Characterization and validation of a chronic retinal neovascularization rabbit model by evaluating the efficacy of anti-angiogenic and anti-inflammatory drugs

AIM: To establish a rabbit model with chronic condition of retinal neovascularization (RNV) induced by intravitreal (IVT) injection of DL-2-aminoadipic acid (DL-AAA), a retinal glial (Müller) cell toxin, extensive characterization of DL-AAA induced angiographic features and the suitability of the model to evaluate anti-angiogenic and anti-inflammatory therapies for ocular vascular diseases. METHODS: DL-AAA (80 mmol/L) was administered IVT into both eyes of Dutch Belted rabbit. Post DL-AAA delivery, clinical ophthalmic examinations were performed weekly following modified McDonald-Shadduck Scoring System. Color fundus photography, fluorescein angiography (FA), and optical coherence tomography (OCT) procedures were performed every 2 or 4wk until stable retinal vascular leakage was observed. Once stable retinal leakage (12wk post DL-AAA administration) was established, anti-vascular endothelial growth factor (VEGF) (bevacizumab, ranibizumab and aflibercept) and anti-inflammatory (triamcinolone, TAA) drugs were tested for their efficacy after IVT administration. Fluorescein angiograms were scored before and after treatment following a novel grading system, developed for the DL-AAA rabbit model. RESULTS: Post DL-AAA administration, eyes were presented with moderate to severe retinal/choroidal inflammation which was accompanied by intense vitreous flare and presence of inflammatory cells in the vitreous humor. Retinal hemorrhage was restricted to the tips of neo-retinal vessels. FA revealed maximum retinal vascular leakage at 2wk after DL-AAA injection and then persisted as evidenced by stable mean FA scores in weeks 8 and 12. Retinal vascular angiographic and tomographic features were stable and consistent up to 36mo among two different staggers induced for RNV at two different occasions. Day 7, mean FA scores showed that 1 µg/eye of bevacizumab, ranibizumab, aflibercept and 2 µg/eye of TAA suppress 65%, 90%, 100% and 50% retinal vascular leakage, respectively. Day 30, bevacizumab and TAA continued to show 66% and 44% suppression while ranibizumab effect was becoming less effective (68%). In contrast, aflibercept was still able to fully (100%) suppress vascular leakage on day 30. On day 60, bevacizumab, ranibizumab and TAA showed suppression of 7%, 12%, and 9% retinal vascular leakage, respectively, however, aflibercept continued to be more effective showing 50% suppression of vascular leakage. CONCLUSION: The DL-AAA rabbit model mimics RNV angiographic features like RNV and chronic retinal leakage. Based on these features the DL-AAA rabbit model provides an invaluable tool that could be used to test the therapeutic efficacy and duration of action of novel anti-angiogenic formulations, alone or in combination with anti-inflammatory compounds.

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Application of Natural Neutrophil Products for Stimulation of Monocyte-Derived Macrophages Obtained before and after Osteochondral or Bone Injury

Microorganisms ◽

10.3390/microorganisms9010124 ◽

2021 ◽

Vol 9 (1) ◽

pp. 124

Author(s):

Joanna Zdziennicka ◽

Tomasz Szponder ◽

Joanna Wessely-Szponder

Keyword(s):

Rabbit Model ◽

Lower Amount ◽

Ovine Model ◽

Macrophage Activity ◽

Bone Injury ◽

Before And After ◽

Neutrophil Degranulation ◽

Anti Inflammatory ◽

Inflammatory Phenotypes ◽

Stimulation Of

We evaluated the use of some neutrophil products, namely; autologous rabbit antimicrobial neutrophil extract (rANE), heterologous porcine antimicrobial neutrophil extract (pANE), neutrophil degranulation products (DGP) and neutrophil microvesicles (MVs) for stimulation of monocyte-derived macrophages (MDMs) to improve healing. Two animal models were evaluated; the rabbit model for autologous osteochondral transplantation (OT) with application of rabbit ANE, DGP or MVs for MDMs stimulation, and the ovine model of the insertion of a Ti implant with the use of porcine ANE, and ovine DGP or MVs for MDMs stimulation. Macrophage activity was assessed on the basis of free radical generation and arginase activity. We estimated that DGP acted in a pro-inflammatory way both on rabbit and ovine MDMs. On the other hand, MVs acted as anti-inflammatory stimulator on MDMs in both experiments. The response to ANE depended on origin of extract (autologous or heterologous). Macrophages from rabbits before and after OT stimulated with autologous extract generated lower amount of NO and superoxide, especially after transplantation. In the ovine model of Ti implant insertion, heterologous ANE evoked increased macrophage pro-inflammatory activity. Our study revealed that these neutrophil products could regulate activity of macrophages, polarizing them into pro-or anti-inflammatory phenotypes that could enhance bone and osteochondral tissue healing.

