Nitric-Oxide-Releasing Dexamethasone Derivative NCX-1005 Improves Lung Function and Attenuates Inflammation in Experimental Lavage-Induced ARDS

Acute respiratory distress syndrome (ARDS) is a common complication of critical illness and remains a major source of morbidity and mortality in the intensive care unit (ICU). ARDS is characterised by diffuse lung inflammation, epithelial and endothelial deterioration, alveolar–capillary leak and oedema formation, and worsening respiratory failure. The present study aimed to investigate the anti-inflammatory activity of nitric-oxide-releasing dexamethasone derivative NCX-1005 as a potential novel drug for ARDS. Adult rabbits with lavage-induced ARDS were treated with dexamethasone i.v. (0.5 mg/kg; DEX) and nitro-dexamethasone i.v. (0.5 mg/kg, NCX-1005) or were untreated (ARDS). Controls represented healthy ventilated animals. The animals were subsequently oxygen-ventilated for an additional 4 h and respiratory parameters were recorded. Lung oedema, inflammatory cell profile in blood and bronchoalveolar lavage, levels of the cytokines (IL-1β, IL-6, IL-8, TNF-α), and oxidative damage (TBARS, 3NT) in the plasma and lung were evaluated. Nitric oxide-releasing dexamethasone derivative NCX-1005 improved lung function, reduced levels of cytokines, oxidative modifications, and lung oedema formation to similar degrees as dexamethasone. Only NCX-1005 prevented the migration of neutrophils into the lungs compared to dexamethasone. In conclusion, the nitric oxide-releasing dexamethasone derivative NCX-1005 has the potential to be effective drug with anti-inflammatory effect in experimental ARDS.

Anti-inflammatory Activity of Sulphated Polysaccharide Isolated from Ulva fasciata

There are various components to an inflammatory reaction that can contribute to the associated symptoms and tissue injury and these include Oedema formation, leukocyte infiltration and granuloma formation. Anti-inflammatory activity of the polysaccharide isolated from Ulva fasciata was analysed by carrageenan induced acute paw Oedema and formalin induced chronic paw Oedema. The isolated polysaccharide showed anti-inflammatory activity. Keywords: Ulva fasciata, Sulphated Polysaccharide, Paw Oedema, Anti-inflammatory Activity

Anti-inflammatory secondary metabolites from Scrophularia kotschyana

The species belonging to Scrophularia genus grow mainly in Irano-Turanian and Mediterranean regions and have been used as folk remedy for inflammatory-related diseases since ancient times. The present study was aimed to evaluate the anti-inflammatory activity of the extracts of Scrophularia kotschyana as well as the isolated compounds. The aerial parts and the roots of the plant were separately extracted with methanol. Anti-inflammatory activities of both extracts were evaluated with formalin test in mice. As the methanolic extract of the aerial parts significantly ( p < .05) inhibited inflammation, it was then submitted to successive solvent extractions with n-hexane, dichloromethane, ethyl acetate and n-butanol to yield subextracts. Anti-inflammatory activities of the subextracts were evaluated within the same test system. Among the subextracts tested, the n-butanol subextract produced a significant ( p < .05) anti-inflammatory activity at all doses (5, 10, and 30 mg/kg, ip.). Sequential chromatographic separation of the n-butanol subextract yielded 8-O-acetyl-4′- O-( E)- p-coumaroylharpagide, 8- O-acetyl-4′- O-( Z)- p-coumaroylharpagide, β-sitosterol 3- O-β-glucopyranoside, apigenin 7- O-β-glucopyranoside, apigenin 7- O-rutinoside, luteolin 7- O-β-glucopyranoside and luteolin 7- O-rutinoside. The anti-inflammatory activities of the isolates were evaluated at 5 mg/kg dose. Luteolin 7- O-β-glucopyranoside and apigenin 7- O-rutinoside caused a significant ( p < .05) inhibition of oedema formation.

Protective Effect of Methyl gallate on Murine Antigen-Induced Arthritis by Inhibiting Inflammatory Process and Bone Erosion

