Inflammation In Rabbits Research Articles

Gax gene transfer inhibits vascular remodeling induced by adventitial inflammation in rabbits

Aims Adventitial fibroblasts (AFs) and inflammation play an important role in neointimal formation and vascular remodeling. The present study was aimed to investigate the therapeutic effects and underlying mechanisms of transcriptional regulator Gax gene transfection in aortic remodeling induced by adventitial inflammation. Methods and results Fifty rabbits fed a chow diet were randomly divided into a normal control group ( n = 10) and experimental group ( n = 40). All rabbits in the experimental group underwent collar placement around the abdominal aorta and intra-collar injection of lipopolysaccharide (LPS) to induce adventitial inflammation and they were further divided into model control group, saline-treated group, green fluorescence protein (Ad-GFP)-treated group and Gax gene (Ad-Gax)-treated group, respectively. Four weeks after treatment, the model control group, saline-treated group and Ad-GFP-treated group showed thickened neointima and adventitia, reduced lumen size and increased eccentricity and remodeling index of the abdominal aorta in comparison with the normal control group, whereas Ad-Gax-treated group exhibited attenuated neointimal formation and vascular remodeling ( P < 0.01–0.05) .The vascular expression levels of interleukin (IL)-1β, IL-6, IL-8, monocyte chemoattractant protein (MCP)-1, matrix metalloproteinase (MMP)-1, MMP-2, MMP-9, vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1, Smads, mitogen-activated protein kinases (MAPKs), integrins and nuclear factor kappa B (NF-kB) were significantly higher in the model control group, saline-treated group and Ad-GFP-treated group than those in the normal control group ( P < 0.01–0.05). In contrast, the local expression levels of these cytokines were substantially reduced by Ad-Gax gene transfer ( P < 0.01–0.05). Similarly, the serum levels of inflammatory cytokines including C-reactive protein (CRP), transforming growth factor (TGF)-β1, IL-1, IL-6, IL-8, tumor necrosis factor (TNF)-α, MCP-1, VCAM-1 and ICAM-1 were significantly higher in the model control group, saline-treated group and Ad-GFP-treated group than those of the Ad-Gax-treated group ( P < 0.01–0.05). In vitro studies showed that Gax overexpression diminished inflammatory cytokine expression in LPS-stimulated arterial fibroblasts. Conclusions Adventitial inflammation induces vascular remodeling via the interactions of multiple inflammatory cytokines and local Gax gene transfer in vivo can significantly inhibit these interactions and thereby attenuate local inflammation and vascular remodeling.

Capsaicin reduced lung ischemia-reperfusion injury via diminishing pulmonary inflammation in rabbits

Capsaicin reduced lung ischemia-reperfusion injury via diminishing pulmonary inflammation in rabbits

Role of cyclooxygenase (COX)‐1 and COX‐2 in a rabbit model of lipopolysaccharide (LPS)‐induced ocular inflammation

ObjectiveTo evaluate relative contribution of COX‐1 and COX‐2 to the LPS‐induced ocular inflammation in rabbits.MethodsAt hour 0, 27 rabbits received either artificial tears (Refresh Tears®; Allergan, Inc.; Irvine, CA) (3 drops 20 min apart), COX‐1 inhibitors trans‐resveratrol 0.1% (TR) (3 drops 20 min apart) or FR122047 0.1% (FR) (1 drop), COX‐2 inhibitor nimesulide 0.1% (1 drop), or COX‐1 and COX‐2 inhibitor ketorolac 0.45% (Acuvail®; Allergan, Inc.; Irvine, CA) (3 drops 20 min apart). At hour 1, rabbits received intravenous injections of LPS and fluorescein isothiocyanate (FITC)‐dextran. At hour 2, aqueous samples were collected for analysis. Six additional rabbits received only FITC‐dextran 2 hours before sample collection.ResultsLPS increased aqueous prostaglandin E2 (PGE2) and FITC‐dextran levels by 4.2‐ and 137.8‐fold, respectively. Ketorolac 0.45% and COX‐1 inhibitors (TR and FR) significantly reduced PGE2 elevation (P &lt; .01) while COX‐2 inhibitor (nimesulide) was ineffective. Of all inhibitors, only ketorolac 0.45% significantly inhibited FITC‐dextran elevation (P &lt; .01). Inefficacy of TR and FR in reducing FITC‐dextran leakage may be due to their poor penetration into iris–ciliary body.ConclusionCOX‐1 was the primary isoenzyme responsible for early inflammatory response to LPS. Ketorolac 0.45% suppressed ocular inflammation by inhibiting PGE2 elevation and FITC‐dextran leakage.

