title: Obliterative airway remodeling: molecular evidence for shared pathways in transplanted and native lungs.
abstract: Obliteration of the small airways is a largely unresolved challenge in pulmonary medicine. It represents either the irreversible cause of functional impairment or a morphologic disorder of limited importance in a multitude of diseases. Bronchiolitis obliterans is a key complication of lung transplantation. No predictive markers for the onset of obliterative remodeling are currently available. To further elucidate the molecular mechanisms of airway remodeling, compartment-specific expression patterns were analyzed in patients. For this purpose, remodeled and nonremodeled bronchioli were isolated from transplanted and nontransplanted lung explants using laser-assisted microdissection (n = 24). mRNA expression of 45 fibrosis-associated genes was measured using quantitative real-time RT-PCR. For 20 genes, protein expression was also analyzed by immunohistochemistry. Infiltrating cells were characterized at conventional histology and immunohistochemistry. Obliterative remodeling of the small airways in transplanted and nontransplanted lungs shared similar grades of chronic inflammation and pivotal fibrotic pathways such as transforming growth factor β signaling and increased collagen expression. Bone morphogenetic protein and thrombospondin signaling, and also matrix metalloproteinases and tissue inhibitor of metalloproteinases, were primarily up-regulated in obliterative airway remodeling in nontransplanted lungs. In transplanted lungs, clinical remodeled bone morphogenetic protein but nonremodeled bronchioli were characterized by a concordant up-regulation of matrix metalloproteinase-9, RANTES, and tissue inhibitor of metalloproteinase-1. These distinct expression patterns warrant further investigation as potential markers of impending airway remodeling, especially for prospective longitudinal molecular profiling.
authors.affiliation: Institute of Pathology, Hannover Medical School, Hannover, Germany. jonigk.danny@mh-hannover.de
authors.forename: Danny
authors.initials: D
authors.lastname: Jonigk
authors.forename: Marlene
authors.initials: M
authors.lastname: Merk
authors.forename: Kais
authors.initials: K
authors.lastname: Hussein
authors.forename: Lavinia
authors.initials: L
authors.lastname: Maegel
authors.forename: Katharina
authors.initials: K
authors.lastname: Theophile
authors.forename: Michaela
authors.initials: M
authors.lastname: Muth
authors.forename: Ulrich
authors.initials: U
authors.lastname: Lehmann
authors.forename: Clemens L
authors.initials: CL
authors.lastname: Bockmeyer
authors.forename: Michael
authors.initials: M
authors.lastname: Mengel
authors.forename: Jens
authors.initials: J
authors.lastname: Gottlieb
authors.forename: Tobias
authors.initials: T
authors.lastname: Welte
authors.forename: Axel
authors.initials: A
authors.lastname: Haverich
authors.forename: Heiko
authors.initials: H
authors.lastname: Golpon
authors.forename: Hans
authors.initials: H
authors.lastname: Kreipe
authors.forename: Florian
authors.initials: F
authors.lastname: Laenger
mesh_terms: D000328:Adult; D056151:Airway Remodeling / Q000235:genetics / Q000502:physiology*; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D055745:Bronchioles / Q000473:pathology / Q000503:physiopathology; D001989:Bronchiolitis Obliterans / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology*; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D008168:Lung / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D016040:Lung Transplantation; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; C483024:CCL5 protein, human; D018946:Chemokine CCL5; D012333:RNA, Messenger; D051785:Smad Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D020780:Matrix Metalloproteinase 9