- Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Qimanguli Saiding
- Center for Nanomedicine and Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Angel Xie
- Center for Nanomedicine and Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Na Kong
- Center for Nanomedicine and Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Yihai Cao
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm 17177, Sweden
| | - Reza Abdi
- Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Charles N. Serhan
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Wei Tao
- Center for Nanomedicine and Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
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Fredman G, Serhan CN. Specialized pro-resolving mediators in vascular inflammation and atherosclerotic cardiovascular disease. Nat Rev Cardiol 2024; 21:808-823. [PMID: 38216693 DOI: 10.1038/s41569-023-00984-x] [Citation(s) in RCA: 38] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/07/2023] [Indexed: 01/14/2024]
Abstract
Timely resolution of the acute inflammatory response (or inflammation resolution) is an active, highly coordinated process that is essential to optimal health. Inflammation resolution is regulated by specific endogenous signalling molecules that function as 'stop signals' to terminate the inflammatory response when it is no longer needed; to actively promote healing, regeneration and tissue repair; and to limit pain. Specialized pro-resolving mediators are a superfamily of signalling molecules that initiate anti-inflammatory and pro-resolving actions. Without an effective and timely resolution response, inflammation can become chronic, a pathological state that is associated with many widely occurring human diseases, including atherosclerotic cardiovascular disease. Uncovering the mechanisms of inflammation resolution failure in cardiovascular diseases and identifying useful biomarkers for non-resolving inflammation are unmet needs. In this Review, we discuss the accumulating evidence that supports the role of non-resolving inflammation in atherosclerosis and the use of specialized pro-resolving mediators as therapeutic tools for the treatment of atherosclerotic cardiovascular disease. We highlight open questions about therapeutic strategies and mechanisms of disease to provide a framework for future studies on the prevention and treatment of atherosclerosis.
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Affiliation(s)
- Gabrielle Fredman
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA.
| | - Charles N Serhan
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anaesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
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Turner TC, Pittman FS, Zhang H, Hymel LA, Zheng T, Behara M, Anderson SE, Harrer JA, Link KA, Ahammed MA, Maner-Smith K, Liu X, Yin X, Lim HS, Spite M, Qiu P, García AJ, Mortensen LJ, Jang YC, Willett NJ, Botchwey EA. Improving Functional Muscle Regeneration in Volumetric Muscle Loss Injuries by Shifting the Balance of Inflammatory and Pro-Resolving Lipid Mediators. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.06.611741. [PMID: 39314313 PMCID: PMC11418947 DOI: 10.1101/2024.09.06.611741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/25/2024]
Abstract
Severe tissue loss resulting from extremity trauma, such as volumetric muscle loss (VML), poses significant clinical challenges for both general and military populations. VML disrupts the endogenous tissue repair mechanisms, resulting in acute and unresolved chronic inflammation and immune cell presence, impaired muscle healing, scar tissue formation, persistent pain, and permanent functional deficits. The aberrant healing response is preceded by acute inflammation and immune cell infiltration which does not resolve. We analyzed the biosynthesis of inflammatory and specialized pro-resolving lipid mediators (SPMs) after VML injury in two different models; muscle with critical-sized defects had a decreased capacity to biosynthesize SPMs, leading to dysregulated and persistent inflammation. We developed a modular poly(ethylene glycol)-maleimide hydrogel platform to locally release a stable isomer of Resolvin D1 (AT-RvD1) and promote endogenous pathways of inflammation resolution in the two muscle models. The local delivery of AT-RvD1 enhanced muscle regeneration, improved muscle function, and reduced pain sensitivity after VML by promoting molecular and cellular resolution of inflammation. These findings provide new insights into the pathogenesis of VML and establish a pro-resolving hydrogel therapeutic as a promising strategy for promoting functional muscle regeneration after traumatic injury.
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Celik Z, Ozen G, Sunar S, Turkyilmaz S, Turkyilmaz G, Kavala AA, Teskin O, Dogan BSU, Topal G. Effect of specialized pro-resolving lipid mediators in the regulation of vascular tone and inflammation in human saphenous vein. Prostaglandins Other Lipid Mediat 2023; 169:106786. [PMID: 37806440 DOI: 10.1016/j.prostaglandins.2023.106786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 09/23/2023] [Accepted: 10/05/2023] [Indexed: 10/10/2023]
Abstract
Specialized pro-resolving lipid mediators (SPMs), derived from polyunsaturated fatty acids are important mediators in the resolution of inflammation. Recent studies have focused on the effects of SPMs in cardiovascular health and diseases. However, little is known about the effect SPMs on human vascular tone. Therefore, in this study it is aimed to investigate the effect of various SPMs including resolvin D- and E-series, maresin-1 (MaR1) and lipoxin-A4 (LxA4) on the vascular tone of human isolated saphenous vein (SV) preparations under inflammatory conditions. In addition, we aimed to evaluate the effects of SPMs on the release of pro-inflammatory mediators, monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF- α) from human SV. Pretreatment of isolated of human SV with resolvin E1 (RvE1), resolvin D1 (RvD1) and MaR1 (100 nM, 18 h) significantly reduced the contractile responses to thromboxane A2 mimetic, U46619 whereas pretreatment with LxA4 and RvD2 (100 nM, 18 h) had no significant effect on the vascular tone of SV. Moreover, RvE1, RvD1 and MaR1 but not LxA4 and RvD2 (100 nM, 18 h) pretreatment diminished the release of MCP-1 and TNF-α from SV. In conclusion, our findings suggest that pre-treatment with RvE1, RvD1, and MaR1 could have potential benefits in decreasing graft vasospasm and vascular inflammation in SV.
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Affiliation(s)
- Zeynep Celik
- Department of Pharmacology, Istanbul University Faculty of Pharmacy, Istanbul, Turkey; Department of Pharmacology, Istanbul University, Institute of Graduate Studies in Health Sciences, Istanbul, Turkey
| | - Gulsev Ozen
- Department of Pharmacology, Istanbul University Faculty of Pharmacy, Istanbul, Turkey
| | - Seynur Sunar
- Department of Pharmacology, Istanbul University Faculty of Pharmacy, Istanbul, Turkey; Department of Pharmacology, Istanbul University, Institute of Graduate Studies in Health Sciences, Istanbul, Turkey
| | - Saygın Turkyilmaz
- Department of Cardiovascular Surgery, Bakirkoy Dr. Sadi Konuk Education and Research Hospital Bakirkoy, Istanbul, Turkey
| | - Gulsum Turkyilmaz
- Department of Cardiovascular Surgery, Bakirkoy Dr. Sadi Konuk Education and Research Hospital Bakirkoy, Istanbul, Turkey
| | - Ali Aycan Kavala
- Department of Cardiovascular Surgery, Bakirkoy Dr. Sadi Konuk Education and Research Hospital Bakirkoy, Istanbul, Turkey
| | - Onder Teskin
- Department of Cardiovascular Surgery, Biruni University, Istanbul, Turkey
| | - B Sonmez Uydes Dogan
- Department of Pharmacology, Istanbul University Faculty of Pharmacy, Istanbul, Turkey
| | - Gokce Topal
- Department of Pharmacology, Istanbul University Faculty of Pharmacy, Istanbul, Turkey.
