Analgesic and anti-inflammatory articular effects of essential oil and camphor isolated from Ocimum kilimandscharicum Gürke leaves.

ETHNOPHARMACOLOGICAL RELEVANCE: Leaves from Ocimum kilimandscharicum Gürke (Lamiaceae) are popularly used against articular pain. AIM OF STUDY: The aim of this study was to test the anti-inflammatory and anti-hyperalgesic (analgesic) properties of the essential oil and camphor isolated from O. Kilimandscharicum leaves (EOOK) in 4 models including zymosan induced-articular inflammation model in mice. MATERIAL AND METHODS: For in vivo models, EOOK was tested in carrageenan-induced paw edema model with oral doses of 30, 100, and 300 mg/kg (oral administration = p.o.) and in zymosan-induced articular inflammation (including knee edema, leukocyte infiltration, mechanical hyperalgesia and nitric oxide), EOOK (100 mg/kg, p. o.) and camphor (30 mg/kg, p. o.) were tested. EOOK (100 mg/kg, p. o.) was tested in the rolling and also in the adhesion of leukocytes to the mesenteric microcirculation in situ model of carrageenan induced inflammation and EOOK (1, 3, 10, 30, and 60 µg/mL) was tested in vitro against neutrophils chemotaxis induced by N-formyl methionyl leucyl phenylalanine (fMLP). RESULTS: The treatment with EOOK significantly inhibited the carrageenan-induced edema, mechanical and cold hyperalgesia. Both, EOOK and camphor inhibited all articular parameters induced by zymosan. In situ intravitral microscopy analysis, EOOK significantly inhibited carrageenan-induced leukocyte rolling and adhesion. In vitro neutrophils chemotaxis, EOOK inhibited the leukocyte chemotaxis induced by fMLP. CONCLUSIONS: The present study showed that EOOK inhibited pain and inflammatory parameters contributing, at least in part, to explain the popular use of this plant as analgesic natural agent. This study also demonstrates that camphor and some known anti-inflammatory compounds present in EOOK could contribute for analgesic and anti-inflammatory articular properties.

The polysaccharide-rich tea of Ximenia americana barks prevents indomethacin-induced gastrointestinal damage via neutrophil inhibition.

ETHNOPHARMACOLOGICAL RELEVANCE: Barks of Ximenia americana are used by the population to treat gastrointestinal inflammatory disorders. Indomethacin is a non-selective non-steroidal anti-inflammatory drug that induces marked gastrointestinal damage. AIMS OF THE STUDIES: To evaluate the gastroprotective activity of total polysaccharides contained in the extract (TPL-Xa) or tea (Tea-Xa) of Ximenia americana barks in the mice gastric damage induced by indomethacin. MATERIALS AND METHODS: TPL-Xa was obtained by a combination of NaOH extraction and ethanol precipitation. Tea-Xa was prepared in distilled water boiled during 5 min. Animals received p.o. 0.9% NaCl (saline - control group), TPL-Xa (1-90 mg/kg) or Tea-Xa 1 h before gastritis induction by indomethacin (20 mg/kg). Mice were sacrificed 7 h after gastritis induction and analyzed for the following parameters: stomach lesions measurement; histological evaluation; myeloperoxidase (MPO) activity; nitrate/nitrite and cytokine levels; leukocyte adhesion and rolling by intravital microscopy. RESULTS: TPL-Xa reduced macroscopic and microscopic damage, MPO activity (59%), leukocyte rolling (86%) and adhesion (84%), nitrite/nitrate ratio (100%) and IL-8 (69%), but increased IL-4 (50%). Tea-Xa (12.8 yield; 39.3% carbohydrate, including 25.8% uronic acid; 4% protein) reduced macroscopic damage (62%) and MPO activity (50%). CONCLUSION: TPL and Tea of Ximenia americana barks ameliorate the gastric injury induced by indomethacin in mice, an effect that was dependent on the reduction of neutrophil infiltration.

Contribution of muscarinic receptors to in vitro and in vivo effects of Ruscus extract.

