title: Steroids and β2-agonists regulate hyaluronan metabolism in asthmatic airway smooth muscle cells.
abstract: Glycosaminoglycans (GAGs), especially hyaluronic acid (HA), regulate tissue flexibility, cell motility, and inflammation. Airway smooth muscle cells (ASMCs) of patients with asthma exhibit abnormal HA metabolism, which contributes to inflammation and remodeling. Here, we investigated the effects of glucocorticoids and long-acting β(2)-agonists (LABAs) on GAG synthesis and HA metabolism by human primary ASMCs. ASMCs were isolated from airway specimens of 10 patients without asthma and 11 patients with asthma. ASMCs were incubated with glucocorticoids, LABAs, or their combination, as well as with their specific receptor antagonists. Secreted and deposited total GAGs were measured by [(3)H]-glucosamine incorporation. The expression of specific GAGs was determined by ELISA and electrophoresis. The expression of HA synthases (HAS), of hyaluronidases (HYALs), and of the HA receptor CD44 was determined by RT-PCR, immunoblotting in cell cultures, and immunohistochemistry in tissue sections of asthmatic lungs. In serum-activated asthmatic ASMCs, glucocorticoids and LABAs significantly inhibited the increased secretion and deposition of total GAGs, but they stimulated secreted and deposited HA of high molecular mass. This effect was attributed to increased mRNA and protein expression of HAS-1 and to the reduced expression of HYAL-1. Furthermore, drug treatment stimulated the expression of CD44 receptors in asthmatic ASMCs. These effects of the drugs were eliminated by their respective receptor inhibitors. Our findings indicate that the combination of glucocorticoids with LABAs counteracts the pathologic degradation of HA, and thereby may reduce the proinflammatory potential of asthmatic ASMCs.
authors.affiliation: Department of Pharmacology, School of Medicine, Aristotle University, Thessaloniki, Greece.
authors.forename: Eleni
authors.initials: E
authors.lastname: Papakonstantinou
authors.forename: Ioannis
authors.initials: I
authors.lastname: Klagas
authors.forename: George
authors.initials: G
authors.lastname: Karakiulakis
authors.forename: Katrin
authors.initials: K
authors.lastname: Hostettler
authors.forename: Chong Teck
authors.initials: CT
authors.lastname: S'ng
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Kotoula
authors.forename: Spasenija
authors.initials: S
authors.lastname: Savic
authors.forename: Michael
authors.initials: M
authors.lastname: Tamm
authors.forename: Michael
authors.initials: M
authors.lastname: Roth
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology*; D001249:Asthma / Q000378:metabolism* / Q000473:pathology; D019819:Budesonide / Q000494:pharmacology; D016022:Case-Control Studies; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004983:Ethanolamines / Q000494:pharmacology; D005109:Extracellular Matrix / Q000378:metabolism; D000068759:Formoterol Fumarate; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D006025:Glycosaminoglycans / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000378:metabolism*; D006821:Hyaluronoglucosaminidase / Q000235:genetics / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D011433:Propranolol / Q000494:pharmacology; D012137:Respiratory System / Q000473:pathology*
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; C497483:CD44 protein, human; D015815:Cell Adhesion Molecules; D004983:Ethanolamines; D058851:GPI-Linked Proteins; D005938:Glucocorticoids; D006025:Glycosaminoglycans; D018960:Hyaluronan Receptors; D019819:Budesonide; D006820:Hyaluronic Acid; D011433:Propranolol; D014453:Glucuronosyltransferase; C523794:HAS1 protein, human; C101754:HAS2 protein, human; D000076002:Hyaluronan Synthases; C473096:Hyal2 protein, human; D006821:Hyaluronoglucosaminidase; D000068759:Formoterol Fumarate