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Almogy M, Moses O, Schiffmann N, Weinberg E, Nemcovsky CE, Weinreb M. Addition of Resolvins D1 or E1 to Collagen Membranes Mitigates Their Resorption in Diabetic Rats. J Funct Biomater 2023; 14:jfb14050283. [PMID: 37233393 DOI: 10.3390/jfb14050283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 05/14/2023] [Accepted: 05/16/2023] [Indexed: 05/27/2023] Open
Abstract
Uncontrolled diabetes is characterized by aberrant inflammatory reactions and increased collagenolysis. We have reported that it accelerates the degradation of implanted collagen membranes (CM), thus compromising their function in regenerative procedures. In recent years, a group of physiological anti-inflammatory agents called specialized pro-resolving lipid mediators (SPMs) have been tested as a treatment for various inflammatory conditions, either systemically or locally, via medical devices. Yet, no study has tested their effect on the fate of the biodegradable material itself. Here, we measured the in vitro release over time of 100 or 800 ng resolvin D1 (RvD1) incorporated into CM discs. In vivo, diabetes was induced in rats with streptozotocin, while buffer-injected (normoglycemic) rats served as controls. Resolvins (100 or 800 ng of RvD1 or RvE1) were added to biotin-labeled CM discs, which were implanted sub-periosteally over the calvaria of rats. Membrane thickness, density, and uniformity were determined by quantitative histology after 3 weeks. In vitro, significant amounts of RvD1 were released over 1-8 days, depending on the amount loaded. In vivo, CMs from diabetic animals were thinner, more porous, and more variable in thickness and density. The addition of RvD1 or RvE1 improved their regularity, increased their density, and reduced their invasion by the host tissue significantly. We conclude that addition of resolvins to biodegradable medical devices can protect them from excessive degradation in systemic conditions characterized by high degree of collagenolysis.
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Affiliation(s)
- Michal Almogy
- Department of Oral Biology, The Maurice and Gabriela Goldschleger School of Dental Medicine, Tel-Aviv University, Tel Aviv-Yafo 6997801, Israel
- Department of Periodontology and Implant Dentistry, The Maurice and Gabriela Goldschleger School of Dental Medicine, Tel-Aviv University, Tel Aviv-Yafo 6997801, Israel
| | - Ofer Moses
- Department of Periodontology and Implant Dentistry, The Maurice and Gabriela Goldschleger School of Dental Medicine, Tel-Aviv University, Tel Aviv-Yafo 6997801, Israel
| | - Nathan Schiffmann
- Department of Oral Biology, The Maurice and Gabriela Goldschleger School of Dental Medicine, Tel-Aviv University, Tel Aviv-Yafo 6997801, Israel
| | - Evgeny Weinberg
- Department of Oral Biology, The Maurice and Gabriela Goldschleger School of Dental Medicine, Tel-Aviv University, Tel Aviv-Yafo 6997801, Israel
- Department of Periodontology and Implant Dentistry, The Maurice and Gabriela Goldschleger School of Dental Medicine, Tel-Aviv University, Tel Aviv-Yafo 6997801, Israel
| | - Carlos E Nemcovsky
- Department of Periodontology and Implant Dentistry, The Maurice and Gabriela Goldschleger School of Dental Medicine, Tel-Aviv University, Tel Aviv-Yafo 6997801, Israel
| | - Miron Weinreb
- Department of Oral Biology, The Maurice and Gabriela Goldschleger School of Dental Medicine, Tel-Aviv University, Tel Aviv-Yafo 6997801, Israel
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Applewhite B, Gupta A, Wei Y, Yang X, Martinez L, Rojas MG, Andreopoulos F, Vazquez-Padron RI. Periadventitial β-aminopropionitrile-loaded nanofibers reduce fibrosis and improve arteriovenous fistula remodeling in rats. Front Cardiovasc Med 2023; 10:1124106. [PMID: 36926045 PMCID: PMC10011136 DOI: 10.3389/fcvm.2023.1124106] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 02/07/2023] [Indexed: 03/04/2023] Open
Abstract
Background Arteriovenous fistula (AVF) postoperative stenosis is a persistent healthcare problem for hemodialysis patients. We have previously demonstrated that fibrotic remodeling contributes to AVF non-maturation and lysyl oxidase (LOX) is upregulated in failed AVFs compared to matured. Herein, we developed a nanofiber scaffold for the periadventitial delivery of β-aminopropionitrile (BAPN) to determine whether unidirectional periadventitial LOX inhibition is a suitable strategy to promote adaptive AVF remodeling in a rat model of AVF remodeling. Methods Bilayer poly (lactic acid) ([PLA)-]- poly (lactic-co-glycolic acid) ([PLGA)] scaffolds were fabricated with using a two-step electrospinning process to confer directionality. BAPN-loaded and vehicle control scaffolds were wrapped around the venous limb of a rat femoral-epigastric AVF during surgery. AVF patency and lumen diameter were followed monitored using Doppler ultrasound surveillance and flow was measured before euthanasia. AVFs were harvested after 21 days for histomorphometry and immunohistochemistry. AVF compliance was measured using pressure myography. RNA from AVF veins was sequenced to analyze changes in gene expression due to LOX inhibition. Results Bilayer periadventitial nanofiber scaffolds extended BAPN release compared to the monolayer design (p < 0.005) and only released BAPN in one direction. Periadventitial LOX inhibition led to significant increases in AVF dilation and flow after 21 days. Histologically, BAPN trended toward increased lumen and significantly reduced fibrosis compared to control scaffolds (p < 0.01). Periadventitial BAPN reduced downregulated markers associated with myofibroblast differentiation including SMA, FSP-1, LOX, and TGF-β while increasing the contractile marker MYH11. RNA sequencing revealed differential expression of matrisome genes. Conclusion Periadventitial BAPN treatment reduces fibrosis and promotes AVF compliance. Interestingly, the inhibition of LOX leads to increased accumulation of contractile VSMC while reducing myofibroblast-like cells. Periadventitial LOX inhibition alters the matrisome to improve AVF vascular remodeling.