The objectives of this study were to evaluate, in vitro and in vivo, the contribution of muscarinic receptors to the effects of Ruscus extract. Ruscus extract was tested in competition binding experiments at recombinant human muscarinic receptors, heterologous expressed in Chinese Hamster Ovary (CHO) cells and in cellular assays measuring Ca2+ liberation and activator protein-1 (AP-1) reporter gene activation. The impact of muscarinic blockade on prolonged treatment outcome was evaluated using the hamster cheek pouch (HCP) microcirculation examining macromolecular permeability increase induced by histamine or ischemia/reperfusion (I/R), mean arteriolar and venular diameters, functional capillary density and I/R-induced leukocyte rolling and sticking. Ruscus extract exhibited affinities for muscarinic receptor subtypes at a range of 50-100µg/ml and behaved as partial agonist at human recombinant M1 and M3 receptors for Ca2+ liberation, confirmed in an AP-1 reporter gene assay. In the HCP model, topical application of atropine completely or partially blocked Ruscus extract-induced reductions of histamine- and I/R-induced increases of macromolecular permeability and leukocyte-endothelium interaction. Our results showed that Ruscus extract in vitro binds and activates different subtypes of muscarinic receptors and in vivo its anti-inflammatory effects are, at least partially, mediated via muscarinic receptors.

Fish Oil and Adjuvant-Induced Arthritis: Inhibitory Effect on Leukocyte Recruitment.

Fish oil, a rich source of n-3 fatty acids, has been studied for its beneficial effects in many diseases. Recent studies have shown the robust anti-inflammatory activity of fish oil (FO), when administered orally to rats, in models of acute inflammation. Herein, we investigated if treatment with fish oil preparation (FOP) could interfere with the recruitment of leukocytes into the joint cavity of arthritic rats. We also evaluated the effect of treatment on rolling behavior and leukocyte adhesion in vivo and on leukocyte chemotaxis in vitro. Treatment with FOP (75, 150, and 300 mg/kg) initiated on the day of induction of arthritis (day 0) and maintained for 21 days reduced the total number of leukocytes recruited into the joint cavity, the number of rolling and adhered leukocytes in arthritic rats, and leukocyte migration in response to stimulation with N-formyl-methionyl-leucyl-phenylalanine (fMLP) and leukotriene B4 (LTB4). Together, our data provide evidence that FOP plays an important inhibitory role in the recruitment of leukocytes into the joint cavity of arthritic rats.

n-3 PUFA induce microvascular protective changes during ischemia/reperfusion.

Ischemia/reperfusion (I/R) injury can occur in consequence of myocardial infarction, stroke and multiple organ failure, the most prevalent cause of death in critically ill patients. I/R injury encompass impairment of endothelial dependent relaxation, increase in macromolecular permeability and leukocyte-endothelium interactions. Polyunsaturated fatty acids (n-3 PUFA), such as eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3) found in fish oil have several anti-inflammatory properties and their potential benefits against I/R injury were investigated using the hamster cheek pouch preparation before and after ischemia. Before the experiments, hamsters were treated orally with saline, olive oil, fish oil and triacylglycerol (TAG) and ethyl ester (EE) forms of EPA and DHA at different daily doses for 14 days. Fish oil restored the arteriolar diameter to pre ischemic values during reperfusion. At onset and during reperfusion, Fish oil and DHA TAG significantly reduced the number of rolling leukocytes compared to saline and olive oil treatments. Fish oil, EPA TAG and DHA TAG significantly prevented the rise on leukocyte adhesion compared to saline. Fish oil (44.83 ± 3.02 leaks/cm(2)), EPA TAG (31.67 ± 2.65 leaks/cm(2)), DHA TAG (41.14 ± 3.63 leaks/cm(2)), and EPA EE (30.63 ± 2.25 leaks/cm(2)), but not DHA EE (73.17 ± 2.82 leaks/cm(2)) prevented the increase in macromolecular permeability compared to saline and olive oil (134.80 ± 1.49 and 121.00 ± 4.93 leaks/cm(2), respectively). On the basis of our findings, we may conclude that consumption of n-3 polyunsaturated fatty acids, especially in the triacylglycerol form, could be a promising therapy to prevent microvascular damage induced by ischemia/reperfusion and its consequent clinical sequelae.

Mechanisms of the anti-inflammatory actions of the angiotensin type 1 receptor antagonist losartan in experimental models of arthritis.