Methyl gallate (MG) is a plant-derived phenolic compound known to present remarkable anti-inflammatory effect in different experimental models such as paw oedema, pleurisy, zymosan-induced arthritis and colitis. Herein we investigated the effect of MG in the mice model of antigen-induced arthritis (AIA), a model with complex inflammatory response, driven primally by immune process and that cause bone and cartilage erosion similarly found in rheumatoid arthritis. Arthritis was induced by i.a injection of albumin methylated from bovine serum (mBSA) in C57BL/6 male mice previously immunized. The dose-response analysis of MG (0.7-70 mg/kg; p.o) showed that maximum inhibition was reached with the dose of 7 mg/kg on paw oedema and cell infiltration induced by AIA at 7 h. Treatment with MG (7mg/kg; p.o) or with the reference drug, dexamethasone (Dexa,10 mg/kg, ip) reduced AIA oedema formation, leukocyte infiltration, release of extracellular DNA and cytokine production 7 and 24 h (acute response). Mice treated daily with MG for seven days showed no significant weight loss or liver and kidney toxicity contrary to Dexa that induced some degree of toxicity. Prolonged treatment with MG inhibited the late inflammatory response (28 days) reducing oedema formation, cell infiltration, synovial hyperplasia, pannus formation and cartilage degradation as observed in histopathological analyses. Ultimately, MG reduced bone resorption as evidenced by a decrease in tartrate-resistant acid phosphate (TRAP)-positive cells number in femur histology. Altogether, we demonstrate that MG ameliorates the inflammatory reaction driven primarily by the immune process, suggesting a potential therapeutic application in arthritis treatment.

First person – Bernhard N. Bohnert

ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Bernhard N. Bohnert is first author on ‘ Essential role of DNA-PKcs and plasminogen for the development of doxorubicin-induced glomerular injury in mice’, published in DMM. Bernhard is a physician/postdoc in the lab of Prof. Dr. med. Ferruh Artunc at the University Hospital Tübingen, Tübingen, Germany, investigating oedema formation in nephrotic syndrome.

Pathogenesis and Treatment of Refractory Oedema in Nephrotic Syndrome

Oedema is a hallmark feature of nephrotic syndrome (NS) and can cause significant patient morbidity. The pathogenesis of oedema formation is complex and results from abnormalities in sodium retention, inter-play of neurohormonal factors, and changes in capillary filtration barrier. Salt retention is often primary (‘overfill’ theory) because of increased sodium-potassium adenosine triphosphatase activity in the collecting duct cells, increased direct epithelial sodium channel activation (ENaC) by urinary proteases (independent of aldosterone), and an overall increased effective arterial blood volume. However, a subset of patients with NS, especially children, demonstrate decreased effective arterial blood volume (‘underfill’ theory) and secondary sodium retention as the primary mechanism of oedema formation. Increased capillary permeability and vascular inflammation contributes as well. Loop diuretics with or without salt-poor albumin are the mainstay of therapy in adults, although no large clinical trials exist to guide diuretic choice or dosage. Combination diuretic therapy is recommended to achieve multi-site nephron blockade and overcome diuretic resistance, which is a frequent challenge. Use of direct ENaC inhibitors (amiloride) in combination with loop diuretics may be especially beneficial given the primary role of ENaC in sodium retention. Aquaretics such as vasopressin receptor antagonists may have a role in treatment as well. Well-designed clinical trials are essential to guide therapy of refractory oedema in NS. In this review, the authors discuss the pathogenesis of oedema formation in patients with NS and propose a treatment algorithm for management of resistant oedema based on the limited available evidence.

Hyperbaric oxygen treatment in recurrent development of complex regional pain syndrome: A case report

A broad spectrum of conditions including neuropathic pain, complex regional pain syndrome (CRPS) and fibromyalgia, have been implicated as causes of chronic pain. There is a need for new and effective treatments that patients can tolerate without significant adverse effects. One potential intervention is hyperbaric oxygen treatment (HBOT). The case reported here is unique in describing repeated HBOT in a patient who developed recurrent post-traumatic CRPS of the lower as well as the upper limbs. In the first event, two months after distortion and abruption of the external right ankle, the patient suffered leg pain, oedema formation, mild hyperaemia, limited mobility of the ankle and CRPS Type 1. In the second event, the same patient suffered fracture-dislocation of the distal radius 1.5 years after the first injury. After the plaster cast was removed the patient developed pain, warmth, colour changes, oedema formation and limited wrist mobility with CRPS Type 1. Pharmacological treatment as well as HBOT were used with significant improvement of functional outcome in both cases. Some studies suggest that patients with a history of CRPS are more likely to develop secondary CRPS compared to the rates reported in the literature among the general population. Patients with a history of CRPS should be counselled that they may be at risk for developing secondary CRPS if they undergo surgery or sustain trauma to another extremity.

Pengaruh Penghambatan Enzim Siklooksigenase-2 dan Aktivitas Antiinflamasi dari Ekstrak Daun Ketumbar (Coriandrum sativum L.)

