title: Cartilage destruction in granulomatosis with polyangiitis (Wegener's granulomatosis) is mediated by human fibroblasts after transplantation into immunodeficient mice.
abstract: A key feature of granulomatosis with polyangiitis (GPA; or Wegener's granulomatosis) is the granulomatous inflammation of the upper respiratory tract, which leads to the subsequent destruction of adjacent tissues. The aim of our work was to study the histopathological and cellular components of tissue destruction of human GPA tissue transplanted into immunodeficient mice. Biopsy specimens from patients with active GPA (n = 10) or sinusitis (controls, n = 6) were s.c. co-implanted with healthy allogeneic human nasal cartilage into immunodeficient pfp/rag2(-/-) mice. Transplants were examined for their destructive capability of the allografted human cartilage. In addition, nasal fibroblasts from patients with GPA (n = 8) and control healthy nasal fibroblasts (n = 5) were cultured, and cell proliferation and apoptosis were quantified. mRNA and protein levels of matrix metalloproteinases and cytokines were evaluated at baseline and after proinflammatory stimulation. GPA implants showed massive destruction of the co-implanted human cartilage, whereas cartilage destruction was only marginal in control samples. Destruction was mediated by human fibroblasts and could be inhibited by corticoid treatment. The up-regulated production of matrix metalloproteinases 1, 3, and 13 and cytokines IL-6 and IL-8 was found in vivo and in vitro. Although proliferation of isolated fibroblasts was comparable between GPA and controls, GPA samples showed a significant delay of apoptosis. The destruction of nasal cartilage in GPA is mainly mediated by fibroblasts that can be blocked by corticosteroids, and this tissue destruction is not dependent on the influx of leukocytes.
authors.affiliation: Department of Anatomy and Experimental Morphology, University Medical Center Hamburg, Hamburg, Germany. n.kesel@uke.uni-hamburg.de
authors.forename: Nina
authors.initials: N
authors.lastname: Kesel
authors.forename: Dorothee
authors.initials: D
authors.lastname: Köhler
authors.forename: Lena
authors.initials: L
authors.lastname: Herich
authors.forename: Martin
authors.initials: M
authors.lastname: Laudien
authors.forename: Konstanze
authors.initials: K
authors.lastname: Holl-Ulrich
authors.forename: Astrid
authors.initials: A
authors.lastname: Jüngel
authors.forename: Michel
authors.initials: M
authors.lastname: Neidhart
authors.forename: Steffen
authors.initials: S
authors.lastname: Gay
authors.forename: Renate E
authors.initials: RE
authors.lastname: Gay
authors.forename: Elena
authors.initials: E
authors.lastname: Csernok
authors.forename: Peter
authors.initials: P
authors.lastname: Lamprecht
authors.forename: Wolfgang L
authors.initials: WL
authors.lastname: Gross
authors.forename: Udo
authors.initials: U
authors.lastname: Schumacher
authors.forename: Sebastian
authors.initials: S
authors.lastname: Ullrich
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D003907:Dexamethasone / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D020869:Gene Expression Profiling / Q000379:methods; D005938:Glucocorticoids / Q000494:pharmacology / Q000627:therapeutic use; D014890:Granulomatosis with Polyangiitis / Q000150:complications / Q000188:drug therapy / Q000473:pathology*; D006801:Humans; D007108:Immune Tolerance; D008297:Male; D020782:Matrix Metalloproteinases / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D055171:Nasal Cartilages / Q000473:pathology* / Q000637:transplantation; D009297:Nasal Mucosa / Q000473:pathology / Q000637:transplantation; D009667:Nose Deformities, Acquired / Q000209:etiology / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D055815:Young Adult
chemical_list: D016207:Cytokines; D005938:Glucocorticoids; D012333:RNA, Messenger; D003907:Dexamethasone; D020782:Matrix Metalloproteinases