Angiotensin (Ang) II and its AT1 receptors have been implicated in the pathogenesis of rheumatoid arthritis. Activation of the counter-regulatory Ang-(1-7)-Mas receptor axis may contribute to some of the effects of AT1 receptor blockers (ARBs). In this study, we have used losartan, an ARB, to investigate the role of and the mechanisms by which AT1 receptors participated in two experimental models of arthritis: antigen-induced arthritis (AIA) in mice and adjuvant-induced arthritis (AdIA) in rats. Treatment with losartan decreased neutrophil recruitment, hypernociception and the production of TNF-α, IL-1ß and chemokine (C-X-C motif) ligand 1 in mice subjected to AIA. Histopathological analysis showed significant reduction of tissue injury and inflammation and decreased proteoglycan loss. In addition to decreasing cytokine production, losartan directly reduced leukocyte rolling and adhesion. Anti-inflammatory effects of losartan were not associated to Mas receptor activation and/or Ang-(1-7) production. Anti-inflammatory effects were reproduced in rats subjected to AdIA. This study shows that ARBs have potent anti-inflammatory effects in animal models of arthritis. Mechanistically, reduction of leukocyte accumulation and of joint damage was associated with local inhibition of cytokine production and direct inhibition of leukocyte-endothelium interactions. The anti-inflammatory actions of losartan were accompanied by functional improvement of the joint, as seen by reduced joint hypernociception. These findings support the use of ARBs for the treatment of human arthritis and provide potential mechanisms for the anti-inflammatory actions of these compounds.

High-dose chlorogenic acid induces inflammation reactions and oxidative stress injury in rats without implication of mast cell degranulation.

ETHNOPHARMACOLOGICAL RELEVANCE: Chlorogenic acid (CA) exits widely in those Chinese herbal injections that have antibacterial and antiphlogistic effects and belongs to the ethnopharmacological family of medicines. Chinese herbal injections containing high levels of CA have been reported to increase the adverse drug reactions, but the mechanism for which is still unclear. In this study, we investigated the mechanism of the CA derived adverse drug reactions. AIM OF THE STUDY: The present study was to explore the potential role of CA in initiating inflammatory reaction and the underlying mechanism. MATERIALS AND METHODS: Male Wistar rats were treated with different dosages of CA for different time period. The variables examined included microcirculation by intravital microscopy, histology of ileum tissue, expression of adhesion molecules CD11b and CD18 on leukocytes by flow cytometry, myeloperoxidase activity and maleic dialdehyde content in ileum tissue by spectrophotometry, activity of superoxide dismutase and catalase in serum by ELISA, and expression of NADPH oxidase subunits by PCR and Western blot. RESULTS: High-dose CA increased the number of adherent leukocytes, generation of peroxides in the venular walls and induced albumin leakage from mesentery venules. High-dose CA induced changes also included an increase in maleic dialdehyde, myeloperoxidase, inflammatory cytokines and NADPH oxidase activities, and a decline in activity of superoxide dismutase and catalase. CONCLUSION: High-dose, but not Low-dose CA induced inflammation reaction, and in this process an imbalance between oxidant and antioxidant mechanism may be involved, providing more information for better understanding the rationale behind the adverse effects of CA.

[Activated protein C, a protein at the crossroads between coagulation and inflammation]. / La protéine C activée: une protéine à l'interface de l'inflammation et de la coagulation.

Sepsis is defined as a systemic response to infection, characterized by an intense inflammatory response linked to coagulation activation and fibrinolysis inhibition, two processes which are intimately associated. In a field where mortality remains very high, administration of activated protein C, a physiological coagulation inhibitor with cytoprotective properties, has demonstrated its effectiveness and was able to reduce mortality. Protein C belongs to a system that involves plasma proteins and endothelial cell receptors. In addition to well documented effects on coagulation and fibrinolysis, activated protein C exhibits anti-inflammatory, anti-apoptotic but also anti-histone activities. Indeed, a recent study focusing on the cytoprotective effects of activated protein C showed that extracellular histones are released during severe sepsis and may participate in the pathophysiology of severe sepsis. These histones appear to be new targets of activated protein C.

Intravenous omega-3, a technique to prevent an excessive innate immune response to cardiac surgery in a rodent gut ischemia model.