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Affiliation(s)
- Brandon Applewhite
- Department of Biomedical Engineering, University of Miami, Coral Gables, FL, United States
| | - Aavni Gupta
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Yuntao Wei
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Xiaofeng Yang
- Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Laisel Martinez
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Miguel G. Rojas
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Fotios Andreopoulos
- Department of Biomedical Engineering, University of Miami, Coral Gables, FL, United States
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, United States
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Spite M, Fredman G. Insights into the role of the resolvin D2-GPR18 signaling axis in cardiovascular physiology and disease. ADVANCES IN PHARMACOLOGY 2023; 97:257-281. [DOI: 10.1016/bs.apha.2022.12.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
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Tackling inflammation in atherosclerosis: Are we there yet and what lies beyond? Curr Opin Pharmacol 2022; 66:102283. [PMID: 36037627 DOI: 10.1016/j.coph.2022.102283] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 06/21/2022] [Accepted: 07/19/2022] [Indexed: 02/06/2023]
Abstract
Atherosclerosis is a lipid-driven disease of the artery characterized by chronic non-resolving inflammation. Despite availability of excellent lipid-lowering therapies, atherosclerosis remains the leading cause of disability and death globally. The demonstration that suppressing inflammation prevents the adverse clinical manifestations of atherosclerosis in recent clinical trials has led to heightened interest in anti-inflammatory therapies. In this review, we briefly highlight some key anti-inflammatory and pro-resolution pathways, which could be targeted to modulate pathogenesis and stall atherosclerosis progression. We also highlight key challenges that must be overcome to turn the concept of inflammation targeting therapies into clinical reality for atherosclerotic heart disease.
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Resolution of Inflammation after Skeletal Muscle Ischemia-Reperfusion Injury: A Focus on the Lipid Mediators Lipoxins, Resolvins, Protectins and Maresins. Antioxidants (Basel) 2022; 11:antiox11061213. [PMID: 35740110 PMCID: PMC9220296 DOI: 10.3390/antiox11061213] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 06/07/2022] [Accepted: 06/15/2022] [Indexed: 02/01/2023] Open
Abstract
Skeletal muscle ischemia reperfusion is very frequent in humans and results not only in muscle destruction but also in multi-organ failure and death via systemic effects related to inflammation and oxidative stress. In addition to overabundance of pro-inflammatory stimuli, excessive and uncontrolled inflammation can also result from defects in resolution signaling. Importantly, the resolution of inflammation is an active process also based on specific lipid mediators including lipoxins, resolvins and maresins that orchestrate the potential return to tissue homeostasis. Thus, lipid mediators have received growing attention since they dampen deleterious effects related to ischemia–reperfusion. For instance, the treatment of skeletal muscles with resolvins prior to ischemia decreases polymorphonuclear leukocyte (PMN) infiltration. Additionally, remote alterations in lungs or kidneys are reduced when enhancing lipid mediators’ functions. Accordingly, lipoxins prevented oxidative-stress-mediated tissue injuries, macrophage polarization was modified and in mice lacking DRV2 receptors, ischemia/reperfusion resulted in excessive leukocyte accumulation. In this review, we first aimed to describe the inflammatory response during ischemia and reperfusion in skeletal muscle and then discuss recent discoveries in resolution pathways. We focused on the role of specialized pro-resolving mediators (SPMs) derived from polyunsaturated fatty acids (PUFAs) and their potential therapeutic applications.
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Kim AS, Werlin EC, Kagaya H, Chen M, Wu B, Mottola G, Jan M, Conte MS. 17R/S-Benzo-RvD1, a synthetic resolvin D1 analogue, attenuates neointimal hyperplasia in a rat model of acute vascular injury. PLoS One 2022; 17:e0264217. [PMID: 35226675 PMCID: PMC8884511 DOI: 10.1371/journal.pone.0264217] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 02/05/2022] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND Persistent inflammation following vascular injury drives neointimal hyperplasia (NIH). Specialized lipid mediators (SPM) mediate resolution which attenuates inflammation and downstream NIH. We investigated the effects of a synthetic analogue of resolvin D1 (RvD1) on vascular cells and in a model of rat carotid angioplasty. METHODS Human venous VSMC and endothelial cells (EC) were employed in migration, cell shape, toxicity, proliferation and p65 nuclear translocation assays. Murine RAW 264.7 cells were utilized to test the effect of pro-resolving compounds on phagocytic activity. A model of rat carotid angioplasty was used to evaluate the effects of 17R/S-benzo-RvD1 (benzo-RvD1) and 17R-RvD1 applied to the adventitia via 25% Pluronic gel. Immunostaining was utilized to examine Ki67 expression and leukocyte recruitment. Morphometric analysis was performed on arteries harvested 14 days after injury. RESULTS Exposure to benzo-RvD1 attenuated PDGF- stimulated VSMC migration across a range of concentrations (0.1-100 nM), similar to that observed with 17R-RvD1. Pre-treatment with either Benzo-RvD1 or 17R-RvD1 (10, 100nM) attenuated PDGF-BB-induced VSMC cytoskeletal changes to nearly baseline dimensions. Benzo-RvD1 demonstrated modest anti-proliferative activity on VSMC and EC at various concentrations, without significant cytotoxicity. Benzo-RvD1 (10nM) inhibited p65 nuclear translocation in cytokine-stimulated EC by 21% (p<0.05), similar to 17R-RvD1. Consistent with pro-resolving activities of other SPM, both 17R-RvD1 and benzo-RvD1 increased the phagocytic activity of RAW 264.7 cells against S. Aureus and Zymosan particles. There were no significant differences in Ki-67 or CD45 staining observed on day 3 after angioplasty. Periadventitial treatment with benzo-RvD1 reduced carotid neointimal area at 14 days compared to control (0.08 mm2 v. 0.18 mm2; p<0.05), with similar efficacy to 17R-RvD1. CONCLUSIONS 17R/S-benzo-RvD1 and 17R-RvD1 exhibit similar pro-resolving and anti-migratory activity in cell-based assays, and both compounds attenuated NIH following acute arterial injury in rats. Further studies of the mechanisms of resolution following vascular injury, and the translational potential of SPM analogues, are indicated.