Anti-inflammatory and Antihistaminic Study of a Unani Eye Drop Formulation

The Unani eye drop is an ophthalmic formulation prepared for its beneficial effects in the inflammatory and allergic conditions of the eyes. In the present study, the Unani eye drop formulation was prepared and investigated for its anti-inflammatory and antihistaminic activity, using in vivo and in vitro experimental models respectively. The Unani eye drop formulation exhibited significant anti-inflammatory activity in turpentine liniment-induced ocular inflammation in rabbits. The preparation also showed antihistaminic activity in isolated guinea-pig ileum. The anti-inflammatory and antihistaminic activity of eye drop may be due to presence of active ingredients in the formulation. Although there are many drugs in Unani repository which are mentioned in classical books or used in Unani clinical practice effectively in treatment of eye diseases by various Unani physicians. Inspite of the availability of vast literature, there is a dearth of commercial Unani ocular preparations. So, keeping this in mind, the eye drop formulation was prepared and its anti-inflammatory and antihistaminic activity was carried out in animal models. Thus, in view of the importance of alternative anti-inflammatory and antiallergic drugs, it becomes imperative to bring these indigenous drugs to the front foot and evaluate their activities.

The scientific validation of Unani Eye drop on conjunctivitis

Material and methods The scientific validation of Unani Eye drop on conjunctivitis is comprises of physico-chemical, experimental studies on animals, safety evaluations and clinical trials on conjunctivitis. The formulation of eye drop consists of the following ingredients: • stem wood of Berberis aristata DC.14.0% • seed of Cassia absus Linn. 2.0% • rhizome of Coptis teeta Wall. 2.4% • bark of Symplocos racemosa Roxb. 2.4% • flower of Azadirachta indica A. Juss. 2.8% • Alum, K2SO4·Al2 (SO4)3·24H2O 0.4% • aqua distillate of Rosa damascena Mill.Q.S. • Phenyl ethyl alcohol (Preservative) 0.5%. Results • In physico-chemical studies the mean percentage of pH values 3.13±0.012. • The refractive index 1.360±0.0008 at 24 °C. The viscosity 0.33165±0.00216. • The specific gravity 1.0075±0.0006 at 25 °C. The qualitative phytochemical of eye drop gave positive test for alkaloids, sugars, saponin and sterols/terpenes. • TLC of the eye drop in Butanol: Acetic acid: water: Ethyl acetate: the Rf values of eye drop formulation was calculated as 0.04, 0.08, 0.16, 0.26, 0.36 and 0.36. In vitro antimicrobial activity of eye drop and standard drug in the dose and standard (Berberine) was carried out using different organic solvent systems of 10 μl/disc against Escherichia coli, Staphylococcusaureus, Streptococcusmutans and Klebsiella, showed significant results. The test drug was also tested for antihistaminic activity on isolated guinea pig ileum. It was antagonized the effect of histamine on the tissue. Anti-inflammatory activity of test drug was observed in turpentine liniment-induced ocular inflammation in rabbit's eye. In anti-inflammatory activity, the signs and symptoms of ocular inflammation was subsided on tenth day in control group, whereas in test group the signs and symptoms subsided within 7 days. In the safety evaluation, no adverse effects were observed in ocular structure in rabbit's eye: cornea, iris and conjunctiva were normal. The clinical study was carried out on 60 patients of diagnosed conjunctivitis. The total therapeutic response of test drug (eye drop formulation) was shown as 93.3% in allergic, 90% in mucopurulent and 100% in viral conjunctivitis as compared with control group. In allergic conjunctivitis 66.7% cases cured, 20% cases relieved and 6.7% cases partially relieved and no response was observed 6.7% cases. Conclusions Thus eye drop have triple action as an anti-inflammatory, antimicrobial and anti-allergic and is safe and effective in the treatment of conjunctivitis.

