title: Enhanced deposition of low-molecular-weight hyaluronan in lungs of cigarette smoke-exposed mice.
abstract: Chronic obstructive pulmonary disease (COPD) is characterized by infiltration of inflammatory cells, destruction of lung parenchyma, and airway wall remodeling. Hyaluronan (HA) is a component of the extracellular matrix, and low-molecular-weight (LMW) HA fragments have proinflammatory capacities. We evaluated the presence of HA in alveolar and airway walls of C57BL/6 mice that were exposed to air or cigarette smoke (CS) for 4 weeks (subacute) or 24 weeks (chronic). We measured deposition of the extracellular matrix proteins collagen and fibronectin in airway walls and determined the molecular weight of HA purified from lung tissue. In addition, we studied the expression of HA-modulating genes by RT-PCR. HA staining in alveolar walls was significantly enhanced upon chronic CS exposure, whereas HA levels in the airway walls were already significantly higher upon subacute CS exposure and remained elevated upon chronic CS exposure. This differed from the deposition of collagen and fibronectin, which are only elevated at the chronic time point. In lungs of CS-exposed mice, the molecular weight of HA clearly shifted toward more LMW HA fragments. CS exposure significantly increased the mRNA expression of the HA synthase gene Has3 in total lung tissue, whereas the expression of Has1 was decreased. These in vivo studies in an experimental model of COPD show that CS exposure leads to enhanced deposition of (mostly LMW) HA in alveolar and bronchial walls by altering the expression of HA-modulating enzymes. This may contribute to airway wall remodeling and pulmonary inflammation in COPD.
authors.affiliation: Department of Respiratory Medicine, Ghent University Hospital, 7K12 IE De Pintelaan, 185 B-9000 Ghent, Belgium. ken.bracke@UGent.be
authors.forename: Ken R
authors.initials: KR
authors.lastname: Bracke
authors.forename: Mieke A
authors.initials: MA
authors.lastname: Dentener
authors.forename: Eleni
authors.initials: E
authors.lastname: Papakonstantinou
authors.forename: Juanita H J
authors.initials: JH
authors.lastname: Vernooy
authors.forename: Tine
authors.initials: T
authors.lastname: Demoor
authors.forename: Nele S
authors.initials: NS
authors.lastname: Pauwels
authors.forename: Jack
authors.initials: J
authors.lastname: Cleutjens
authors.forename: Robert Jan
authors.initials: RJ
authors.lastname: van Suylen
authors.forename: Guy F
authors.initials: GF
authors.lastname: Joos
authors.forename: Guy G
authors.initials: GG
authors.lastname: Brusselle
authors.forename: Emiel F M
authors.initials: EF
authors.lastname: Wouters
mesh_terms: D056151:Airway Remodeling / Q000235:genetics; D000818:Animals; D001980:Bronchi / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005353:Fibronectins / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D014453:Glucuronosyltransferase / Q000235:genetics; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000378:metabolism*; D006821:Hyaluronoglucosaminidase / Q000235:genetics; D016676:Macrophages, Alveolar / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008970:Molecular Weight; D011650:Pulmonary Alveoli / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D011656:Pulmonary Emphysema / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects*; D013997:Time Factors
chemical_list: D005353:Fibronectins; D012333:RNA, Messenger; D006820:Hyaluronic Acid; D003094:Collagen; D014453:Glucuronosyltransferase; C491356:Has3 protein, mouse; D000076002:Hyaluronan Synthases; D006821:Hyaluronoglucosaminidase