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Affiliation(s)
- Alexander S. Kim
- Department of Surgery and Cardiovascular Research Institute, UCSF, San Francisco, California, United States of America
| | - Evan C. Werlin
- Department of Surgery and Cardiovascular Research Institute, UCSF, San Francisco, California, United States of America
| | - Hideo Kagaya
- Department of Surgery and Cardiovascular Research Institute, UCSF, San Francisco, California, United States of America
| | - Mian Chen
- Department of Surgery and Cardiovascular Research Institute, UCSF, San Francisco, California, United States of America
| | - Bian Wu
- Department of Surgery and Cardiovascular Research Institute, UCSF, San Francisco, California, United States of America
| | - Giorgio Mottola
- Department of Surgery and Cardiovascular Research Institute, UCSF, San Francisco, California, United States of America
| | - Masood Jan
- Department of Surgery and Cardiovascular Research Institute, UCSF, San Francisco, California, United States of America
| | - Michael S. Conte
- Department of Surgery and Cardiovascular Research Institute, UCSF, San Francisco, California, United States of America
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Okeyo PO, Rajendran ST, Zór K, Boisen A. Sensing technologies and experimental platforms for the characterization of advanced oral drug delivery systems. Adv Drug Deliv Rev 2021; 176:113850. [PMID: 34182015 DOI: 10.1016/j.addr.2021.113850] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 06/17/2021] [Accepted: 06/22/2021] [Indexed: 12/18/2022]
Abstract
Complex and miniaturized oral drug delivery systems are being developed rapidly for targeted, controlled drug release and improved bioavailability. Standard analytical techniques are widely used to characterize i) drug carrier and active pharmaceutical ingredients before loading into a delivery device (to ensure the solid form), and ii) the entire drug delivery system during the development process. However, in light of the complexity and the size of some of these systems, standard techniques as well as novel sensing technologies and experimental platforms need to be used in tandem. These technologies and platforms are discussed in this review, with a special focus on passive delivery systems in size range from a few 100 µm to a few mm. Challenges associated with characterizing these systems and evaluating their effect on oral drug delivery in the preclinical phase are also discussed.
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Briottet M, Shum M, Urbach V. The Role of Specialized Pro-Resolving Mediators in Cystic Fibrosis Airways Disease. Front Pharmacol 2020; 11:1290. [PMID: 32982730 PMCID: PMC7493015 DOI: 10.3389/fphar.2020.01290] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 08/04/2020] [Indexed: 12/26/2022] Open
Abstract
Cystic Fibrosis (CF) is a recessive genetic disease due to mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene encoding the CFTR chloride channel. The ion transport abnormalities related to CFTR mutation generate a dehydrated airway surface liquid (ASL) layer, which is responsible for an altered mucociliary clearance, favors infections and persistent inflammation that lead to progressive lung destruction and respiratory failure. The inflammatory response is normally followed by an active resolution phase to return to tissue homeostasis, which involves specialized pro-resolving mediators (SPMs). SPMs promote resolution of inflammation, clearance of microbes, tissue regeneration and reduce pain, but do not evoke unwanted immunosuppression. The airways of CF patients showed a decreased production of SPMs even in the absence of pathogens. SPMs levels in the airway correlated with CF patients' lung function. The prognosis for CF has greatly improved but there remains a critical need for more effective treatments that prevent excessive inflammation, lung damage, and declining pulmonary function for all CF patients. This review aims to highlight the recent understanding of CF airway inflammation and the possible impact of SPMs on functions that are altered in CF airways.
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Affiliation(s)
| | | | - Valerie Urbach
- Institut national de la santé et de la recherche médicale (Inserm) U955, Institut Mondor de Recherche Biomédicale (IMRB), Créteil, France
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Specialized pro-resolving mediators in diabetes: novel therapeutic strategies. Clin Sci (Lond) 2019; 133:2121-2141. [DOI: 10.1042/cs20190067] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 10/07/2019] [Accepted: 10/08/2019] [Indexed: 02/07/2023]
Abstract
AbstractDiabetes mellitus (DM) is an important metabolic disorder characterized by persistent hyperglycemia resulting from inadequate production and secretion of insulin, impaired insulin action, or a combination of both. Genetic disorders and insulin receptor disorders, environmental factors, lifestyle choices and toxins are key factors that contribute to DM. While it is often referred to as a metabolic disorder, modern lifestyle choices and nutrient excess induce a state of systemic chronic inflammation that results in the increased production and secretion of inflammatory cytokines that contribute to DM. It is chronic hyperglycemia and the low-grade chronic-inflammation that underlies the development of microvascular and macrovascular complications leading to damage in a number of tissues and organs, including eyes, vasculature, heart, nerves, and kidneys. Improvements in the management of risk factors have been beneficial, including focus on intensified glycemic control, but most current approaches only slow disease progression. Even with recent studies employing SGLT2 inhibitors demonstrating protection against cardiovascular and kidney diseases, kidney function continues to decline in people with established diabetic kidney disease (DKD). Despite the many advances and a greatly improved understanding of the pathobiology of diabetes and its complications, there remains a major unmet need for more effective therapeutics to prevent and reverse the chronic complications of diabetes. More recently, there has been growing interest in the use of specialised pro-resolving mediators (SPMs) as an exciting therapeutic strategy to target diabetes and the chronic complications of diabetes.
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Preparation of fibrin hydrogels to promote the recruitment of anti-inflammatory macrophages. Acta Biomater 2019; 89:152-165. [PMID: 30862554 DOI: 10.1016/j.actbio.2019.03.011] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 02/25/2019] [Accepted: 03/06/2019] [Indexed: 12/31/2022]
Abstract
Macrophages play an important role in regulating inflammation and tissue regeneration. In the present study, uniform fibrin hydrogel scaffolds were engineered in millimeters. These scaffolds induced anti-inflammatory macrophages to digest and infiltrate the scaffold. The culture conditions of the fibrin hydrogels decreased the secretion of tumor necrosis factor-α (TNF-α), a pro-inflammatory cytokine, and increased the secretion of interleukin-10 (IL-10), an anti-inflammatory cytokine, in mouse bone marrow-derived macrophages. Similar results were also observed in human monocyte-derived macrophages (HMDMs). In addition, most of cells that infiltrated the fibrin hydrogels were macrophages expressing CD163, CD204, and CD206, which are anti-inflammatory macrophages markers, both in mice and in human cells. Therefore, to induce increased macrophage infiltration, we attempted to combine fibrin hydrogels with SEW2871, a monocyte/macrophage recruitment agent that is known to be a sphingosine-1 phosphate receptor 1 agonist, solubilized in water by micelle formation with a cholesterol-grafted gelatin. However, the fibrin hydrogels alone retained the same monocyte migration activity as the hydrogels with SEW2871-incorporated micelles in the hydrogel-bearing mouse model. These findings indicate that fibrin hydrogels have a strong promoting effect on the recruitment of anti-inflammatory macrophages. Therefore, fibrin hydrogels may be an optimal biomaterial in the design of medicines for macrophage-induced regenerative therapies. STATEMENT OF SIGNIFICANCE: The immune response to tissue injury is important for determining the speed and the result of the regeneration. Alternatively activated macrophages (M2 macrophages) resolve inflammatory response and promote tissue repair by producing anti-inflammatory factors. Promoting the recruitment of macrophages is a hopeful strategy in the design of biomaterials for tissue regeneration. In the present study, we combined the fibrin hydrogel, which promotes anti-inflammatory polarization, with a macrophage recruitment agent. We revealed that the fibrin hydrogel significantly promoted anti-inflammatory polarization in mouse in vivo and human in vitro. Moreover, macrophages significantly infiltrated into the fibrin hydrogel regardless of the agent combination. Fibrin hydrogels may become a reliable biomaterial for tissue regeneration, and the present study is believed to provide information for many researchers.