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Anti-inflammatory effects of simvastatin during the resolution phase of experimentally formed venous thrombi

Journal of Investigative Medicine ◽

10.1136/jim-2017-000442 ◽

2017 ◽

Vol 65 (6) ◽

pp. 999-1007 ◽

Cited By ~ 4

Author(s):

Yaping Feng ◽

Bo Lei ◽

Fuxian Zhang ◽

Luyuan Niu ◽

Huan Zhang ◽

...

Keyword(s):

Venous Thrombosis ◽

Therapeutic Potential ◽

Rabbit Model ◽

Vena Cava ◽

Inflammatory Cells ◽

Chemotactic Protein ◽

Anti Inflammatory ◽

Underlying Mechanisms ◽

Venous Wall ◽

Local Expression

Deep venous thrombosis (DVT) is a common vascular disease and is closely linked to inflammation. Over the past decade, the potential antithrombotic effect of statins has been elucidated by clinical studies, primarily through focusing on DVT prevention. The effects of statins on DVT resolution and its underlying mechanisms have been rarely addressed. We established a rabbit model of theinferior vena cava(IVC) venous thrombosis. After 48 hours, the rabbits were treated with saline, heparin, simvastatin, or simvastatin combined with heparin, respectively, for 14 days. The migration of inflammatory cells (neutrophils, monocytes, lymphocytes) in the thrombi and injured venous wall, the plasma levels of interleukin (IL)-6, monocyte chemotactic protein 1 (MCP-1) and P-selectin, and local expression of MCP-1 and P-selectin in the venous wall were evaluated by histology, immunohistochemistry, and ELISA examinations. Our data showed that compared with saline and heparin controls, monotherapy of simvastatin and the adjunctive therapy with simvastatin and heparin significantly improved the thrombus resolution and reduced inflammatory cells migration into the venous wall, the release of the inflammatory cell adhesion molecule (P-selectin), inflammatory chemokine (MCP-1) and pleiotropic proinflammatory cytokines (IL-6) into the blood, and the local expression of P-selectin and MCP-1 in the venous wall. Simvastatin targets anti-inflammatory pathways during the resolution phase of a thrombus, providing a therapeutic potential in DVT resolution and post-thrombotic syndrome prevention.

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Vascular and cardiac oxidative stress and inflammation as targets for cardioprotection

Current Pharmaceutical Design ◽

10.2174/1381612827666210125155821 ◽

2021 ◽

Vol 27 ◽

Author(s):

Andreas Daiber ◽

Sebastian Steven ◽

Gerhild Euler ◽

Rainer Schulz

Keyword(s):

Oxidative Stress ◽

Large Scale ◽

Vascular Diseases ◽

Cardiovascular Effects ◽

Inflammatory Cells ◽

Cellular Redox ◽

Cardiac Inflammation ◽

Inflammatory Processes ◽

Anti Inflammatory ◽

Shed Light

: Cardiac and vascular diseases are often associated with increased oxidative stress and inflammation, and both may contribute to the disease progression. However, successful applications of antioxidants in the clinical setting are very rare and specific anti-inflammatory therapeutics only emerged recently. Reasons for this rely on the great diversity of oxidative stress and inflammatory cells that can either act as cardioprotective or cause tissue damage in the heart. Recent large-scale clinical trials found that highly specific anti-inflammatory therapies using monoclonal antibodies against cytokines resulted in lower cardiovascular mortality in patients with pre-existing atherosclerotic disease. In addition, unspecific antiinflammatory medication and established cardiovascular drugs with pleiotropic immunomodulatory properties such as angiotensin converting enzyme (ACE) inhibitors or statins have proven beneficial cardiovascular effects. Normalization of oxidative stress seems to be a common feature of these therapies, which can be explained by a close interaction/crosstalk of the cellular redox state and inflammatory processes. In this review we give an overview about cardiac reactive oxygen species (ROS) sources and processes of cardiac inflammation, as well as the connection of ROS and inflammation, in ischemic cardiomyopathy in order to shed light on possible cardioprotective interventions.

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Effects of Gentiana lutea root on vascular diseases

Current Vascular Pharmacology ◽

10.2174/1570161118666200529111314 ◽

2020 ◽

Vol 18 ◽

Author(s):

Gordana Joksic ◽

Djordje Radak ◽

Emina Sudar-Milovanovic ◽

Milan Obradovic ◽

Jelena Radovanovic ◽

...