OBJECTIVES: Neutrophil infiltration of tissues as part of the inflammatory response to cardiac surgery is one of the major mediators of postoperative multiple-organ dysfunction. Omega-3 fatty acids markedly attenuate endothelial cell inflammatory responses, including upregulation of neutrophil adhesion molecules. The efficacy of a clinically safe form of omega-3 to produce this effect in vivo was examined. METHODS: Rat gut intravital microscopic analysis was used to visualize neutrophil transmigration from the microcirculation into the tissues of the gut. Inflammatory activation was in the form of 30 minutes of ischemia and 90 minutes of reperfusion. Sham, control (0.9% saline infusion over 4 hours), and omega-3 (Omegaven [Fresenius Kabi, Bad Homburg, Germany] infusion over 4 hours) pretreatments were compared. RESULTS: Ischemia-reperfusion resulted in a 4-fold increase in neutrophil adherence to the endothelium (baseline: 4.3 ± 0.2 vs control group: 19.2 ± 3.5 adherent neutrophils per 100 µm, P < .01), which intravenous omega-3 suppressed (7.8 ± 1.7 adherent neutrophils per 100 µm, P < .01). Omega-3 pretreatment also reduced neutrophil transmigration into the tissues after reperfusion (sham group: 6.3 ± 0.8 vs control group: 13.2 ± 1.4 vs omega-3 group: 9.4 ± 0.9 neutrophils per field, P = .037). Gut tissue levels of the neutrophil-released enzyme myeloperoxidase were similarly markedly reduced with omega-3 pretreatment (sham group: 10.5 ± 1.6 vs control group: 19.0 ± 3.3 vs omega-3 group: 10.1 ± 1.2 U/g, P = .03). CONCLUSIONS: Four hours' pretreatment with a relatively safe form of intravenous omega-3 suppressed neutrophil adherence and tissue infiltration, resulting in lower levels of the tissue-damaging enzyme myeloperoxidase. This suggests a possible strategy for diminishing postoperative multiple-organ dysfunction.

Cerebralcare Granule, a Chinese herb compound preparation, improves cerebral microcirculatory disorder and hippocampal CA1 neuron injury in gerbils after ischemia-reperfusion.

AIM OF THE STUDY: Cerebralcare Granule (CG) is a Chinese herb compound preparation that has been used for treatment of cerebrovascular related diseases. However, the effect of post-treatment with CG on ischemia and reperfusion (I/R) induced cerebral injury is so far unclear. MATERIALS AND METHODS: In present study, cerebral global I/R was induced in Mongolian gerbils by clamping bilateral carotid arteries for 30 min followed by reperfusion for 5 days, and CG (0.4 g/kg or 0.8 g/kg) was administrated 3h after the initiation of reperfusion. RESULTS: Post-treatment with CG for 5 days attenuated the I/R-induced production of hydrogen peroxide in, leukocyte adhesion to, and albumin leakage from cerebral microvessels, and, meanwhile, protected neuron from death, reduced the number of caspase-3- and Bax-positive cells, and increased Bcl-2-positive cells in hippocampal CA1 region. CONCLUSION: The results suggest that CG given after initiation of reperfusion is able to ameliorate cerebral microvascular dysfunction and hippocampal CA1 neuron damage caused by I/R.

Anti-inflammatory activity and possible mechanism of extract from Mikania laevigata in carrageenan-induced peritonitis.

OBJECTIVES: The aim was to test the potential use of an extract of Mikania laevigata (popularly known in Brazil as guaco), made from leaves harvested in different months of the year, on neutrophil migration after an inflammatory stimulus and investigate the underlying molecular mechanisms. METHODS: We examined the effect of guaco on vascular permeability and leucocyte function in carrageenan-induced peritonitis in mice. KEY FINDINGS: Our results demonstrated that guaco extract administered subcutaneously (3 mg/kg) decreased the vascular permeability and also leucocyte rolling and adhesion to the inflamed tissues by a mechanism dependent on nitric oxide. Specifically, inhibitors of nitric oxide synthase remarkably abrogated the guaco extract-mediated suppression of neutrophil migration to the inflammatory site. In addition, guaco extract-mediated suppression of neutrophil migration appeared to be dependent on the production of the cytokines interleukin-1beta and tumour necrosis factor-alpha. One of the major constituents of the guaco extract, coumarin, was able to inhibit the neutrophil migration towards the inflammatory focus. CONCLUSIONS: In conclusion the anti-inflammatory effect induced by guaco extract may be by inhibition of pro-inflammatory cytokine production at the inflammatory site.