Rapid-Clearance Iron Nanoparticles for Inflammation Imaging of Atherosclerotic Plaque: Initial Experience in Animal Model

To evaluate the use of a recently developed fast-clearing ultrasmall superparamagnetic iron oxide (USPIO) for detection of vascular inflammation in atherosclerotic plaque. The study protocol was approved by the animal experimentation ethics committee. A recently introduced USPIO, P904, and a reference-standard USPIO, ferumoxtran-10, were tested in a rabbit model of induced aortic atherosclerosis. In vivo magnetic resonance (MR) angiography and T2*-weighted plaque MR imaging were performed at baseline and after administration of P904 and ferumoxtran-10 (administered dose for both, 1000 micromol of iron per kilogram of body weight) in 26 hyperlipidemic New Zealand white rabbits. The variation in vessel wall area over time was evaluated with nonparametric testing. Ex vivo MR imaging findings were compared with iron content at linear regression analysis. With in vivo MR imaging, plaque analysis was possible as early as 24 hours after P904 injection. The authors observed a 27.75% increase in vessel wall area due to susceptibility artifacts on day 2 (P = .04) and a 38.81% increase on day 3 (P = .04) after P904 administration compared with a 44.5% increase in vessel wall area on day 7 (P = .04) and a 34.8% increase on day 10 (P = .22) after ferumoxtran-10 administration. These susceptibility artifacts were correlated with intraplaque iron uptake in the corresponding histologic slices. The number of pixels with signal loss on the ex vivo MR images was linearly correlated with the logarithm of the iron concentration (P = .0001; R(2) = 0.93). Plaque inflammation in rabbits can be detected earlier with P904 than with ferumoxtran-10 owing to the faster blood pharmacokinetics and the early uptake of P904 in the reticuloendothelial system. http://radiology.rsnajnls.org/cgi/content/full/252/2/401/DC1.

Effect of a high dose of glucosamine on systemic and tissue inflammation in an experimental model of atherosclerosis aggravated by chronic arthritis

Glucosamine sulfate (GS) is a glycosaminoglycan with anti-inflammatory and immunoregulatory properties. Here we set out to explore the effect of GS administration on markers of systemic and local inflammation in rabbits with atherosclerosis aggravated by chronic arthritis. Atherosclerosis was induced in rabbits by maintaining them on a hyperlipidemic diet after producing an endothelial lesion in the femoral arteries. Simultaneously, chronic arthritis was induced in these animals by repeated intra-articular injections of ovalbumin in previously immunized rabbits. A group of these rabbits was treated prophylactically with oral GS (500 mg.kg(-1).day(-1)), and, when the animals were killed, serum was extracted and peripheral blood mononuclear cells (PBMC) were isolated. Furthermore, the femoral arteries, thoracic aorta, and synovial membranes were examined in gene expression studies and histologically. GS administration reduced circulating levels of the C-reactive protein and of interleukin-6. GS also lowered nuclear factor-kappaB activation in PBMC, and it downregulated the expression of both the CCL2 (monocyte chemoattractant protein) and cyclooxygenase-2 genes in these cells. Lesions at the femoral wall were milder after GS treatment, as reflected by the intimal-to-media thickened ratio and the absence of aortic lesions. Indeed, GS also attenuated the histological lesions in synovial tissue. In a combined rabbit model of chronic arthritis and atherosclerosis, orally administered GS reduced the markers of inflammation in peripheral blood, as well as the femoral and synovial membrane lesions. GS also prevented the development of inflammation-associated aortic lesions. These results suggest an atheroprotective effect of GS.