Inflammation is a normal protective response to tissue damage that mediated by Cyclooxygenase-2 (COX-2) enzyme. The enhancement incidence and impact of inflammatory diseases have encouraged the search for new pharmacological strategies to overcome the problem. Ketumbar (Coriandrumsativum L.) has been traditionally used as an anti-inflammatory and antioxidant, thus giving chance for anti-inflammatory studies. This study aims to determine the ethanol extract of Ketumbar (Coriandrumsativum L.) leaves anti-inflammatory activity and inhibitory effect on COX-2 enzyme. This study uses male wistar rats with 180–220 g body weights. The rats is divided into six groups by the dose of 125 mg/kg BW, 250 mg/kg BW, and 500 mg/kg BW; positive control (Carrageenan 1%); negative control (Na. CMC 0,5%); and comparative group (Celecoxib 9 mg/kg BW). Determining the anti-inflammatory activity, the oedema formation is measured using a plethysmometer and the inhibition activity is determined by ELISA methods. The results showed that the ethanol extract of Ketumbar leaves by the dose of 125 mg/kg BW, 250 mg/kg BW, and 500 mg/kg BW was significantly inhibitted COX-2 valued 65,61%, 76,83%, and 62,93%. The anti-inflammatory activity was shown by inhibiting oedema valued of 62.26%, 70.59%, and 54.90% respectively. These findings suggested that the ethanol extract of Ketumbar leaves had anti-inflammatory activity, that was possibly mediated through inhibition of COX-2 enzymes

Neutrophil extracellular traps mediate joint hyperalgesia induced by immune inflammation

Objective To evaluate the role of neutrophil extracellular traps (NETs) in the genesis of joint hyperalgesia using an experimental model of arthritis and transpose the findings to clinical investigation. Methods C57BL/6 mice were subjected to antigen-induced arthritis (AIA) and treated with Pulmozyme (PLZ) to degrade NETs or Cl-amidine to inhibit NET production. Oedema formation, the histopathological score and mechanical hyperalgesia were evaluated. NETs were injected intra-articularly in wild type (WT), Tlr4−/−, Tlr9−/−, Tnfr1−/− and Il1r−/− mice, and the levels of cytokines and Cox2 expression were quantified. NETs were also quantified from human neutrophils isolated from RA patients and individual controls. Results AIA mice had increased NET concentration in joints, accompanied by increased Padi4 gene expression in the joint cells. Treatment of AIA mice with a peptidyl arginine deiminase 4 inhibitor or with PLZ inhibited the joint hyperalgesia. Moreover, the injection of NETs into joints of naïve animals generated a dose-dependent reduction of mechanical threshold, an increase of articular oedema, inflammatory cytokine production and cyclooxygenase-2 expression. In mice deficient for Tnfr1, Il1r, Tlr4 and Tlr9, joint hyperalgesia induced by NETs was prevented. Last, we found that neutrophils from RA patients were more likely to release NETs, and the increase in synovial fluid NET concentration correlated with an increase in joint pain. Conclusion The findings indicate that NETs cause hyperalgesia possibly through Toll-like receptor (TLR)-4 and TLR-9. These data support the idea that NETs contribute to articular pain, and this pathway can be an alternative target for the treatment of pain in RA.

Effect of thrombectomy on oedema progression and clinical outcome in patients with a poor collateral profile

Background and purposeThe impact of the cerebral collateral circulation on lesion progression and clinical outcome in ischaemic stroke is well established. Moreover, collateral status modifies the effect of endovascular treatment and was therefore used to select patients for therapy in prior trials. The purpose of this study was to quantify the effect of vessel recanalisation on lesion pathophysiology and clinical outcome in patients with a poor collateral profile.Materials and methods129 patients who had an ischaemic stroke with large vessel occlusion in the anterior circulation and a collateral score (CS) of 0–2 were included. Collateral profile was defined using an established 5-point scoring system in CT angiography. Lesion progression was determined using quantitative lesion water uptake measurements on admission and follow-up CT (FCT), and clinical outcome was assessed using modified Rankin Scale (mRS) scores after 90 days.ResultsOedema formation in FCT was significantly lower in patients with vessel recanalisation compared with patients with persistent vessel occlusion (mean 19.5%, 95% CI: 17% to 22% vs mean 27%, 95% CI: 25% to 29%; p<0.0001). In a multivariable linear regression analysis, vessel recanalisation was significantly associated with oedema formation in FCT (ß=−7.31, SD=0.015, p<0.0001), adjusted for CS, age and Alberta Stroke Program Early CT Score (ASPECTS). Functional outcome was significantly better in patients following successful recanalisation (mRS at day 90: 4.5, IQR: 2–6 vs 5, IQR: 5–6, p<0.001).ConclusionAlthough poor collaterals are known to be associated with poor outcome, endovascular recanalisation was still associated with significant oedema reduction and comparably better outcome in this patient group. Patients with poor collaterals should not generally be excluded from thrombectomy.