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15
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Fredman G. Can Inflammation-Resolution Provide Clues to Treat Patients According to Their Plaque Phenotype? Front Pharmacol 2019; 10:205. [PMID: 30899222 PMCID: PMC6416173 DOI: 10.3389/fphar.2019.00205] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Accepted: 02/18/2019] [Indexed: 12/28/2022] Open
Abstract
Inflammation-resolution is an active process that is governed in part by specialized pro-resolving mediators (SPMs) such as lipoxins, resolvins, protectins, and maresins. SPMs, which are endogenously biosynthesized, quell inflammation and repair tissue damage in a manner that does not compromise host defense. Importantly, failed inflammation-resolution is an important driving force in the progression of several prevalent diseases including atherosclerosis. Atherosclerosis is a leading cause of death worldwide and uncovering mechanisms that underpin defective inflammation-resolution and whether SPMs themselves can revert the progression of the disease are of utmost clinical interest. Because atherosclerosis is a disease in which low-grade persistent inflammation results in tissue injury, SPMs have garnered immense interest as a potential treatment strategy. This mini review will highlight recent work that describes mechanisms associated with defective inflammation-resolution in atherosclerosis, as well as the protective actions of SPMs and their potential use as a therapeutic.
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Affiliation(s)
- Gabrielle Fredman
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, United States
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16
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Wu B, Werlin EC, Chen M, Mottola G, Chatterjee A, Lance KD, Bernards DA, Sansbury BE, Spite M, Desai TA, Conte MS. Perivascular delivery of resolvin D1 inhibits neointimal hyperplasia in a rabbit vein graft model. J Vasc Surg 2018; 68:188S-200S.e4. [PMID: 30064835 PMCID: PMC6252159 DOI: 10.1016/j.jvs.2018.05.206] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Accepted: 05/15/2018] [Indexed: 12/31/2022]
Abstract
OBJECTIVE Inflammation is a key driver of excessive neointimal hyperplasia within vein grafts. Recent work demonstrates that specialized proresolving lipid mediators biosynthesized from omega-3 polyunsaturated fatty acids, such as resolvin D1 (RvD1), actively orchestrate the process of inflammation resolution. We investigated the effects of local perivascular delivery of RvD1 in a rabbit vein graft model. METHODS Ipsilateral jugular veins were implanted as carotid interposition grafts through an anastomotic cuff technique in New Zealand white rabbits (3-4 kg; N = 80). RvD1 (1 μg) was delivered to the vein bypass grafts in a perivascular fashion, using either 25% Pluronic F127 gel (Sigma-Aldrich, St. Louis, Mo) or a thin bilayered poly(lactic-co-glycolic acid) (PLGA) film. No treatment (bypass only) and vehicle-loaded Pluronic gels or PLGA films served as controls. Delivery of RvD1 to venous tissue was evaluated 3 days later by liquid chromatography-tandem mass spectrometry. Total leukocyte infiltration, macrophage infiltration, and cell proliferation were evaluated by immunohistochemistry. Elastin and trichrome staining was performed on grafts harvested at 28 days after bypass to evaluate neointimal hyperplasia and vein graft remodeling. RESULTS Perivascular treatments did not influence rates of graft thrombosis (23%), major wound complications (4%), or death (3%). Leukocyte (CD45) and macrophage (RAM11) infiltration was significantly reduced in the RvD1 treatment groups vs controls at 3 days (60%-72% reduction; P < .01). Cellular proliferation (Ki67 index) was also significantly lower in RvD1-treated vs control grafts at 3 days (40%-50% reduction; P < .01). Treatment of vein grafts with RvD1-loaded gels reduced neointimal thickness at 28 days by 61% vs bypass only (P < .001) and by 63% vs vehicle gel (P < .001). RvD1-loaded PLGA films reduced neointimal formation at 28 days by 50% vs bypass only (P < .001). RvD1 treatment was also associated with reduced collagen deposition in vein grafts at 28 days. CONCLUSIONS Local perivascular delivery of RvD1 attenuates vein graft hyperplasia without associated toxicity in a rabbit carotid bypass model. This effect appears to be mediated by both reduced leukocyte recruitment and decreased cell proliferation within the graft. Perivascular PLGA films may also impart protection through biomechanical scaffolding in this venous arterialization model. Our studies provide further support for the potential therapeutic role of specialized proresolving lipid mediators such as D-series resolvins in modulating vascular injury and repair.
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Affiliation(s)
- Bian Wu
- Department of Surgery and Cardiovascular Research Institute, University of California, San Francisco, Calif
| | - Evan C Werlin
- Department of Surgery and Cardiovascular Research Institute, University of California, San Francisco, Calif
| | - Mian Chen
- Department of Surgery and Cardiovascular Research Institute, University of California, San Francisco, Calif
| | - Giorgio Mottola
- Department of Surgery and Cardiovascular Research Institute, University of California, San Francisco, Calif
| | - Anuran Chatterjee
- Department of Surgery and Cardiovascular Research Institute, University of California, San Francisco, Calif
| | - Kevin D Lance
- Department of Bioengineering, University of California, San Francisco, Calif
| | - Daniel A Bernards
- Department of Bioengineering, University of California, San Francisco, Calif
| | - Brian E Sansbury
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass
| | - Matthew Spite
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass
| | - Tejal A Desai
- Department of Bioengineering, University of California, San Francisco, Calif
| | - Michael S Conte
- Department of Surgery and Cardiovascular Research Institute, University of California, San Francisco, Calif.
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17
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Conte MS, Desai TA, Wu B, Schaller M, Werlin E. Pro-resolving lipid mediators in vascular disease. J Clin Invest 2018; 128:3727-3735. [PMID: 30168805 PMCID: PMC6118638 DOI: 10.1172/jci97947] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Unresolved inflammation is central to the pathophysiology of commonly occurring vascular diseases such as atherosclerosis, aneurysm, and deep vein thrombosis - conditions that are responsible for considerable morbidity and mortality. Surgical or catheter-based procedures performed on affected blood vessels induce acute-on-chronic inflammatory responses. The resolution of vascular inflammation is an important driver of vessel wall remodeling and functional recovery in these clinical settings. Specialized pro-resolving lipid mediators (SPMs) derived from omega-3 polyunsaturated fatty acids orchestrate key cellular processes driving resolution and a return to homeostasis. The identification of their potent effects in classic animal models of sterile inflammation triggered interest in their vascular properties. Recent studies have demonstrated that SPMs are locally synthesized in vascular tissues, have direct effects on vascular cells and their interactions with leukocytes, and play a protective role in the injury response. Early translational work has established the potential for SPMs as vascular therapeutics, and as candidate biomarkers in vascular disease. Further investigations are needed to understand the molecular and cellular mechanisms of resolution in the vasculature, to improve tools for clinical measurement, and to better define the potential for "resolution therapeutics" in vascular patients.