HDL, lipid peroxidation, and atherosclerosis

Genetic, clinical, and pharmacological studies implicate elevated levels of LDL in the pathogenesis of atherosclerotic vascular disease, the leading cause of death in industrialized societies (1). Paradoxically, native LDL fails to exert potentially atherogenic effects in vitro, suggesting that it must be modified to promote vascular disease. Indeed, many lines of evidence support the LDL oxidation hypothesis, which suggests that oxidative damage to LDL is one important mechanism for rendering lipoproteins atherogenic (as reviewed in Refs. 2, 3).

Downregulation of endotoxin-induced uveitis by intravitreal injection of polylactic-glycolic acid (PLGA) microspheres loaded with dexamethasone

We tested the short- and long-term ability of polylactic-glycolic acid (PLGA) microspheres loaded with dexamethasone to reduce ocular inflammation in rabbits elicited by intravitreal lipopolysaccharide (LPS) injection. PLGA microspheres loaded with dexamethasone were prepared by the solvent evaporation technique from an oil/water emulsion and sterilized by gamma irradiation (25 kGy). The microsphere fraction selected was 2:10 (dexamethasone:PLGA) and contained 141 ± 0.38 μg dexamethasone/mg PLGA. Microsphere diameters were 20–53 μm, and the mean encapsulation efficiency was 92.97 ± 0.75%. Seven days prior to the induction of panuveitis, 10 mg of dexamethasone-free or dexamethasone-loaded microspheres were injected into the vitreous. Control animals received no injection. Panuveitis was induced in male New Zealand rabbits (2.5–3.0 kg) by intravitreal injection of Escherichia coli LPS. Clinical evaluation, electroretinography and histopathologic studies were performed in short-term studies of 15 days and in long-term studies of 33 days. Efficacy in reducing inflammation was also studied in vitrectomized eyes. In short-term studies eyes injected with dexamethasone-loaded microspheres had less inflammation than control eyes and eyes injected with blank microspheres. Inflammation reverted in all groups by 15 days after LPS injection. A second LPS dose given on Day 30 provoked a high peak of inflammation in control eyes and in those injected with blank microspheres. In contrast, only slight inflammation occurred in eyes injected with dexamethasone-loaded microspheres. Histopathology and electroretinography supported these results. Dexamethasone-loaded microspheres effectively reduced intraocular inflammation caused by LPS in both short- and long-term studies.

Identification of biologically active peptides that inhibit binding of human CXCL8 to its receptors from a random phage-epitope library

A random bacteriophage peptide library was used to map structural features of human (h)CXCR1 and hCXCR2 by determining the epitopes of neutralizing mAb 5A12 anti-hCXCR1 and mAb 6C6 anti-hCXCR2. After three rounds of biopanning, five mAb5 A12- and four mAb 6C6-binding peptides were identified from a 6-mer peptide library. Consensus sequences (S/T)(1)(F/A/N/D)(2)(I/M)(3)W(4)D(5)F(6) and F/L/M)(1)W(2)(D/N/L)(3)D(4)F(5)W(6) were deduced from sequences of these peptides. They correspond to a highly conserved N-domain sequence (9)MWDF(12) of hCXCR1 and (13)DFW(15) of hCXCR2. The phage bearing the peptides showed specific binding to immobilized mAb 5A12 or mAb 6CC, and over 86% of phages bound were competitively inhibited by free synthetic peptides. In FACScan analysis, all selected phage peptides were able to strongly inhibit the binding of mAb 5A12 and mAb 6C6 to hCXCR1- and hCXCR2-transfected preB 300-19 murine cells. Furthermore, synthetic peptides of the corresponding phage epitopes were effective in blocking the antibody-CXCR1/2 interactions and to inhibit the binding of hCXCL8 to hCXCR1 and hCXCR2 transfectants. Peptides 5A12/2 (SAMWDF) and 6C6/1 (FWDDFW) competed effectively for (125)I-hCXCL8 binding to hCXCR1 and hCXCR2 with IC(50), respectively, equal to 10 muM and 5.4 muM. Calcium release and chemotaxis of hCXCR1/2 transfectants or human neutrophils were inhibited by all peptides in a dose-dependent manner. Furthermore, the peptide 6C6/1 FWDDFW showed inhibitory effects on chemotaxis of human netrophils induced by hCXCR2 chemokines such as hCXCL1-3 and hCXCL5. Specificities of peptides 5A12/2 and 6C6/1 were assessed with hCXCR3, hCXCR4, hCXCR5, hCCR3, and hCCR5 receptors. In vivo, peptides 5A12/2 and p6C6/1 blockade hCXCL8-induced neutrophil recruitment in skin inflammation in rabbits. Taken together, these data demonstrate that phage-display analysis provides information about the relative location of amino acids on the N-domain surfaces of hCXCR1 and hCXCR2 proteins using antibody imprints of the receptor-surface structure. The derived mimotopes could be used as inhibitors of hCXCL8-induced activities related to its interaction with the N-domain of hCXCR1 and hCXCR2.

