heparitin-sulfate and Chronic-Disease

Remarkable progress has been achieved in understanding the regulation of gene expression and protein translation, and how aberrancies in these template-driven processes contribute to disease pathogenesis. However, much of cellular physiology is controlled by non-DNA, nonprotein mediators, such as glycans. The focus of this Translational Review is to highlight the importance of a specific glycan polymer-the glycosaminoglycan heparan sulfate (HS)-on lung health and disease. We demonstrate how HS contributes to lung physiology and pathophysiology via its actions as both a structural constituent of the lung parenchyma as well as a regulator of cellular signaling. By highlighting current uncertainties in HS biology, we identify opportunities for future high-impact pulmonary and critical care translational investigations.

Topics: Acute Disease; Animals; Chronic Disease; Heparitin Sulfate; Humans; Lung; Lung Injury; Signal Transduction

Stewart-Bluefarb syndrome (SBS), also known as acroangiodermatitis or pseudo-Kaposi, is a condition rarely encountered. It involves skin lesions that are clinically similar to Kaposi sarcoma but are histologically different, and are usually secondary to an underlying arteriovenous fistula. Treatment of this disease usually involves the correction of the underlying vascular abnormality, with the mainstay of therapy ranging from compression devices for venous stasis, limited oral medications (dapsone and erythromycin) and local wound care including topical steroids. Different methods of treatment showed varied success but none is ideal. We report a case of a lower extremity ulcer in a 22-year-old male recently diagnosed with SBS successfully treated with heparan sulphate (Cacipliq20®).

Topics: Acrodermatitis; Arteriovenous Fistula; Chronic Disease; Heparitin Sulfate; Humans; Leg Ulcer; Male; Syndrome; Young Adult

This study investigated levels of hyaluronan and chondroitin-4-sulphate in the crevicular fluid of patients with chronic adult periodontitis at diseased and healthy sites before and after treatment. The relationship between clinical diagnostic parameters and levels of glycosaminoglycans in gingival crevicular fluid were also analysed. Within each patient, 4 sites either mesial or distal and on single rooted teeth were classified as diseased or healthy using a modified gingival index, pocket depth and attachment loss. Crevicular fluid was collected from each site using glass micropipettes and analyzed for glycosaminoglycan content by cellulose acetate electrophoresis. Significantly higher levels of chondroitin-4-sulphate were detected at diseased sites prior to treatment correlating with increased pocket depth or attachment levels. Following a period of treatment consisting of oral hygiene instruction and root planing, the patients were reassessed for their response to treatment by measuring the modified gingival index, pocket depth, attachment loss and levels of glycosaminoglycans. Analysis of glycosaminoglycan levels at diseased sites that demonstrated a poor response to treatment also demonstrated significantly higher levels of chondroitin-4-sulphate than those sites that responded well to treatment. Hyaluronan levels were less significantly associated with clinically succesful treatment. This study confirmed the use of the sulphated glycosaminoglycan chondroitin-4-sulphate as a potential diagnostic aid of periodontal tissue destruction; however, further longitudinal studies are required to assess their performance.

Topics: Adult; Analysis of Variance; Chondroitin Sulfates; Chronic Disease; Cross-Sectional Studies; Dermatan Sulfate; Gingival Crevicular Fluid; Glycosaminoglycans; Heparitin Sulfate; Humans; Hyaluronic Acid; Oral Hygiene; Periodontal Index; Periodontitis; Root Planing; Statistics, Nonparametric

Fifty patients suffering from chronic venous disease were treated for 30 days with heparan sulphate 100 mg per os, b.i.d., or mesoglycan 50 mg per os, t.i.d., in a single blind random study. Both therapies led to a marked improvement in comparison to basal clinical values, but patients treated with heparan sulphate showed the greatest and most rapid regression of symptoms, associated with a significant improvement in plethysmographic index of capacitance and venous flow. Patients treated with heparan sulphate also showed an increased fibrinolytic activity and a reduced antithrombin III consumption, both of which were statistically significant.

Topics: Administration, Oral; Adult; Aged; Chronic Disease; Female; Glycosaminoglycans; Heparitin Sulfate; Humans; Male; Middle Aged; Safety; Single-Blind Method; Venous Insufficiency

One of the biggest challenges faced by healthcare providers is the treatment of chronic, non-healing wounds. This paper reports for the first time in the UK the results of five case studies in which a novel regenerating matrix-based therapy, CACIPLIQ20, was used. CACIPLIQ20 is a heparan sulphate mimetic designed to replace the destroyed heparan sulphate in the extracellular matrix of wound cells. All five patients in this case series had chronic, non-healing ulcers that had not improved with conventional care. Treatment included two applications of CACIPLIQ20 per week, for a maximum of 12 weeks. Three of the five wounds healed completely, and the remaining two showed significant improvements in size and quality. The treatment was well tolerated by the patients and also led to a significant reduction in pain. Moreover, CACIPLIQ20 treatment was found to be highly cost-effective when compared to conventional care, with the potential to save healthcare systems significant resources. Further studies are needed to build a strong evidence base on the use of this product, but these preliminary findings are certainly promising.

