title: Hyaluronidase modulates bleomycin-induced lung injury detected noninvasively in small rodents by radial proton MRI.
abstract: OBJECTIVE
  To assess whether hyaluronic acid, a building block of proteoglycans and extracellular matrix with hydrophilic characteristics, might contribute to magnetic resonance imaging (MRI)-detected proton signals elicited by bleomycin in the lung. To this end, hyaluronidase, which degrades hyaluronic acid, was administered to bleomycin-challenged animals.
  
  
  METHODS
  Fibrosis was induced by oropharyngeal aspiration (OA) of bleomycin. Mice received bleomycin once daily (0.1 mg/kg) on 6 consecutive days, while rats were given a single dose (2 or 4 mg/kg). Hyaluronidase, budesonide, and the respective vehicles were also administered via OA. Animals were examined using a radial ultrashort echo time sequence. Histology of picrosirius reflecting collagen and tissue gene analysis were performed postmortem.
  
  
  RESULTS
  In mice, hyaluronidase induced an increase of high intensity signals by 34 ± 12 μL (means ± SD, P = 0.007), consistent with the ability of the degradation products of hyaluronic acid to provoke acute inflammation. Budesonide was able to resolve hyaluronidase-induced signals or to prevent their formation. Combined administration of budesonide and hyaluronidase to bleomycin-treated rats resulted in an overall decrease (-17.1 ± 7%, P = 0.02) of the MRI-detected bleomycin-induced signals. Moreover, the relative gene expression of hyaluronidase was reduced (-61.8 ± 10.2%, P < 0.001) in fibrotic lungs.
  
  
  CONCLUSIONS
  The present data indicate that hyaluronic acid contributes to the bleomycin-induced responses detected by MRI in the lung.
authors.affiliation: Novartis Institutes for BioMedical Research, Analytical Sciences and Imaging, Basel, Switzerland; University of Basel, Biocenter, Basel, Switzerland.
authors.forename: Christine
authors.initials: C
authors.lastname: Egger
authors.forename: Catherine
authors.initials: C
authors.lastname: Cannet
authors.forename: Christelle
authors.initials: C
authors.lastname: Gérard
authors.forename: Andrew
authors.initials: A
authors.lastname: Dunbar
authors.forename: Bruno
authors.initials: B
authors.lastname: Tigani
authors.forename: Nicolau
authors.initials: N
authors.lastname: Beckmann
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001761:Bleomycin; D004195:Disease Models, Animal; D005355:Fibrosis / Q000150:complications / Q000503:physiopathology; D006821:Hyaluronoglucosaminidase / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000503:physiopathology; D055370:Lung Injury / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011522:Protons; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D011522:Protons; D001761:Bleomycin; D006821:Hyaluronoglucosaminidase
keywords: bleomycin; fibrosis; hyaluronic acid (hyaluronan); lung; magnetic resonance imaging (MRI); ultrashort echo time (UTE)