Curcumin inhibits the increase of glutamate, hydroxyl radicals and PGE 2 in the hypothalamus and reduces fever during LPS-induced systemic inflammation in rabbits

Evidence has accumulated to suggest that systemic administration of lipopolysaccharide (LPS), in addition to elevating tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) as well as fever, induces overproduction of glutamate, hydroxyl radicals and prostaglandin E 2 (PGE 2) in the rabbit's hypothalamus. Current study was attempted to assess whether Curcumin exerts its antipyresis by reducing circulating pro-inflammatory cytokines and hypothalamic glutamate, hydroxyl radicals and PGE 2 in rabbits. The microdialysis probes were stereotaxically and chronically implanted into the preoptic anterior hypothalamus of rabbit brain for determination of glutamate, hydroxyl radicals, and PGE 2 in situ. It was found that systemic administration of LPS (2 µg/kg) induced increased levels of both core temperature and hypothalamic levels of both glutamate and hydroxyl radicals accompanied by increased plasma levels of TNF-α, IL-1β, and IL-6. The rise in both the core temperature and hypothalamic glutamate and hydroxyl radicals could also be induced by direct injection of TNF-α, IL-1β, or IL-6 into the lateral ventricle of rabbit brain. Pretreatment with Curcumin (5–40 mg/kg, i.p.) 1 h before an i.v. dose of LPS significantly reduced the LPS-induced overproduction of circulating TNF-α, IL-1β, and IL-6, and brain glutamate, PGE 2, and hydroxyl radicals. Both the febrile response and overproduction of both glutamate and hydroxyl radicals in the hypothalamus caused by central administration of TNF-α, IL-1β, or IL-6 could be suppressed by Curcumin. These results indicate that systemic injection of Curcumin may exert its antipyresis by inhibiting the glutamate-hydroxyl radicals-PGE 2 pathways in the hypothalamus and circulating TNF-α, IL-1β, and IL-6 accumulation during LPS fever.

Involvement of platelet-activating factor and tumour necrosis factor in the pathogenesis of joint inflammation in rabbits.

We have studied the participation of platelet-activating factor (PAF) in antigen-induced arthritis in rabbits, as well as the possible co-operation between PAF and tumour necrosis factor (TNF) in their ability to induce joint inflammation when injected into the knees of healthy rabbits. The administration of two structurally different PAF receptor antagonists, BN52021 and Alprazolam, from 4 h before the intra-articular injection of ovalbumin in preimmunized rabbits, induced an important reduction in the synovial fluid volume, in the amount of cells infiltrating the articular cavity and the synovial membrane, as well as in the prostaglandin E2 (PGE2) concentration. Furthermore, proteoglycans of the articular cartilage, which were found diminished in animals with non-treated arthritis, were well preserved in rabbits treated with PAF antagonists. All the synovial fluids from joints with arthritis had detectable amounts of PAF. The injection of either TNF or PAF into the joints of normal rabbits induced a mild inflammation. When TNF was administered 1 h before PAF, a synergistic response was noted in the synovial fluid volume, in the accumulation of leucocytes, and in the amount of PGE2. The administration of BN50726, a hetrazepine with a potent PAF-receptor antagonist effect, induced a diminution in those parameters. Our results suggest that PAF may be an early and important mediator of joint damage, and that TNF can amplify the inflammatory response induced by PAF. PAF receptor antagonists could play some role in the treatment of inflammatory joint diseases.