Keyword(s):

Recent Literature ◽

Vascular Diseases ◽

Lipid Lowering ◽

Primary Data ◽

Electronic Database ◽

Active Components ◽

Gentiana Lutea ◽

Search Terms ◽

Anti Oxidant ◽

Anti Inflammatory

Background: Gentiana lutea (GL), commonly known as yellow gentian, bitter root, and bitterwort, belongs to family Gentianaceae. GL belongs to genus Gentiana, which is a rich natural source of iridoids, secoiridoids, xantones, flavonoids, triterpenoids, and carbohydrates. Medicinal plants from Gentiana species have anti-oxidant, anti-inflammatory, anti-mitogenic, anti-proliferative, and lipid-lowering effects, as well as a cardioprotective, hypotensive, vasodilator and anti-platelet activities. Objective: We reviewed the recent literature related to the effects of Gentiana species, and their active components on vascular diseases. Methods: Data used for this review were obtained by searching the electronic database [PUBMED/MEDLINE 1973 - February 2020]. The primary data search terms of interest were: Gentiana lutea, Gentienacea family, phytochemistry, vascular diseases, treatment of vascular diseases, anti-oxidant, anti-inflammatory, anti-atherogenic. Conclusion: Gentiana species and their constituents affect many different factors related to vascular disease development and progression. Therefore, Gentiana-based therapeutics represent potentially useful drugs for the management of vascular diseases.

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Frühgeborene unter maschineller Beatmung: Immunmodulatorischer Effekt der präventiven Gabe von Azithromycin

Karger Kompass Pneumologie ◽

10.1159/000513487 ◽

2020 ◽

pp. 1-3

Author(s):

Maximilian Jorczyk

Keyword(s):

Very Low Birth Weight ◽

Controlled Trial ◽

Preterm Neonates ◽

Double Blind ◽

Mechanically Ventilated ◽

Before And After ◽

Anti Inflammatory ◽

To Receive ◽

Therapeutic Possibilities ◽

Inflammatory Effect

Introduction: Macrolides have anti-inflammatory and immunomodulatory properties that give this class of antibiotics a role that differs from its classical use as an antibiotic, which opens new therapeutic possibilities. Objective: The aim of this study was to evaluate the anti-inflammatory effect of azithromycin in preventing mechanical ventilation (MV)-induced lung injury in very-low-birth-weight preterm neonates. Methods: This is a randomized, double-blind, placebo-controlled trial of preterm neonates who received invasive MV within 72 h of birth. Patients were randomized to receive intravenous azithromycin (at a dose of 10/mg/kg/day for 5 days) or placebo (0.9% saline) within 12 h of the start of MV. Two blood samples were collected (before and after intervention) for measurement of interleukins (ILs) and PCR for Ureaplasma. Patients were followed up throughout the hospital stay for the outcomes of death and bronchopulmonary dysplasia defined as need for oxygen for a period of ≥28 days of life (registered at ClinicalTrials.gov, No. NCT03485703). Results: Forty patients were analyzed in the azithromycin group and 40 in the placebo group. Five days after the last dose, serum IL-2 and IL-8 levels dropped significantly in the azithromycin group. There was a significant reduction in the incidence of death and O2 dependency at 28 days/death in azithromycin-treated patients regardless of the detection of Ureaplasma in blood. Conclusions: Azithromycin has anti-inflammatory effects, with a decrease in cytokines after 5 days of use and a reduction in death and O2 dependency at 28 days/death in mechanically ventilated preterm neonates.

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Anti-inflammatory genes in PBMCs post-spontaneous intracerebral hemorrhage

Translational Neuroscience ◽

10.1515/tnsci-2021-0003 ◽

2021 ◽

Vol 12 (1) ◽

pp. 58-66

Author(s):

Doan Nguyen ◽

Vi Tran ◽

Alireza Shirazian ◽

Cruz Velasco-Gonzalez ◽

Ifeanyi Iwuchukwu

Keyword(s):