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Affiliation(s)
- Michael S. Conte
- Division of Vascular and Endovascular Surgery, Department of Surgery, and Cardiovascular Research Institute, UCSF, San Francisco, California, USA
| | - Tejal A. Desai
- Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, California, USA
| | - Bian Wu
- Division of Vascular and Endovascular Surgery, Department of Surgery, and Cardiovascular Research Institute, UCSF, San Francisco, California, USA
| | - Melinda Schaller
- Division of Vascular and Endovascular Surgery, Department of Surgery, and Cardiovascular Research Institute, UCSF, San Francisco, California, USA
| | - Evan Werlin
- Division of Vascular and Endovascular Surgery, Department of Surgery, and Cardiovascular Research Institute, UCSF, San Francisco, California, USA
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18
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Serhan CN, Levy BD. Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators. J Clin Invest 2018; 128:2657-2669. [PMID: 29757195 DOI: 10.1172/jci97943] [Citation(s) in RCA: 913] [Impact Index Per Article: 130.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Countless times each day, the acute inflammatory response protects us from invading microbes, injuries, and insults from within, as in surgery-induced tissue injury. These challenges go unnoticed because they are self-limited and naturally resolve without progressing to chronic inflammation. Peripheral blood markers of inflammation are present in many common diseases, including inflammatory bowel disease, cardiovascular disease, neurodegenerative disease, and cancer. While acute inflammation is protective, excessive swarming of neutrophils amplifies collateral tissue damage and inflammation. Hence, understanding the mechanisms that control the resolution of acute inflammation provides insight into preventing and treating inflammatory diseases in multiple organs. This Review focuses on the resolution phase of inflammation with identification of specialized pro-resolving mediators (SPMs) that involve three separate biosynthetic and potent mediator families, which are defined using the first quantitative resolution indices to score this vital process. These are the resolvins, protectins, and maresins: bioactive metabolomes that each stimulate self-limited innate responses, enhance innate microbial killing and clearance, and are organ-protective. We briefly address biosynthesis of SPMs and their activation of endogenous resolution programs as terrain for new therapeutic approaches that are not, by definition, immunosuppressive, but rather new immunoresolvent therapies.
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Affiliation(s)
- Charles N Serhan
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, and
| | - Bruce D Levy
- Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
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19
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Fredman G, Tabas I. Boosting Inflammation Resolution in Atherosclerosis: The Next Frontier for Therapy. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 187:1211-1221. [PMID: 28527709 DOI: 10.1016/j.ajpath.2017.01.018] [Citation(s) in RCA: 138] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Accepted: 01/30/2017] [Indexed: 02/08/2023]
Abstract
Defective inflammation resolution is the underlying cause of prevalent chronic inflammatory diseases, such as arthritis, asthma, cancer, and neurodegenerative and cardiovascular diseases. Inflammation resolution is governed by several endogenous factors, including fatty acid-derived specialized proresolving mediators and proteins, such as annexin A1. Specifically, specialized proresolving mediators comprise a family of mediators that include arachidonic acid-derived lipoxins, omega-3 fatty acid eicosapentaenoic acid-derived resolvins, docosahexaenoic acid-derived resolvins, protectins, and maresins. Emerging evidence indicates that imbalances between specialized proresolving mediators and proinflammatory mediators are associated with several prevalent human diseases, including atherosclerosis. Mechanisms that drive this imbalance remain largely unknown and will be discussed in this review. Furthermore, the concept of dysregulated inflammation resolution in atherosclerosis has been known for several decades. Recently, there has been an explosion of new work with regard to the therapeutic application of proresolving ligands in experimental atherosclerosis. Therefore, this review will highlight recent advances in our understanding of how inflammation resolution may become defective in atherosclerosis and the potential for proresolving therapeutics in atherosclerosis. Last, we offer insight for future implications of the field.
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Affiliation(s)
- Gabrielle Fredman
- Department of Molecular and Cellular Physiology, Center for Cardiovascular Sciences, Albany Medical College, Albany, New York.
| | - Ira Tabas
- Departments of Medicine, Pathology and Cell Biology, and Physiology, Columbia University Medical Center, New York, New York
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20
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Wu B, Mottola G, Schaller M, Upchurch GR, Conte MS. Resolution of vascular injury: Specialized lipid mediators and their evolving therapeutic implications. Mol Aspects Med 2017; 58:72-82. [PMID: 28765077 DOI: 10.1016/j.mam.2017.07.005] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Revised: 07/05/2017] [Accepted: 07/05/2017] [Indexed: 12/25/2022]
Abstract
Acute vascular injury occurs in a number of important clinical contexts, including spontaneous disease-related events (e.g. plaque rupture, thrombosis) and therapeutic interventions such as angioplasty, stenting, or bypass surgery. Endothelial cell (EC) disruption exposes the underlying matrix, leading to a rapid deposition of platelets, coagulation proteins, and leukocytes. A thrombo-inflammatory response ensues characterized by leukocyte recruitment, vascular smooth muscle cell (VSMC) activation, and the elaboration of cytokines, reactive oxygen species and growth factors within the vessel wall. A resolution phase of vascular injury may be described in which leukocyte efflux, clearance of debris, and re-endothelialization occurs. VSMC migration and proliferation leads to the development of a thickened neointima that may lead to lumen compromise. Subsequent remodeling involves matrix protein deposition, and return of EC and VSMC to quiescence. Recent studies suggest that specialized pro-resolving lipid mediators (SPM) modulate key aspects of this response, and may constitute an endogenous homeostatic pathway in the vasculature. SPM exert direct effects on vascular cells that counteract inflammatory signals, reduce leukocyte adhesion, and inhibit VSMC migration and proliferation. These effects appear to be largely G-protein coupled receptor-dependent. Across a range of animal models of vascular injury, including balloon angioplasty, bypass grafting, and experimental aneurysm formation, SPM accelerate repair and reduce lesion formation. With bioactivity in the pM-nM range, a lack of discernible cytotoxicity, and a spectrum of vasculo-protective properties, SPM represent a novel class of vascular therapeutics. This review summarizes current research in this field, including a consideration of critical next steps and challenges in translation.
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Affiliation(s)
- Bian Wu
- Division of Vascular and Endovascular Surgery, Department of Surgery, Cardiovascular Research Institute, University of California at San Francisco, San Francisco, CA, United States
| | - Giorgio Mottola
- Division of Vascular and Endovascular Surgery, Department of Surgery, Cardiovascular Research Institute, University of California at San Francisco, San Francisco, CA, United States
| | - Melinda Schaller
- Division of Vascular and Endovascular Surgery, Department of Surgery, Cardiovascular Research Institute, University of California at San Francisco, San Francisco, CA, United States
| | - Gilbert R Upchurch
- Department of Surgery, University of Virginia, Charlottesville, VA, United States
| | - Michael S Conte
- Division of Vascular and Endovascular Surgery, Department of Surgery, Cardiovascular Research Institute, University of California at San Francisco, San Francisco, CA, United States.