Aqueous, oil, and ointment formulations of ketorolac: efficacy against prostaglandin E2-induced ocular inflammation and safety: A technical note

The efficacy of aqueous, oil, and ointment formulations of ketorolac against PGE2-induced ocular inflammation in rabbits was evaluated, with monitoring of blinking rate and PMN and protein migration in tear fluid, following topical PGE2 instillation. Ketorolac ophthalmic formulations protected the eye against inflammatory insult. Chronic topical administration of formulations for 10 days into rats' eyes did not lead to any appreciable gastrointestinal ulceration, which indicates that the formulations are safe for long-term use.

Effect of dehydroepiandrosterone on cartilage and synovium of knee joints with osteoarthritis in rabbits

The aim of this study was to investigate the effects of intra-articular injection of dehydroepiandrosterone (DHEA) on cartilage and synovium of knee joints with osteoarthritis (OA) in rabbits and the underlying mechanism. Forty rabbits underwent unilateral anterior cruciate ligament transaction and were divided into two groups. Rabbits were injected with 100 mumol/l DHEA dissolved in the dimethylsulphoxide (DMSO) in the knee joints 5 weeks after transaction, once a week for 5 weeks. Rabbits injected with DMSO under the same condition were served as a control. All rabbits were killed 1 week after the last injection. The knee joints were evaluated by gross morphology, histology, and gene expression analysis. Gross morphologic inspection and histological evaluation showed that the DHEA group appeared less damage in cartilage and synovium as compared with the control. Gene expression analysis revealed that the mRNA expression of matrix metalloproteinase-3 (MMP-3) in cartilage and synovium decreased significantly in the DHEA group and that of tissue inhibitor of metalloproteinase-1 (TIMP-1) increased. No significant difference of interleukin-1 beta (IL-1beta) mRNA expression was found in the cartilage between two groups while the mRNA expression of IL-1beta in the synovium was largely suppressed in the DHEA group. The study suggests that DHEA plays a protective role against cartilage degradation and synovium inflammation in rabbits with OA. This role may be achieved through the regulation of the MMP-3, TIMP-1, and IL-1beta gene expression in the cartilage and synovium.

Dexamethasone Alleviates Meconium‐Induced Airway Hyperresponsiveness and Lung Inflammation in Rabbits

The effects of dexamethasone on in vitro airway reactivity associated with lung inflammation were investigated in rabbits with meconium aspiration. Oxygen-ventilated adult rabbits received an intratracheal bolus of 4 ml/kg body weight of saline (Sal, n = 4) or human meconium (25 mg/ml). Thirty minutes later, meconium-instilled animals intravenously received 0.5 mg/kg of dexamethasone (Dexa, n = 6), or were left without treatment (Meco, n = 5). The animals were ventilated for a further 5 hr and then sacrificed. The left lungs were lavaged with saline, and the white blood cell (WBC) count was estimated. Tracheal and right-lung tissue strips were placed into organ chambers with Krebs-Henseleit solution. Cumulative doses of histamine (10(-8)-10(-3) mol/l) and acetylcholine (10(-8)-10(-3) mol/l) were added to the chambers, and recordings of contractions were made after a 30-min loading phase with a tension of 4 grams, and another 30-min adaptation phase with a tension of 2 g. Tracheal smooth muscle in vitro reactivity to histamine was higher in the Meco than in the Sal group, and dexamethasone decreased the reactivity compared to the Meco group (P < 0.05). Lung tissue in vitro reactivity to histamine was slightly higher in the Meco than in the Sal group (P > 0.05), and dexamethasone decreased the reactivity compared to both the Meco and Sal groups (P < 0.05). No between-group differences were observed in tracheal or lung in vitro reactivity to acetylcholine (P > 0.05). In the Meco group, blood WBC (P > 0.05) and neutrophil (P < 0.05) counts were lower than in the Sal and Dexa groups. Lung neutrophils and eosinophils were higher in both the Meco and Dexa groups than in the Sal group (P < 0.01). Dexamethasone decreased neutrophils (P < 0.05) compared to the Meco group. Meconium-induced airway hyperreactivity to histamine and lung inflammation were alleviated by dexamethasone.