Topics: Adult; Aged; Aged, 80 and over; Amputation, Surgical; Bandages; Chronic Disease; Cost-Benefit Analysis; Extracellular Matrix; Female; Glucans; Heparitin Sulfate; Humans; Inflammation; Male; Middle Aged; Peripheral Vascular Diseases; Pressure Ulcer; Regeneration; Surgical Wound; Varicose Ulcer; Wounds and Injuries

Topics: Administration, Topical; Child; Chronic Disease; Glycosaminoglycans; Heparitin Sulfate; Herpes Zoster Ophthalmicus; Humans; Keratitis; Male; Nanoparticles; Polymers; Treatment Failure; Treatment Outcome

Heparan sulfate (HS) plays a crucial role in the fibrosis associated with chronic allograft dysfunction by binding and presenting cytokines and growth factors to their receptors. These interactions critically depend on the distribution of 6-O-sulfated glucosamine residues, which is generated by glucosaminyl-6-O-sulfotransferases (HS6STs) and selectively removed by cell surface HS-6-O-endosulfatases (SULFs). Using human renal allografts we found increased expression of 6-O-sulfated HS domains in tubular epithelial cells during chronic rejection as compared with the controls. Stimulation of renal epithelial cells with TGF-β induced SULF2 expression. To examine the role of 6-O-sulfated HS in the development of fibrosis, we generated stable HS6ST1 and SULF2 overexpressing renal epithelial cells. Compared with mock transfectants, the HS6ST1 transfectants showed significantly increased binding of FGF2 (p = 0.0086) and pERK activation. HS6ST1 transfectants displayed a relative increase in mono-6-O-sulfated disaccharides accompanied by a decrease in iduronic acid 2-O-sulfated disaccharide structures. In contrast, SULF2 transfectants showed significantly reduced FGF2 binding and phosphorylation of ERK. Structural analysis of HS showed about 40% down-regulation in 6-O-sulfation with a parallel increase in iduronic acid mono-2-O-sulfated disaccharides. To assess the relevance of these data in vivo we established a murine model of fibrosis (unilateral ureteric obstruction (UUO)). HS-specific phage display antibodies (HS3A8 and RB4EA12) showed significant increase in 6-O-sulfation in fibrotic kidney compared with the control. These results suggest an important role of 6-O-sulfation in the pathogenesis of fibrosis associated with chronic rejection.

Topics: Animals; Chronic Disease; Disease Models, Animal; Fibroblast Growth Factor 2; Fibrosis; Graft Rejection; Heparitin Sulfate; Humans; Kidney; Kidney Transplantation; Male; Mice; Mice, Inbred C57BL; Recombinant Proteins; Signal Transduction; Sulfatases; Sulfates; Sulfotransferases

Depending on the glycan structure, proteoglycans can act as coreceptors for growth factors. We hypothesized that proteoglycans and their growth factor ligands orchestrate tissue remodeling in chronic transplant dysfunction. We have previously shown perlecan to be selectively up-regulated in the glomeruli and arteries in a rat renal transplantation model. Using the same model, here we present quantitative RT-PCR profiling data on proteoglycans and growth factors from laser-microdissected glomeruli, arterial tunicae mediae, and neointimae at 12 weeks after transplantation. In glomeruli and neointimae of allografts, selective induction of the matrix heparan sulfate proteoglycan perlecan was observed, along with massive accumulation of fibroblast growth factor 2 (FGF2). Profiling the heparan sulfate polysaccharide side chains revealed conversion from a non-FGF2-binding heparan sulfate phenotype in control and isografted kidneys toward a FGF2-binding phenotype in allografts. In vitro experiments with perlecan-positive rat mesangial cells showed that FGF2-induced proliferation is dependent on sulfation and can be inhibited by exogenously added heparan sulfate. These findings indicate that matrix proteoglycans such as perlecan serve as functional docking platforms for FGF2 in chronic transplant dysfunction. We speculate that heparin-like glycomimetics could be a promising intervention to retard development of glomerulosclerosis and neointima formation in chronic transplant dysfunction.