Intracerebral Hemorrhage ◽

Negative Correlation ◽

Mononuclear Cells ◽

Inflammatory Cells ◽

Favorable Outcome ◽

Hospital Length Of Stay ◽

Spontaneous Intracerebral Hemorrhage ◽

Hematoma Volume ◽

Peripheral Blood Mononuclear ◽

Anti Inflammatory

Abstract Background Neuroinflammation is important in the pathophysiology of spontaneous intracerebral hemorrhage (ICH) and peripheral inflammatory cells play a role in the clinical evolution and outcome. Methodology Blood samples from ICH patients (n = 20) were collected at admission for 5 consecutive days for peripheral blood mononuclear cells (PBMCs). Frozen PBMCs were used for real-time PCR using Taqman probes (NFKB1, SOD1, PPARG, IL10, NFE2L2, and REL) and normalized to GAPDH. Data on hospital length of stay and modified Rankin score (MRS) were collected with 90-day MRS ≤ 3 as favorable outcome. Statistical analysis of clinical characteristics to temporal gene expression from early to delayed timepoints was compared for MRS groups (favorable vs unfavorable) and hematoma volume. Principle findings and results IL10, SOD1, and REL expression were significantly higher at delayed timepoints in PBMCs of ICH patients with favorable outcome. PPARG and REL increased between timepoints in patients with favorable outcome. NFKB1 expression was not sustained, but significantly decreased from higher levels at early onset in patients with unfavorable outcome. IL10 expression showed a negative correlation in patients with high hematoma volume (>30 mL). Conclusions and significance Anti-inflammatory, pro-survival regulators were highly expressed at delayed time points in ICH patients with a favorable outcome, and IL10 expression showed a negative correlation to high hematoma volume.

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Hyaluronic Acid-Modified and TPCA-1-Loaded Gold Nanocages Alleviate Inflammation

Pharmaceutics ◽

10.3390/pharmaceutics11030143 ◽

2019 ◽

Vol 11 (3) ◽

pp. 143 ◽

Cited By ~ 4

Author(s):

Jingnan Zhao

Keyword(s):

Hyaluronic Acid ◽

Inflammatory Cells ◽

Oxygen Species ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Nanogold Particles ◽

Gold Nanocages ◽

Factor Alpha ◽

Anti Inflammatory ◽

Necrosis Factor

Gold nanocages (AuNCs) are biocompatible and porous nanogold particles that have been widely used in biomedical fields. In this study, hyaluronic acid (HA) and peptide- modified gold nanocages (HA-AuNCs/T/P) loaded with 2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide (TPCA-1) were prepared to investigate their potential for combating inflammation. TPCA-1 was released from AuNCs, intracellularly when HA was hydrolyzed by hyaluronidase. HA-AuNCs/T/P show a much higher intracellular uptake than AuNCs/T/P, and exhibit a much higher efficacy on the suppression of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) than free TPCA-1, suggesting great improvement to the anti-inflammatory efficacy of TPCA-1 through the application of AuNCs. HA-AuNCs/T/P can also reduce the production of reactive oxygen species in inflammatory cells. This study suggests that HA-AuNCs/T/P may be potential agents for anti-inflammatory treatment, and are worthy of further investigation.

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Capsaicin-Sensitive Peptidergic Sensory Nerves Are Anti-Inflammatory Gatekeepers in the Hyperacute Phase of a Mouse Rheumatoid Arthritis Model

International Journal of Molecular Sciences ◽

10.3390/ijms22041682 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1682

Author(s):

Bálint Botz ◽

Gábor Kriszta ◽

Kata Bölcskei ◽

Ádám István Horváth ◽

Attila Mócsai ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Morphological Changes ◽

Vascular Leakage ◽

Sensory Nerves ◽

Clinical Severity ◽

Severity Scores ◽

Clinical Scoring ◽

Anti Inflammatory ◽

Ros Burst

Capsaicin-sensitive peptidergic sensory nerves play complex, mainly protective regulatory roles in the inflammatory cascade of the joints via neuropeptide mediators, but the mechanisms of the hyperacute arthritis phase has not been investigated. Therefore, we studied the involvement of these afferents in the early, “black box” period of a rheumatoid arthritis (RA) mouse model. Capsaicin-sensitive fibres were defunctionalized by pretreatment with the ultrapotent capsaicin analog resiniferatoxin and arthritis was induced by K/BxN arthritogenic serum. Disease severity was assessed by clinical scoring, reactive oxygen species (ROS) burst by chemiluminescent, vascular permeability by fluorescent in vivo imaging. Contrast-enhanced magnetic resonance imaging was used to correlate the functional and morphological changes. After sensory desensitization, both early phase ROS-burst and vascular leakage were significantly enhanced, which was later followed by the increased clinical severity scores. Furthermore, the early vascular leakage and ROS-burst were found to be good predictors of later arthritis severity. We conclude that the anti-inflammatory role of peptidergic afferents depends on their activity in the hyperacute phase, characterized by decreased cellular and vascular inflammatory components presumably via anti-inflammatory neuropeptide release. Therefore, these fibres might serve as important gatekeepers in RA.