Intravitreal implantation of the biodegradable cyclosporin A drug delivery system for experimental chronic uveitis

The purpose was to evaluate the efficacy of the intravitreal implantation of the biodegradable cyclosporin A (CsA) drug delivery system (DDS) for experimental chronic uveitis. The DDS was prepared by formulating CsA into glycolide-co-lactide-co-caprolactone copolymer (PGLC). Right eyes of 30 New Zealand white rabbits were used to establish a model of uveitis and randomized into control, intravitreal non-medicated DDS, oral CsA (15 mg/kg daily), and intravitreal CsA-PGLC DDS (each containing 2 mg CsA) groups. The progress of ocular inflammation, results of electroretinography, and histopathological examination of ocular, renal, and hepatic functions were recorded. Intravitreal CsA levels were measured in another 13 rabbits receiving an implant of the CsA-PGLC DDS. Chronic uveitis was successfully induced in all 30 eyes. The inflammation in the eyes with no treatment, non-medicated implant, and oral CsA was more severe than those with the CsA-PGLC DDS at each timepoint. The electroretinography b-wave was depressed much less in the CsA-PGLC DDS group than in the other three groups (p<0.05). No renal or hepatic tissue damage was found in eyes with the CsA-PGLC DDS. The mean intravitreal CsA level was 102.2~145.5 ng/ml at 1~3 weeks after CsA-PGLC DDS implantation, 491.0~575.2 ng/ml at 4~10 weeks, and 257.3 ng/ml at 14 weeks; no toxicity was detected. Intravitreal implantation of the biodegradable CsA-PGLC DDS may effectively reduce the intraocular inflammation in rabbits with no toxicity, which provides a potentially safe and convenient approach for the treatment of chronic uveitis.

Inhibition of Na+-H+ exchange by cariporide reduces inflammation and heart failure in rabbits with myocardial infarction.

The aim of this study was to assess the effects of the Na+-H+ exchange inhibitor cariporide on left ventricular (LV) morphology and function as well as inflammation in rabbits with heart failure. Rabbits with myocardial infarction (MI) and sham controls were randomized to receive either standard chow or chow supplemented with cariporide for 9 weeks. LV morphology was determined by echocardiography. LV systolic and diastolic function was assessed under load-dependent and -independent conditions by analysis of LV pressure-volume loops using piezo-electric crystals. Plasma concentrations of C-reactive protein and aldosterone were measured. Rabbits with MI developed LV dilatation that was reduced by cariporide. Systolic and diastolic LV function was impaired in rabbits with MI when compared to sham, as indicated by a decreased dP/dtmax (MI: 3537 +/- 718 mmHg s(-1), sham: 5839 +/- 247 mmHg s(-1), P < 0.05), the load-independent preload recruitable stroke work (PRSW)(MI: 22 +/-7 mmHg, sham: 81 +/- 23 mmHg, P < 0.05) and a reduction in the time constant of relaxation tau (tau) (MI: 27+/-1 ms, sham: 17+/-1 ms, P < 0.05), and significantly improved by cariporide (dP/dtmax: 4586 +/- 374 mmHg s(-1), PRSW: 67 +/- 18 mmHg, tau: 20 +/- 2 ms; P < 0.05 vs MI/control). Induction of MI was associated with an increase in aldosterone and CRP, indicating activation of the neurohormonal and the inflammatory system that were largely reduced by cariporide. Cariporide improves LV morphology and function post MI and suppresses inflammation and neurohormonal activation in congestive heart failure (CHF). Na+-H+ exchange inhibition may represent a new pharmaceutical approach for the treatment of CHF.