Involvement of NO in the inhibitory effect of Calotropis procera latex protein fractions on leukocyte rolling, adhesion and infiltration in rat peritonitis model.

AIM OF THE STUDY: The latex of Calotropis procera has been used in the traditional medicinal system for the treatment of leprosy, ulcers, tumors, piles and diseases of liver, spleen, abdomen and toothache. It comprises of a non-dialyzable protein fraction (LP) that exhibits anti-inflammatory properties and a dialyzable fraction (DF) exhibiting pro-inflammatory properties. The present study was carried out to evaluate the effect of LP sub-fractions on neutrophil functions and nociception in rodent models and to elucidate the mediatory role of nitric oxide (NO). MATERIAL AND METHODS: The LP was subjected to ion exchange chromatography and the effect of its three sub-fractions (LP(PI), LP(PII) and LP(PIII)) thus obtained was evaluated on leukocyte functions in the rat peritonitis model and on nociception in the mouse model. RESULTS: LP sub-fractions exhibit distinct protein profile and produce a significant decrease in the carrageenan and DF induced neutrophil influx and exhibit anti-nociceptive property. The LP and its sub-fractions produced a marked reduction in the number of rolling and adherent leukocytes in the mesenteric microvasculature as revealed by intravital microscopy. The anti-inflammatory effect of LP(PI), the most potent anti-inflammatory fraction of LP, was accompanied by an increase in the serum levels of NO. Further, our study shows that NO is also involved in the inhibitory effect of LP(PI) on neutrophil influx. CONCLUSIONS: Our study shows that LP fraction of Calotropis procera comprises of three distinct sets of proteins exhibiting anti-inflammatory and anti-nociceptive properties of which LP(PI) was most potent in inhibiting neutrophil functions and its effects are mediated through NO production.

Budlein A from Viguiera robusta inhibits leukocyte-endothelial cell interactions, adhesion molecule expression and inflammatory mediators release.

Budlein A has been reported to exert some analgesic and anti-inflammatory properties. In this study, we have evaluated its effect on LPS-induced leukocyte recruitment in vivo and the mechanisms involved in its anti-inflammatory activity. In vivo, intravital videomicroscopy was used to determine the effects of budlein A on LPS-induced leukocyte-endothelial cell interactions in the murine cremasteric microcirculation. In vitro, the effects of budlein A on LPS-induced cytokine, chemokine and nitrites release, T-cell proliferative response as well as cell adhesion molecule expression (CAM) were evaluated. In vivo, intraperitoneal administration of budlein A (2.6 mM/kg) caused a significant reduction of LPS-induced leukocyte rolling flux, adhesion and emigration by 84, 92 and 96% respectively. In vitro, T-cell proliferative response was also affected by budlein A. When murine J774 macrophages were incubated with the sesquiterpene lactone, LPS-induced IL-1beta, tumor necrosis factor-alpha (TNF-alpha) and keratinocyte-derived chemokine (KC) release were concentration-dependently inhibited. In human umbilical vein endothelial cells (HUVECs), budlein A also reduced the production of TNF-alpha, monocyte chemoattractant protein-1 (MCP-1), IL-8, nitrites and CAM expression elicited by LPS. Budlein A is a potent inhibitor of LPS-induced leukocyte accumulation in vivo. This effect appears to be mediated through inhibition of cytokine and chemokine release and down-regulation of CAM expression. Thus, it has potential therapeutic interest for the control of leukocyte recruitment that occurs in different inflammatory disorders.

Involvement of nitric oxide in microcirculatory reactions after ischemia-reperfusion of the rat urinary bladder.

