title: Mesenchymal stem cells and serelaxin synergistically abrogate established airway fibrosis in an experimental model of chronic allergic airways disease.
abstract: This study determined if the anti-fibrotic drug, serelaxin (RLN), could augment human bone marrow-derived mesenchymal stem cell (MSC)-mediated reversal of airway remodeling and airway hyperresponsiveness (AHR) associated with chronic allergic airways disease (AAD/asthma). Female Balb/c mice subjected to the 9-week model of ovalbumin (OVA)-induced chronic AAD were either untreated or treated with MSCs alone, RLN alone or both combined from weeks 9-11. Changes in airway inflammation (AI), epithelial thickness, goblet cell metaplasia, transforming growth factor (TGF)-β1 expression, myofibroblast differentiation, subepithelial and total lung collagen deposition, matrix metalloproteinase (MMP) expression, and AHR were then assessed. MSCs alone modestly reversed OVA-induced subepithelial and total collagen deposition, and increased MMP-9 levels above that induced by OVA alone (all p<0.05 vs OVA group). RLN alone more broadly reversed OVA-induced epithelial thickening, TGF-β1 expression, myofibroblast differentiation, airway fibrosis and AHR (all p<0.05 vs OVA group). Combination treatment further reversed OVA-induced AI and airway/lung fibrosis compared to either treatment alone (all p<0.05 vs either treatment alone), and further increased MMP-9 levels. RLN appeared to enhance the therapeutic effects of MSCs in a chronic disease setting; most likely a consequence of the ability of RLN to limit TGF-β1-induced matrix synthesis complemented by the MMP-promoting effects of MSCs.
authors.affiliation: Fibrosis Laboratory, Department of Pharmacology, Monash University, Clayton, Victoria 3800, Australia. Electronic address: simon.royce@monash.edu.
authors.forename: Simon G
authors.initials: SG
authors.lastname: Royce
authors.affiliation: Fibrosis Laboratory, Department of Pharmacology, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Matthew
authors.initials: M
authors.lastname: Shen
authors.affiliation: Fibrosis Laboratory, Department of Pharmacology, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Krupesh P
authors.initials: KP
authors.lastname: Patel
authors.affiliation: Kidney Regeneration and Stem Cell Laboratory, Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Brooke M
authors.initials: BM
authors.lastname: Huuskes
authors.affiliation: Kidney Regeneration and Stem Cell Laboratory, Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria 3800, Australia. Electronic address: sharon.ricardo@monash.edu.
authors.forename: Sharon D
authors.initials: SD
authors.lastname: Ricardo
authors.affiliation: Fibrosis Laboratory, Department of Pharmacology, Monash University, Clayton, Victoria 3800, Australia. Electronic address: chrishan.samuel@monash.edu.
authors.forename: Chrishan S
authors.initials: CS
authors.lastname: Samuel
mesh_terms: D056151:Airway Remodeling; D000818:Animals; D001249:Asthma / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012065:Relaxin / Q000235:genetics* / Q000378:metabolism*
chemical_list: D011994:Recombinant Proteins; C577649:serelaxin protein, human; D012065:Relaxin
keywords: Airway remodeling; Asthma; Fibrosis; Mesenchymal stem cells; Serelaxin