Effect of Topical Betaxolol on the Acute Rise of Aqueous Flare Induced by Highly Selective Agonists for Prostaglandin E2 Receptor Subtypes in Pigmented Rabbits

Purpose: To evaluate the role of topical betaxolol on experimental ocular inflammation in rabbits. Method: Transcorneal diffusion of highly selective agonists for prostaglandin E₂ receptor subtypes (EP), 25 µg/ml, with the use of a glass cylinder, was performed to produce aqueous flare elevation in pigmented rabbits. Betaxolol was topically administered before EP agonist application. Aqueous flare was measured with a laser flare cell meter. Results: Performing topical instillation of 0.5% betaxolol 4 times inhibited 52 ± 9% of EP2-agonist (ONO-AE1-259-01)-induced aqueous flare elevation. The inhibition of flare elevation was dependent on the number of betaxolol instillations. Betaxolol did not suppress the elevation induced by an EP4 agonist (ONO-AE1-392). Conclusion: Betaxolol inhibited EP2-agonist-induced aqueous flare elevation in pigmented rabbits.

Melanocortins are comparable to corticosteroids as inhibitors of traumatic ocular inflammation in rabbits

Melanocyte-stimulating hormone (MSH) is a known anti-inflammatory agent and we investigated whether it reduces the inflammatory reaction following ocular surgery. Rabbits received a perforating corneolimbal cut. Treatment involved topical (10(-8)M) or intramuscular (50 mg/kg/day) MSH, topical steroids or saline. The parameters studied were hyperemia, edema, aqueous protein levels and the number of inflammatory cells in the aqueous, as well as their number determined histologically in the injured cornea. Each parameter was assessed at 24 h post injury. Topically and systematically applied MSH reduced edema to levels 60% and 76%, respectively, of those observed in operated saline-treated eyes (P<0.001), and their efficacy was comparable to that of topical steroids. The decrease in hyperemia brought about by MSH was more pronounced than that produced by steroids. Aqueous protein levels were reduced by a similar degree in the steroid- and MSH-treated eyes as in the saline group (P<0.001 for each treatment group); In MSH- and ste-roid-treated eyes the number of inflammatory cells in the aqueous was reduced by 80% and 50%, respectively. We demonstrated that MSH reduced the clinical signs of ocular inflammation, curtailed blood-aqueous barrier (BAB) disruption, and reduced aqueous inflammatory cell number. The efficacy of MSH applied systemically or topically was similar to that of steroids in reducing clinical signs of trauma, but MSH efficacy in maintaining BAB integrity surpassed that of steroids. We suggest that the melanocortins might be a useful anti-inflammatory agents in ocular trauma.

Recombinant human Fas ligand induces alveolar epithelial cell apoptosis and lung injury in rabbits

This study investigated whether recombinant human soluble Fas ligand (rh-sFasL) induces apoptosis of primary type II pneumocytes in vitro and lung injury in vivo. Type II cells isolated from normal rabbit lung expressed Fas on their surface and became apoptotic after an 18-h incubation with rh-sFasL. Fas expression in normal rabbit lungs was localized by immunohistochemistry to alveolar and airway epithelia and alveolar macrophages. The administration of 10 microg of rh-sFasL into the right lungs of rabbits resulted 24 h later in both significantly more bronchoalveolar lavage fluid total protein and significantly more tissue changes compared with those in the left lungs, which received rh-sFasL plus Fas:Ig (a fusion protein that binds and blocks sFasL). Tissue changes included thickening of the alveolar walls, neutrophilic infiltrates, apoptotic (terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling-positive) cells in the alveolar walls, and increased expression of interleukin-8 by alveolar macrophages (as determined by immunohistochemistry). We conclude that the alveolar epithelium of normal rabbits expresses Fas and that sFasL induces lung injury and inflammation in rabbits.