BACKGROUND: Nitric oxide (NO) plays a role in inflammation. Our aim was to investigate the role of NO in the microcirculatory changes after ischemia-reperfusion (I/R) of the bladder using intravital videomicroscopy (IVM). METHODS: In rats, 60 min of bladder ischemia followed by 30 min of reperfusion was performed in the presence of N(G)-nitro-L-arginine methyl ester (L-NAME), the NO precursor L-arginine, or saline pre-treatments. Venular red blood cell velocity (RBCV), functional capillary density (FCD), vessel diameters, and leukocyte-endothelial cell interactions in postcapillary venules were determined. Concentrations of nitrite/nitrate in the plasma and myeloperoxidase (MPO) levels in the lungs and the bladder were measured. RESULTS: Elevations of the numbers of rolling and adherent leukocytes, and of plasma nitrite/nitrate levels were found, while FCD and RBCV decreased. L-NAME pretreatment ameliorated the enhanced leukocyte-endothelial cell interactions without influencing the microcirculatory perfusion. In contrast, the L-arginine pretreatment further increased plasma nitrite/nitrate levels and preserved the FCD and RBCV, but did not affect leukocyte-endothelial interactions. None of these treatments influenced MPO activities. CONCLUSION: Our results suggest that NO plays an enhancing role in the I/R-induced neutrophil-endothelial interactions of the bladder. Supplementation of NO ameliorates the microcirculatory perfusion deficit without influencing the postischemic microcirculatory inflammatory reactions.

Effect of mangiferin on the development of periodontal disease: involvement of lipoxin A4, anti-chemotaxic action in leukocyte rolling.

UNLABELLED: Mangiferin is a polyphenol compound obtained from mango and has been reported to possess antioxidant and anti-inflammatory properties. AIM: We propose to evaluate the influence of mangiferin in preventing and treating experimental periodontitis induced in Wistar rats. MAIN METHODS: Periodontitis was induced in rats by applying a ligature around the lower right first molar. After ligature, groups of animals were submitted orally to the following treatments: saline 10 mL/kg, piroxicam 20 mg/kg or mangiferin 100 mg/kg. On days 1, 4 or 7 after ligature application the alveolar bone loss (ABL) was determined. We evaluated the effect of mangiferin on ABL by histological techniques (alveolar bone loss and cellularity), enzyme immunoassay (lipoxin A(4)), intravital microscopy (rolling leukocytes and endothelial-leukocyte adhesion), zymographic analyses (metalloproteinases, MMPs 2 and 9), immunohistochemistry (PCNA, COX-2 and CXCR4) and toxicology. KEY FINDINGS: Oral administration of mangiferin significantly reduced ABL. We also observed the reduction of cellularity in mangiferin-treated rats. Treatment with mangiferin inhibited COX-2 expression and the rolling and adhesion of leukocytes, while maintaining normal lipoxin A(4) levels. The mangiferin did not interfere in the activity of MMP-2 or -9. The mangiferin-treated rats presented an earlier peak of cell proliferation and augmented angiogenesis in the injured region. SIGNIFICANCE: Our results have demonstrated promising therapeutic potential of mangiferin both in the prevention and treatment of periodontitis.

Intravenous immunoglobulins reverse acute vaso-occlusive crises in sickle cell mice through rapid inhibition of neutrophil adhesion.

Previous studies using intravital microscopy in a sickle cell disease (SCD) mouse model suggest that adherent white blood cells (WBCs) play a key role in vaso-occlusion by capturing circulating red blood cells (RBCs) in venules. Commercial intravenous immunoglobulin (IVIG) given before the inflammatory stimuli increased microcirculatory blood flow and survival. To mimic the clinical situation in which SCD patients seek medical attention after the onset of symptoms, we developed an in vivo model in which the therapeutic intervention (eg, IVIG) was administered after in the inflammatory challenge. In this setting, IVIG rapidly (<10 minutes) reduced adherent leukocyte numbers and dramatically inhibited interactions between RBCs and WBCs, resulting in improved microcirculatory blood flow and survival of sickle cell "Berkeley" mice. Longer survival correlated positively with blood flow (P=.001) and negatively with the number of adherent leukocytes (P=.001) and RBC-WBC interactions (P=.002). Using multichannel digital fluorescence videomicroscopy, we found that IVIG affected specifically the recruitment of neutrophils. Moreover, further analyses of leukocyte behavior revealed that IVIG significantly increased rolling velocities, indicating that it alters adhesion pathways involved in slow rolling. These data suggest that the potential therapeutic benefits of IVIG in SCD crises should be evaluated in a clinical trial.

Primary immune surveillance: some like it hot.

The thermal element of fever has been found to be beneficial in models of infectious disease. The contributions of fever-range temperatures to the efficacy of the adaptive immune response have only begun to be delineated. There is accumulating evidence that fever-range thermal stress bolsters primary immune surveillance of lymph nodes and Peyer patches by augmenting lymphocyte extravasation across specialized vessels termed high endothelial venules. Molecular mechanisms have recently come to light by which the thermal component of fever alone may promote lymphocyte trafficking, and thereby the probability of mounting a defense against microbial infection. Acquired knowledge of the molecular changes associated with thermal stress may allow for the development of novel therapies for a variety of disease processes.

