The cannabinoid receptor agonist WIN 55,212-2 inhibits antigen-induced plasma extravasation in guinea pig airways.

BACKGROUND: Although neurogenic inflammation of the airways via activation of C-fibers is thought to be important in the pathogenesis of asthma, the mechanisms regulating C-fiber activity remain uncertain. OBJECTIVE: The influence of a cannabinoid receptor agonist, WIN 55,212-2, on C-fiber activation in guinea pig airways was investigated, as was the mechanism by which cannabinoids regulate antigen-induced airway inflammation. METHODS: The inhibitory effect of WIN 55,212-2 on antigen-induced plasma extravasation was assessed in guinea pig tracheal tissues by photometric measurement of extravasated Evans blue dye after extraction with formamide. RESULTS: Pretreatment with WIN 55,212-2 (0.001, 0.01 or 0.1 mg/kg) significantly and dose-dependently reduced tracheal plasma extravasation induced by inhaling a 5% ovalbumin solution for 2 min after pretreatment with a neutral endopeptidedase inhibitor (phosphoramidon at 2.5 mg/kg i.v.). A cannabinoid CB2 receptor antagonist (SR144528) blunted the inhibitory effect of WIN 55,212-2, while a cannabinoid CB1 antagonist (SR141716A) did not. Pretreatment with a neurokinin-1 receptor antagonist (FK888) significantly reduced ovalbumin-induced extravasation of Evans blue dye. Pretreatment with the combination of WIN 55,212-2 and FK888 reduced antigen-induced plasma extravasation more markedly than FK888 alone. CONCLUSIONS: These findings suggest that WIN 55,212-2 inhibits C-fiber activation via the cannabinoid CB2 receptor and thus suppresses antigen-induced inflammation in guinea pig airways.

Evaluation of inflammatory response of EDTA, EDTA-T, and citric acid in animal model.

INTRODUCTION: The biocompatibility of chelating agents and organic acids have been explained by a variety of methods, and suggestions for use have been based more on clinical observations and physicochemical properties than on biological aspects. The present study aimed to evaluate the inflammatory response of 17% EDTA, 17% EDTA-T, and 10% citric acid in bony defect created in rat jaws. METHODS: Mandibular through and through critical size defects were created bilaterally in 60 rats. Fibrinol (Baldacchi SA, São Paulo, Brazil), a cube-shaped compound of absorbable bovine fibrin foam and sodium chloride, was used as a carrier of the substances. One side had received Fibrinol (control), whereas the opposite side had received Fibrinol soaked with each substance on the 1st, on the 7th, on the 14th, and on the 28th day (n=5 for each day). Hemijaws were prepared for light microscopy, and samples were stained with hematoxylin and eosin. Digitized images were analyzed with a morphometric software (ImageJ; National Institute of Mental Health, Bethesda, MD). to obtain the number of inflammatory cells per area. Comparisons were performed by using the Kruskal-Wallis test (p=0.05). RESULTS: For all days, 10% citric acid and 17% EDTA-T showed, respectively, the lowest and highest number of inflammatory cells per area. All tested substances and controls showed the highest inflammatory cell response on the 14th day. CONCLUSION: Among the tested substances, 10% citric acid proved to be the less aggressive tested solution at 14 days. At 28 days, all solutions were similar, but EDTA-T kept showing the higher number of inflammatory cells.

Suppression of endotoxin-induced inflammation by taxol.

The pathogenesis of acute lung injury includes transendothelial diapedesis of leukocytes into lung tissues and disruption of endothelial/epithelial barriers leading to protein-rich oedema. In vitro studies show that the microtubule network plays a role in the regulation of endothelial permeability as well as in neutrophil locomotion. It was hypothesised that the microtubule-stabilising agent, taxol, might attenuate inflammation and vascular leak associated with acute lung injury in vivo. The effect of intravenously delivered taxol was assessed using a model of murine lung injury induced by intratracheal lipopolysaccharide (LPS) administration. Parameters of lung injury and inflammation were assessed 18 h after treatment. Intravenously delivered taxol significantly reduced inflammatory histological changes in lung parenchyma and parameters of LPS-induced inflammation: infiltration of proteins and inflammatory cells into bronchoalveolar lavage fluid, lung myeloperoxidase activity, and extravasation of Evans blue-labelled albumin into lung tissue. Taxol alone (in the absence of LPS) had no appreciable effect on these parameters. In addition to lung proteins, intravenous taxol reduced accumulation of leukocytes in ascitic fluid in a model of LPS-induced peritonitis. Taken together, the present data demonstrate that microtubule stabilisation with taxol systemically attenuates lipopolysaccharide-induced inflammation and vascular leak.

Contribution of vascular endothelial growth factor to airway hyperresponsiveness and inflammation in a murine model of toluene diisocyanate-induced asthma.