Topics: Allografts; Amino Acid Motifs; Animals; Cell Membrane; Cell Proliferation; Chronic Disease; Female; Fibroblast Growth Factor 2; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Kidney; Kidney Glomerulus; Kidney Transplantation; Mesangial Cells; Protein Binding; Proteoglycans; Rats; Signal Transduction; Up-Regulation

Heparan sulfate (HS), due to its ability to interact with a multitude of HS-binding factors, is involved in a variety of physiological and pathological processes. Remarkably diverse fine structure of HS, shaped by non-exhaustive enzymatic modifications, influences the interaction of HS with its partners. Here we characterized the HS profile of normal human and rat liver, as well as alterations of HS related to liver fibrogenesis and carcinogenesis, by using sulfation-specific antibodies. The HS immunopattern was compared with the immunolocalization of selected HS proteoglycans. HS samples from normal liver and hepatocellular carcinoma (HCC) were subjected to disaccharide analysis. Expression changes of nine HS-modifying enzymes in human fibrogenic diseases and HCC were measured by quantitative RT-PCR. Increased abundance and altered immunolocalization of HS was paralleled by elevated mRNA levels of HS-modifying enzymes in the diseased liver. The strong immunoreactivity of the normal liver for 3-O-sulfated epitope further increased with disease, along with upregulation of 3-OST-1. Modest 6-O-undersulfation of HCC HS is probably explained by Sulf overexpression. Our results may prompt further investigation of the role of highly 3-O-sulfated and partially 6-O-desulfated HS in pathological processes such as hepatitis virus entry and aberrant growth factor signaling in fibrogenic liver diseases and HCC.

Topics: Agrin; Animals; Carcinoma, Hepatocellular; Chronic Disease; Disaccharides; Focal Nodular Hyperplasia; Glucuronidase; Glypicans; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Immunohistochemistry; Liver; Liver Cirrhosis; Liver Neoplasms; Male; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sulfotransferases; Syndecan-1

The mechanism of bile ductular reaction and accompanying fibrogenesis depends on interactions of ductular cells with the matrix and growth factors. Heparan sulfate proteoglycans (HSPGs) are essential cofactors in cell-matrix adhesion processes, in cell-cell recognition systems, and in receptor-growth factor interactions. We used monoclonal antibodies specific for the cell surface HSPGs (syndecans, glypican), for matrix HSPG (perlecan), and for heparan sulfate carbohydrate (HS) to investigate their immunohistochemical expression in 20 specimens with chronic cholestatic liver disease and in five normal human liver specimens. Because activated hepatic stellate cells (HSC are a major source of fibrosis in the liver, we also examined HSPG expression in primary cultures of human activated HSC using immunocytochemistry and Western blotting and for syndecan-1 also Northern blotting. In comparison with bile ductular cells of normal liver, reactive ductules in chronic cholestasis were marked by an elevated expression of syndecan-1, surrounded by an increased perlecan expression. In acinar zone 1, large stimulated macrophages and HSC, present in increased numbers, were strongly positive for syndecan-3. Cultured HSC showed a membranous staining pattern for syndecan-1, syndecan-3, and heparan sulfate, and in addition intracellular staining for syndecan-2, -3, and 4. Perlecan immunoreactivity was detected as intercellular strings. Western blotting revealed positive bands with all antibodies and Northern blotting for syndecan-1 was also positive. These results show that cultured human HSC can synthesize all four syndecans, glypican, and perlecan. These data reveal changes in the expression of syndecan-1, syndecan-3, and perlecan in human chronic cholestatic liver disease, that may be important in the deposition of matrix components and activation of growth factors that support ductular reaction and accompanying fibrogenesis.

Topics: Antibodies, Monoclonal; Bile Ducts; Cholestasis, Intrahepatic; Chronic Disease; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Immunohistochemistry; Membrane Glycoproteins; Microscopy, Immunoelectron; Proteoglycans; Syndecan-1; Syndecan-3; Syndecan-4; Syndecans

Amyloid is a term for extracellular protein fibril deposits that have characteristic tinctorial and structural properties. Heparan sulphate, or the heparan sulphate proteoglycan perlecan, has been identified in all amyloids and implicated in the earliest stages of inflammation-associated (AA) amyloid induction. Heparan sulphate interacts with the AA amyloid precursor and the beta-peptide of Alzheimer's amyloid, imparting characteristic secondary and tertiary amyloid structural features. These observations suggest that molecules that interfere with this interaction may prevent or arrest amyloidogenesis. We synthesized low-molecular-weight (135-1,000) anionic sulphonate or sulphate compounds. When administered orally, these compounds substantially reduced murine splenic AA amyloid progression. They also interfered with heparan sulphate-stimulated beta-peptide fibril aggregation in vitro.

Topics: Acute Disease; Alkanesulfonates; Alzheimer Disease; Amyloidosis; Animals; Anions; Chronic Disease; Glycols; Heparitin Sulfate; Mice; Polyvinyls; Serum Amyloid A Protein; Spleen; Sulfates