heparitin-sulfate and Asthma

Glycosaminoglycans (GAGs) are large, polyanionic molecules expressed throughout the body. The GAG heparin, co-released with histamine, is synthesised by and stored exclusively in mast cells, whereas the closely related molecule heparan sulphate is expressed, as part of a proteoglycan, on cell surfaces and throughout tissue matrices. These molecules are increasingly thought to play a role in regulation of the inflammatory response and heparin, for many years, has been considered to hold potential in the treatment of diseases such as asthma. Heparin and related molecules have been found to exert antiinflammatory effects in a wide range of in vitro assays, animal models and, indeed, human patients. Moreover, the results of studies carried out to date indicate that the antiinflammatory activities of heparin are dissociable from its well-established anticoagulant nature, suggesting that the separation of these characteristics could yield novel antiinflammatory drugs which may be useful in the future treatment of diseases such as asthma

Topics: Animals; Anticoagulants; Asthma; Glycosaminoglycans; Heparin; Heparitin Sulfate; Humans; Inflammation; Mast Cells

Identification of carbohydrate sequences that determine affinity to specific chemokines is a critical step for strategies to interfere with chemokine-mediated leukocyte trafficking. Here, we first characterized the development of allergic asthma in Tie2-dependent and inducible Ext1-knockout (Tie2-Ext1(iKO)) mice. We showed that heparan sulfate is essential for leukocyte recruitment in the peribronchial region and bronchoalveolar lavage fluid (BALF), and is crucial for induction of airway hyperresponsiveness. Our glycan microarray showed a unique affinity profile of chemokine CCL20 to substructures of heparin and heparin-like oligo/di/monosaccharides. Among them, we identified a synthetic and not naturally occurring monosaccharide, 2,4-O-di-sulfated iduronic acid (Di-S-IdoA), as a potential inhibitor for CCL20-heparan sulfate interaction. Mice injected with Di-S-IdoA via tail vain or nasal inhalation showed attenuated leukocyte recruitment into inflammatory sites and BALF. These results demonstrate a critical role of chemokine-heparan sulfate interaction in the asthma development and Di-S-IdoA as a potential drug for asthma treatment.

Topics: Animals; Asthma; Bronchoalveolar Lavage Fluid; Carbohydrate Sequence; Chemokine CCL20; Chemotaxis; Disease Models, Animal; Eosinophils; Heparitin Sulfate; Iduronic Acid; Lung; Mice; Mice, Knockout; N-Acetylglucosaminyltransferases; Ovalbumin; Polysaccharides; Receptor, TIE-2; Sulfates; T-Lymphocytes

Heparan sulfate proteoglycans (HSPGs) are glycoproteins consisting of a core protein to which linear heparan sulfate (HS) side chains are covalently attached. These HS side chains mediate a variety of biologic functions involved in inflammation. Radionuclide imaging of HS side chains in tissues with inflammation may be used for the stratification of patients who would most likely benefit from HSPG-targeting therapy. The goal of this study was to evaluate the feasibility of in vivo radionuclide imaging of HS side chain expression in a mouse model of asthma using the recombinant eosinophil cationic protein (rECP).. rECP was radioiodinated with (125)I or (123)I using the Chloramine-T method. The 50% inhibitory concentration value for (125)I-labeled rECP was determined in a competitive cell-binding assay using Beas-2B cells. The binding of radiolabeled rECP to HS side chains was evaluated both in vitro and in vivo. The biodistribution of radiolabeled rECP was assessed in asthma mice or in control mice using SPECT imaging, ex vivo biodistribution measurements, and microautoradiography.. The 50% inhibitory concentration value for (125)I-rECP was 7.4 ± 0.1 nM. The loss of HS side chains substantially inhibited the cellular and tissue uptake of (125)I- or (123)I-rECP, indicating that HS side chains of HSPGs are required for (125)I- or (123)I-eosinophil cationic protein binding and uptake both in vitro and in vivo. SPECT imaging demonstrated an appreciably higher accumulation of radioactivity in the lungs of asthma mice than in those of control mice. Ex vivo biodistribution studies also confirmed that there was at least a 4-fold increase in the lung-to-muscle ratio of asthma mice, compared with control mice. The accumulation of radiolabeled rECP was linearly correlated with leukocyte infiltration.. This study illustrates the feasibility of using radiolabeled rECP for the visualization of HS side chains of HSPGs and the evaluation of allergic lung inflammation in living subjects. Our data indicate that radiolabeled rECP is a novel imaging agent for HS side chains of HSPGs in predicting allergic lung inflammation in living mice.

Topics: Allergens; Animals; Asthma; Biological Transport; Cell Line, Tumor; Disease Models, Animal; Drug Stability; Eosinophil Cationic Protein; Female; Gene Expression Regulation; Heparitin Sulfate; Humans; Hypersensitivity; Inflammation; Iodine Radioisotopes; Isotope Labeling; Leukocytes; Mice; Molecular Imaging; Multimodal Imaging; Positron-Emission Tomography; Radiochemistry; Recombinant Proteins; Tomography, X-Ray Computed

There is no consensus concerning thromboembolic prophylaxis in high-risk pregnant women with a previous history of heparin-induced thrombocytopenia. An alternative anticoagulant therapy is danaparoïd, whereas unfractioned and low-molecular-weight heparin therapy is contraindicated. We report a case of successful thrombosis prophylaxis using danaparoïd in a high-thrombosis-risk pregnant woman with a history of heparin-induced thrombocytopenia during a previous pregnancy and Widal's disease.

Topics: Adult; Anticoagulants; Aspirin; Asthma; Cephalosporins; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Drug Hypersensitivity; Female; Heparin; Heparinoids; Heparitin Sulfate; Humans; Pregnancy; Pregnancy Complications, Hematologic; Risk Factors; Thrombocytopenia; Thromboembolism

Diabetes mellitus and asthma have many antipodal features. Although both are common disorders, concurrence occurs less often than would be predicted. When co-existence does occur, the cases are generally mild, and effective treatment of one disease frequently exacerbates the other. The hypothesis is advanced that basilar membrane concentrations of heparan sulfate differ in these two diseases and that this difference may account for the antithetical features. An experimental basis for postulating increased concentrations of extracellular heparan sulfate in asthma and diminished concentrations in diabetes is cited. A rationale for tying these differences to the polar activities of cholinergic transmission and atherogenesis in the two diseases is advanced. Diminished heparan sulfate concentrations in diabetes may down-regulate the transmission of vagal impulses to insulin-producing pancreatic cells, and thereby impair both the continued vitality of these cells, and the acetylcholine modulated potentiation of glucose-induced insulin release.

Topics: Arteriosclerosis; Asthma; Diabetes Complications; Diabetes Mellitus; Heparin; Heparitin Sulfate; Humans; Models, Biological; Synaptic Transmission

In a previous study, and in the present study, we have found that the baseline plasma samples of patients with asthma contain average levels of an endogenous heparin-like material (EHM) that is significantly higher than that noted in non-allergic, non-asthmatic controls. This material appears to have properties of both heparin and heparan sulfate. Three out of six patients responding to inhalational antigen challenge displayed an acute increment in EHM concentration that coincided with a fall in FEV values. The relation of EHM concentration to provoked asthma, or to asthma in general, remains to be determined.

Topics: Adult; Anticoagulants; Antigens; Asthma; Female; Forced Expiratory Volume; Heparin; Heparitin Sulfate; Humans; Male