Isocyanate chemicals, including toluene diisocyanate (TDI), are currently the most common causes of occupational asthma. Although considerable controversy remains regarding its pathogenesis, TDI-induced asthma is characterized by hyperresponsiveness and inflammation of the airways. One of the histological hallmarks of inflammation is angiogenesis, but the possible role of vascular endothelial growth factor (VEGF), a potent angiogenic cytokine, in TDI-induced asthma is unknown. We developed a murine model to investigate TDI-induced asthma by performing two courses of sensitization with 3% TDI and one challenge with 1% TDI using ultrasonic nebulization to examine the potential involvement of VEGF in that disease. These mice develop the following typical pathophysiological features: airway hyperresponsiveness, airway inflammation, and increased VEGF levels in the airway. Administration of VEGFR inhibitors reduced all these pathophysiological symptoms. These results suggest that VEGF is one of the major determinants of TDI-induced asthma and that the inhibition of VEGF may be a good therapeutic strategy.

Lack of systemic anaphylaxis and aeroallergen-induced airway plasma extravasation in allergic immunoglobulin-deficient mice.

BACKGROUND: In Ig-deficient mice allergen challenge-induced pulmonary late phase inflammation is at least as pronounced as in wild-type animals. This study investigates immediate hypersensitivity responses in these mice. METHODS: To examine the acute plasma extravasation response in airway tissue, immunized Ig-deficient and wild-type mice and sham-immunized wild-type controls were subjected to 15 min ovalbumin aerosol challenge. 125I-albumin was injected (i.v.) 1 min prior to challenge. Immediately after challenge 131I-albumin was injected and the experiment was terminated. Plasma and trachea were analyzed for 125I and 131I, and the amount of extravasated plasma in the trachea was calculated. To study the development of systemic anaphylaxis immunized Ig-deficient and wild-type animals received intravenous allergen challenge followed by determination of mast cell responses and plasma histamine levels. RESULTS: Allergen aerosol-exposed immunized wild-type mice exhibited marked plasma extravasation in the trachea (pd0.01 vs. wild-type controls), but in the corresponding Ig-deficient mice there was no increased extravasation. Immunized Ig-deficient mice receiving intravenous allergen challenge were resistant to anaphylactic shock. By contrast, the wild-type animals developed systemic anaphylaxis, accompanied by plasma extravasation, mast cell degranulation, elevated plasma histamine and rapid death. CONCLUSION: The present data are evidence that immunoglobulins are crucial for the development of immediate (type 1) responses. These findings together with our previous observations on late-phase pulmonary responses suggest that immediate hypersensitivity processes are unimportant for development of the late phase inflammation in the respiratory tract of mice.

[Effect of Daflon 500 mg on reperfusion damage following ischemia and reperfusion of striated muscle]. / Effekte von Daflon 500 mg auf den Reperfusionsschaden nach Ischämie und Reperfusion im quergestreiften Muskel.

The results of the current study indicate that Daflon 500 mg effectively reduces permeability for macromolecules induced by ischemia-reperfusion, thus reducing postischemic edema formation in the early reperfusion period. The inhibitory effect of Daflon 500 mg on leukocyte emigration may account for the reduction of edema formation in the postischemic tissue and favor the therapeutic use Daflon 500 mg of reperfusion-injury.

ICAM-1 and iNOS expression increased in the skin of mice after vaccination with gamma-irradiated cercariae of Schistosoma mansoni.

Host responses to migrating schistosomula of Schistosoma mansoni were compared in the skin of naive, multiply infected, or vaccinated (with gamma-irradiated cercariae) mice during the first 72 hr after cercarial penetration. Cellular response to the migrating parasite was minimal in the skin of naive mice for up to 72 hr after infection. In sharp contrast, the multiply infected or vaccinated animals exhibited a marked inflammatory response in the skin as early as 8 hr after cutaneous penetration of the challenge cercariae. This early inflammatory response in the skin of sensitized animals was characterized by a significant increase in the number of infiltrating cells, predominantly mononuclear cells and neutrophils. Increased exudation of serum proteins was also present in the skin of sensitized animals in areas of cercarial challenge. A time course of analyses revealed that mononuclear cell numbers increased significantly in the skin of vaccinated animals as early as 60 min after a challenge infection and continued to be present at a significantly higher level up to 72 hr after challenge. Peak neutrophil responses occurred in the skin at 24 hr (in multiply infected animals) and at 48 hr (in vaccinated animals) after a challenge infection. Along with the massive cellular infiltration there was an increased tissue expression of ICAM-1 and mRNA for iNOS in the skin of sensitized animals. Further analysis showed that in sensitized animals increased ICAM-1 expression was predominantly found on endothelial cells lining dermal capillaries, especially in areas around schistosomular migration and on cells that surrounded schistosomula in the dermis. In naive animals, however, a similar infection did not induce any ICAM-1 expression or iNOS production in the skin. Thus, an ICAM-1 mediated early accumulation of mononuclear cells in the skin and local production of nitric oxide may be important for the initial cutaneous inflammatory immune responses to migrating schistosomula of S. mansoni in vaccinated animals. On the contrary, in naive animals a potential parasite-induced suppression of ICAM-1 may play an important role in reducing cellular reaction in the skin and consequently help the parasite evade immune responses in the skin.