Compound Danshen injection improves endotoxin-induced microcirculatory disturbance in rat mesentery.

AIM: To investigate the effect of compound Danshen injection on lipopolysaccharide (LPS)-induced rat mesenteric microcirculatory dysfunctions and the underlying possible mechanism by an inverted intravital microscope and high-speed video camera system. METHODS: LPS was continuously infused through the jugular artery of male Wistar rats at the dose of 2 mg/kg per hour. Changes in mesenteric microcirculation, such as diameters of arterioles and venules, velocity of RBCs in venules, leukocyte rolling, adhesion and emigration, free radicals released from post-capillary venules, FITC-albumin leakage and mast cell degranulation, were observed through an inverted intravital microscope assisted with CCD camera and SIT camera. Meanwhile, the expression of adhesion molecules CD11b/CD18 and the production of free radical in neutrophils, and the expression of intercellular adhesion molecule 1 (ICAM-1) in human umbilical vein endothelial cells (HUVECs) were quantified by flow cytometry (FACS) in vitro. RESULTS: The continuous infusion with LPS resulted in a number of responses in microcirculation, including a significant increase in the positive region of venule stained with Monastral blue B, rolling and adhesion of leukocytes, production of oxygen radical in venular wall, albumin efflux and enhanced mast cell degranulation in vivo, all of which, except for the leukocyte rolling, were attenuated by the treatment with compound Danshen injection. Experiments performed in vitro further revealed that the expression of CD11b/CD18 and the production of oxygen free radical in neutrophils, and the expression of ICAM-1 in HUVECs were increased by exposure to LPS, and they were attenuated by compound Danshen injection. CONCLUSION: These results suggest that compound Danshen injection is an efficient drug with multi-targeting potential for improving the microcirculatory disturbance.

Combined effects of curcumin and vitamin C to protect endothelial dysfunction in the iris tissue of STZ-induced diabetic rats.

This study was aimed to evaluate the combined effect of curcumin with vitamin C supplementation on hyperglycemic and dyslipidemia conditions and endothelial cell dysfunction induced in diabetic rats. Wistar Furth rats were used and divided into four groups: control (single injection of 0.9% sterile saline), STZ (streptozotocin, Sigma, 55 mg/kg.BW, i.v.), STZ-vitC (1 g/l ascorbic acid mixed in drinking water), STZ-cur (daily oral treatment of 300 mg/kg.BW curcumin; Cayman Chemical Co., USA), and STZ-cur+vitC (1 g/l ascorbic acid mixed in drinking water and oral treatment of 300 mg/kg.BW curcumin). On 8th week after STZ-injection, the microcirculation in the iris tissue was observed using intravital fluorescence videomicroscopy, and also leukocyte adhesion in the venule was examined for each group. Blood glucose (BG), lipid profiles, glycosylated hemoglobin (HbA1c) were measured in blood samples collected at the end of each experiment. The contents of liver malondialdehyde (MDA) were also quantified for each group. Feeding curcumin (STZ-cur) could decrease BG, HbA1c, dyslipidemia, and MDA significantly, compared to STZ. In cases of feedings curcumin with vitamin C, these results were more effective in all aspects, including leukocyte adhesion. In conclusion, curcumin might increase the effect of vitamin C in protecting the function of endothelial cells through its anti-oxidant with hypoglycemic and hypolipidemic actions.

Handle with care: targeting neutrophils in chronic obstructive pulmonary disease and severe asthma?

Neutrophils play an important role in the pathogenesis of airway inflammation in both chronic obstructive pulmonary disease (COPD) and severe asthma. Currently available drugs have only limited effects on neutrophilic airway inflammation, particularily in COPD. Therefore, great efforts are undertaken to address neutrophilic inflammation in chronic respiratory disorders, in particular COPD. This review summarizes the rationale for anti-neutrophilic treatment in COPD and asthma and gives a critical overview of current developments in drug therapy. Moreover, unanswered questions and limitations of clinical trial design and choice of outcome parameters for proof-of-concept studies with novel anti-neutrophilic drugs are discussed as well as potential safety issues.