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21
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Chatterjee A, Komshian S, Sansbury BE, Wu B, Mottola G, Chen M, Spite M, Conte MS. Biosynthesis of proresolving lipid mediators by vascular cells and tissues. FASEB J 2017; 31:3393-3402. [PMID: 28442547 PMCID: PMC6207217 DOI: 10.1096/fj.201700082r] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Accepted: 04/05/2017] [Indexed: 12/31/2022]
Abstract
Recent evidence suggests that specialized proresolving lipid mediators (SPMs) generated from docosahexaenoic acid (DHA) can modulate the vascular injury response. However, cellular sources for these autacoids within the vessel wall remain unclear. Here, we investigated whether isolated vascular cells and tissues can produce SPMs and assessed expression and subcellular localization of the key SPM biosynthetic enzyme 5-lipoxygenase (LOX) in vascular cells. Intact human arteries incubated with DHA ex vivo produced 17-hydroxy DHA (17-HDHA) and D-series resolvins, as assessed by liquid chromatography-tandem mass spectrometry. Addition of 17-HDHA to human arteries similarly increased resolvin production. Primary cultures of human saphenous vein endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) converted 17-HDHA to SPMs, including resolvin D1 (RvD1) and other D-series resolvins and protectins. This was accompanied by a rapid translocation of 5-LOX from nucleus to cytoplasm in both ECs and VSMCs, potentially facilitating SPM biosynthesis. Conditioned medium from cells exposed to 17-HDHA inhibited monocyte adhesion to TNF-α-stimulated EC monolayers. These downstream effects were partially reversed by antibodies against the RvD1 receptors ALX/FPR2 and GPR32. These results suggest that autocrine and/or paracrine signaling via locally generated SPMs in the vasculature may represent a novel homeostatic mechanism of relevance to vascular health and disease.-Chatterjee, A., Komshian, S., Sansbury, B. E., Wu, B., Mottola, G., Chen, M., Spite, M., Conte, M. S. Biosynthesis of proresolving lipid mediators by vascular cells and tissues.
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Affiliation(s)
- Anuran Chatterjee
- Cardiovascular Research Institute, University of California San Francisco, San Francisco, California, USA
- Department of Surgery, University of California San Francisco, San Francisco, California, USA
| | - Sevan Komshian
- School of Medicine, Boston University, Boston, Massachusetts, USA
| | - Brian E Sansbury
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Bian Wu
- Cardiovascular Research Institute, University of California San Francisco, San Francisco, California, USA
- Department of Surgery, University of California San Francisco, San Francisco, California, USA
| | - Giorgio Mottola
- Cardiovascular Research Institute, University of California San Francisco, San Francisco, California, USA
- Department of Surgery, University of California San Francisco, San Francisco, California, USA
| | - Mian Chen
- Cardiovascular Research Institute, University of California San Francisco, San Francisco, California, USA
- Department of Surgery, University of California San Francisco, San Francisco, California, USA
| | - Matthew Spite
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Michael S Conte
- Cardiovascular Research Institute, University of California San Francisco, San Francisco, California, USA;
- Department of Surgery, University of California San Francisco, San Francisco, California, USA
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22
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Chen G, Shi X, Wang B, Xie R, Guo LW, Gong S, Kent KC. Unimolecular Micelle-Based Hybrid System for Perivascular Drug Delivery Produces Long-Term Efficacy for Neointima Attenuation in Rats. Biomacromolecules 2017; 18:2205-2213. [PMID: 28613846 DOI: 10.1021/acs.biomac.7b00617] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
At present, there are no clinical options for preventing neointima-caused (re)stenosis after open surgery such as bypass surgery for treating flow-limiting vascular disease. Perivascular drug delivery is a promising strategy, but in translational research, it remains a major challenge to achieve long-term (e.g., > 3 months) anti(re)stenotic efficacy. In this study, we engineered a unique drug delivery system consisting of durable unimolecular micelles, formed by single multiarm star amphiphilic block copolymers with only covalent bonds, and a thermosensitive hydrogel formed by a poly(lactide-co-glycolide)-poly(ethylene glycol)-poly(lactide-co-glycolide) triblock copolymer (abbreviated as triblock gel) that is stable for about 4 weeks in vitro. The drug-containing unimolecular micelles (UMs) suspended in Triblock gel were able to sustain rapamycin release for over 4 months. Remarkably, even 3 months after perivascular application of the rapamycin-loaded micelles in Triblock gel in the rat model, the intimal/medial area ratio (a restenosis measure) was still 80% inhibited compared to the control treated with empty micelle/gel (no drug). This could not be achieved by applying rapamycin in Triblock gel alone, which reduced the intimal/medial ratio only by 27%. In summary, we created a new UM/Triblock gel hybrid system for perivascular drug delivery, which produced a rare feat of 3-month restenosis inhibition in animal tests. This system exhibits a real potential for further translation into an anti(re)stenotic application with open surgery.