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Activation of complement by tissue plasminogen activator, but not acute cerebral ischemia, in a rabbit model of thromboembolic stroke

Journal of Neurosurgery ◽

10.3171/jns.1997.86.1.0139 ◽

1997 ◽

Vol 86 (1) ◽

pp. 139-142 ◽

Cited By ~ 10

Author(s):

Martin M. Bednar ◽

Cordell E. Gross ◽

Sheila R. Russell ◽

David Short ◽

Patricia C. Giclas

Keyword(s):

Cerebral Ischemia ◽

Plasminogen Activator ◽

Complement Activation ◽

Rabbit Model ◽

Thromboembolic Stroke ◽

Content Type ◽

Acute Cerebral Ischemia ◽

Tissue Plasminogen ◽

Before And After ◽

Fine Print

✓ Although complement activation is associated with tissue injury during inflammatory and ischemic states, complement activation in states of acute cerebral ischemia before and after administration of tissue plasminogen activator (TPA) has not yet been examined and is the focus of this investigation. Twenty-four New Zealand White rabbits weighing 3 to 3.5 kg were used for this study. Of these, 20 were subjected to intracranial autologous clot embolization via the internal carotid artery. Three hours postembolization, rabbits received an intravenous infusion of TPA (6.3 mg/kg, 20% bolus with the remainder infused over a 2-hour interval; 12 animals) or vehicle (eight animals). All animals were observed for a total of 7 or 8 hours postembolization. These two groups were compared to a cohort undergoing sham operation with subsequent TPA infusion (four animals). Plasma samples to quantify complement component C5 hemolytic activity (C5H5O) were obtained at the following time points: 30 minutes before and after clot embolization; 1 hour before and 1 hour after the initiation of therapy with TPA or vehicle and at the completion of the protocol; 7 to 8 hours after clot embolization. The C5 activation was not detected as the result of acute cerebral ischemia. However, animals receiving TPA with or without concomitant clot embolization exhibited C5 activation as assessed by a reduction in C5 hemolytic function, both 1 hour after initiation of TPA infusion (78.7 ± 10.3% and 77.5 ± 9.9% of baseline value, respectively; mean ± standard error of the mean [SEM]) and at the end of the protocol, 2 hours after the completion of the TPA infusion (72.5 ± 8.8% and 53.3 ± 8.1%, respectively; mean ± SEM, p < 0.05, each group). This study supports the conclusion that TPA, but not acute cerebral ischemia, may activate the complement cascade in this rabbit model of thromboembolic stroke.

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Therapeutic Effect of Camel Milk in Children with Autism: Its Impact on Serum Levels of Vasoactive Intestinal Peptide

International Journal Of Medical Science And Clinical Invention ◽

10.18535/ijmsci/v8i10.05 ◽

2021 ◽

Vol 8 (10) ◽

pp. 5698-5707

Author(s):

Gehan Ahmed Mostafa ◽

Geir Bjørklund ◽

Laila Al- Ayadhi

Keyword(s):

Vasoactive Intestinal Peptide ◽

Rating Scale ◽

Serum Levels ◽

Camel Milk ◽

Cow Milk ◽

Daily Diet ◽

Before And After ◽

Anti Inflammatory ◽

Apoptotic Pathways ◽

Regulatory Functions

Background: Camel milk (CAM) regulates the inflammatory process, apoptotic pathways and oxidative stress. Thus, it is a therapeutic possibility for many autoimmune disorders, including autism. Vasoactive intestinal peptide (VIP) is an anti-inflammatory peptide that facilitates the immune regulatory functions by recruiting regulatory T cells to induce immune tolerance and prevent the occurrence of autoimmunity. This study aimed to investigate the effect of CAM consumption on both serum VIP levels and the severity of autism assessed by measuring the Childhood Autism Rating Scale (CARS). Mehods: Sixty-five autistic children, aged between 3-12 years, were studied. Forty-seven patients received 500 mL of CAM (either raw "24 patients" or boiled "23 patients") in their regular daily diet for two weeks. Eighteen patients received 500 mL of cow milk for two weeks. For all patients, CARS and serum VIP levels were assessed before and after milk consumption. Results: Although there was a decrease in CARS scores in patients who received raw CAM, this decrease was non-significant (P=0.070). Serum VIP levels were increased in patients who consumed CAM, either raw (P=0.076) or boiled (P=0.065), but this increase was non-significant. Conclusions: CAM consumption for 2 weeks neither significantly decreased the severity of autism nor increased serum anti-inflammatory VIP levels. The lack of a significant response to CAM in this study may be attributable to the short duration of CAM consumption. Further studies are required to investigate the effect of CAM consumption for a longer duration on serum VIP levels and the severity of autism.

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