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Affiliation(s)
- Guojun Chen
- Department of Materials Science and Engineering, and Wisconsin Institute for Discovery and ‡Department of Biomedical Engineering and Department of Chemistry, University of Wisconsin-Madison , Madison, Wisconsin 53715, United States.,Department of Surgery, 5151 Wisconsin Institutes for Medical Research and ⊥McPherson Eye Research Institute, University of Wisconsin-Madison , Madison, Wisconsin 53705, United States.,Department of Surgery, Department of Physiology & Cell Biology, Davis Heart and Lung Research Institute and #Department of Surgery, College of Medicine, The Ohio State University , Columbus, Ohio 43210, United States
| | - Xudong Shi
- Department of Materials Science and Engineering, and Wisconsin Institute for Discovery and ‡Department of Biomedical Engineering and Department of Chemistry, University of Wisconsin-Madison , Madison, Wisconsin 53715, United States.,Department of Surgery, 5151 Wisconsin Institutes for Medical Research and ⊥McPherson Eye Research Institute, University of Wisconsin-Madison , Madison, Wisconsin 53705, United States.,Department of Surgery, Department of Physiology & Cell Biology, Davis Heart and Lung Research Institute and #Department of Surgery, College of Medicine, The Ohio State University , Columbus, Ohio 43210, United States
| | - Bowen Wang
- Department of Materials Science and Engineering, and Wisconsin Institute for Discovery and ‡Department of Biomedical Engineering and Department of Chemistry, University of Wisconsin-Madison , Madison, Wisconsin 53715, United States.,Department of Surgery, 5151 Wisconsin Institutes for Medical Research and ⊥McPherson Eye Research Institute, University of Wisconsin-Madison , Madison, Wisconsin 53705, United States.,Department of Surgery, Department of Physiology & Cell Biology, Davis Heart and Lung Research Institute and #Department of Surgery, College of Medicine, The Ohio State University , Columbus, Ohio 43210, United States
| | - Ruosen Xie
- Department of Materials Science and Engineering, and Wisconsin Institute for Discovery and ‡Department of Biomedical Engineering and Department of Chemistry, University of Wisconsin-Madison , Madison, Wisconsin 53715, United States.,Department of Surgery, 5151 Wisconsin Institutes for Medical Research and ⊥McPherson Eye Research Institute, University of Wisconsin-Madison , Madison, Wisconsin 53705, United States.,Department of Surgery, Department of Physiology & Cell Biology, Davis Heart and Lung Research Institute and #Department of Surgery, College of Medicine, The Ohio State University , Columbus, Ohio 43210, United States
| | - Lian-Wang Guo
- Department of Materials Science and Engineering, and Wisconsin Institute for Discovery and ‡Department of Biomedical Engineering and Department of Chemistry, University of Wisconsin-Madison , Madison, Wisconsin 53715, United States.,Department of Surgery, 5151 Wisconsin Institutes for Medical Research and ⊥McPherson Eye Research Institute, University of Wisconsin-Madison , Madison, Wisconsin 53705, United States.,Department of Surgery, Department of Physiology & Cell Biology, Davis Heart and Lung Research Institute and #Department of Surgery, College of Medicine, The Ohio State University , Columbus, Ohio 43210, United States
| | - Shaoqin Gong
- Department of Materials Science and Engineering, and Wisconsin Institute for Discovery and ‡Department of Biomedical Engineering and Department of Chemistry, University of Wisconsin-Madison , Madison, Wisconsin 53715, United States.,Department of Surgery, 5151 Wisconsin Institutes for Medical Research and ⊥McPherson Eye Research Institute, University of Wisconsin-Madison , Madison, Wisconsin 53705, United States.,Department of Surgery, Department of Physiology & Cell Biology, Davis Heart and Lung Research Institute and #Department of Surgery, College of Medicine, The Ohio State University , Columbus, Ohio 43210, United States
| | - K Craig Kent
- Department of Materials Science and Engineering, and Wisconsin Institute for Discovery and ‡Department of Biomedical Engineering and Department of Chemistry, University of Wisconsin-Madison , Madison, Wisconsin 53715, United States.,Department of Surgery, 5151 Wisconsin Institutes for Medical Research and ⊥McPherson Eye Research Institute, University of Wisconsin-Madison , Madison, Wisconsin 53705, United States.,Department of Surgery, Department of Physiology & Cell Biology, Davis Heart and Lung Research Institute and #Department of Surgery, College of Medicine, The Ohio State University , Columbus, Ohio 43210, United States
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23
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Sok MCP, Tria MC, Olingy CE, San Emeterio CL, Botchwey EA. Aspirin-Triggered Resolvin D1-modified materials promote the accumulation of pro-regenerative immune cell subsets and enhance vascular remodeling. Acta Biomater 2017; 53:109-122. [PMID: 28213094 DOI: 10.1016/j.actbio.2017.02.020] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Revised: 02/10/2017] [Accepted: 02/13/2017] [Indexed: 12/18/2022]
Abstract
Many goals in tissue engineering rely on modulating cellular localization and polarization of cell signaling, including the inhibition of inflammatory infiltrate, facilitation of inflammatory cell egress, and clearance of apoptotic cells. Omega-3 polyunsaturated fatty acid-derived resolvins are gaining increasing recognition for their essential roles in inhibition of neutrophil invasion into inflamed tissue and promotion of macrophage phagocytosis of cellular debris as well as their egress to the lymphatics. Biomaterial-based release of lipid mediators is a largely under-explored approach that provides a method to manipulate local lipid signaling gradients in vivo and direct the recruitment and/or polarization of anti-inflammatory cell subsets to suppress inflammatory signaling and enhance angiogenesis and tissue regeneration. The goal of this study was to encapsulate Aspirin-Triggered Resolvin D1 (AT-RvD1) into a degradable biomaterial in order to elucidate the effects of sustained, localized delivery in a model of sterile inflammation. Flow cytometric and imaging analysis at both 1 and 3days after injury showed that localized AT-RvD1 delivery was able significantly increase the accumulation of anti-inflammatory monocytes and M2 macrophages while limiting the infiltration of neutrophils. Additionally, cytokine profiling and longitudinal vascular analysis revealed a shift towards a pro-angiogenic profile with increased concentrations of VEGF and SDF-1α, and increased arteriolar diameter and tortuosity. These results demonstrate the ability of locally-delivered AT-RvD1 to increase pro-regenerative immune subpopulations and promote vascular remodeling. STATEMENT OF SIGNIFICANCE This work is motivated by our efforts to explore the underlying mechanisms of inflammation resolution after injury and to develop biomaterial-based approaches to amplify endogenous mechanisms of resolution and repair. Though specific lipid mediators have been identified that actively promote the resolution of inflammation, biomaterial-based localized delivery of these mediators has been largely unexplored. We loaded Aspirin-Triggered Resolvin D1 into a PLGA scaffold and examined the effects of sustained, localized delivery on the innate immune response. We found that biomaterial delivery of resolvin was able to enhance the accumulation of pro-regenerative populations of immune cells, including anti-inflammatory monocytes, population that has never before been shown to respond to resolvin treatment, and also enhance vascular remodeling in response to tissue injury.
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Affiliation(s)
- Mary Caitlin P Sok
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA
| | - Maxianne C Tria
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA
| | - Claire E Olingy
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA
| | - Cheryl L San Emeterio
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA
| | - Edward A Botchwey
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA.
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24
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Specialized pro-resolving mediators in cardiovascular diseases. Mol Aspects Med 2017; 58:65-71. [PMID: 28257820 DOI: 10.1016/j.mam.2017.02.003] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Accepted: 02/26/2017] [Indexed: 12/31/2022]
Abstract
The resolution of inflammation is a highly regulated process enacted by endogenous mediators including specialized pro-resolving lipid mediators (SPMs): the lipoxins, resolvins, protectins and maresins. SPMs activate specific cellular receptors to temper the production of pro-inflammatory mediators, diminish the recruitment of neutrophils, and promote the clearance of dead cells by macrophages. These mediators also enhance host-defense and couple resolution of inflammation to subsequent phases of tissue repair. Given that unresolved inflammation plays a causal role in the development of cardiovascular diseases, an understanding of these endogenous pro-resolving processes is critical for determining why cardiovascular inflammation does not resolve. Here, we discuss the receptor-dependent actions of resolvins and related pro-resolving mediators and highlight their emerging roles in the cardiovascular system. We propose that stimulating resolution could be a novel approach for treating chronic cardiovascular inflammation without promoting immunosuppression.
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