title: Aberrant nonfibrotic parenchyma in idiopathic pulmonary fibrosis is correlated with decreased β-catenin inhibition and increased Wnt5a/b interaction.
abstract: Idiopathic pulmonary fibrosis (IPF), an insidious disease with grave prognosis, is characterized by heterogeneous fibrosis with densely fibrotic areas surrounded by nonfibrotic normal-looking tissue, believed to reflect a temporal development. The etiology is incompletely elucidated, but aberrant wound healing is believed to be involved. Embryonic signaling pathways, including Wnt signaling, are reactivated in wound healing, and we therefore aimed to investigate Wnt signaling, and hypothesized that Wnt signaling would correspond to degree of fibrosis. Material from 10 patients with IPF were included (four diagnostic biopsies and six donated lungs) and compared to healthy controls (n = 7). We investigated markers of Wnt signaling (β-catenin, Wnt3a, ICAT, Wnt5a/b, DAAM1 and NLK) histologically in lung parenchyma with variable degree of fibrosis. Our results suggest that Wnt signaling is significantly altered (P < 0.05) already in normal-looking parenchyma. The expression of Wnt3a and ICAT decreased (both P < 0.01) in IPF compared to healthy lungs, whereas β-catenin, Wnt5a/b, DAAM1 and NLK increased (P < 0.05 for all). ICAT is further decreased in dense fibrosis compared to normal-looking parenchyma in IPF (P < 0.001). On the basis of our results, we conclude that from a Wnt perspective, there is no normal parenchyma in IPF, and Wnt signaling corresponds to degree of fibrosis. In addition, β-catenin and Wnt5a appears coupled, and decreased inhibition of β-catenin may be involved. We suggest that the interaction between β-catenin, ICAT, and Wnt5a/b may represent an important research area and potential target for therapeutic intervention.
authors.affiliation: Lung Biology, Department Experimental Medical Science, Lund University, Lund, Sweden kristina.rydell-tormanen@med.lu.se.
authors.forename: Kristina
authors.initials: K
authors.lastname: Rydell-Törmänen
authors.affiliation: Department of BioSciences, RIA iMed, AstraZeneca R&D Gothenburg, Mölndal, Sweden.
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Zhou
authors.affiliation: Lung Biology, Department Experimental Medical Science, Lund University, Lund, Sweden Respiratory Medicine and Allergology, Department Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Oskar
authors.initials: O
authors.lastname: Hallgren
authors.affiliation: Respiratory Medicine and Allergology, Department Clinical Sciences, Lund University, Lund, Sweden Department Respiratory Medicine and Allergology, Skåne University Hospital, Lund, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Einarsson
authors.affiliation: Lung Biology, Department Experimental Medical Science, Lund University, Lund, Sweden Respiratory Medicine and Allergology, Department Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Leif
authors.initials: L
authors.lastname: Eriksson
authors.affiliation: Lung Biology, Department Experimental Medical Science, Lund University, Lund, Sweden.
authors.forename: Annika
authors.initials: A
authors.lastname: Andersson-Sjöland
authors.affiliation: Lung Biology, Department Experimental Medical Science, Lund University, Lund, Sweden.
authors.forename: Gunilla
authors.initials: G
authors.lastname: Westergren-Thorsson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000378:metabolism* / Q000473:pathology*; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011485:Protein Binding / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D051153:Wnt Proteins / Q000096:biosynthesis*; D000071818:Wnt-5a Protein; D051176:beta Catenin / Q000096:biosynthesis*
chemical_list: C495270:CTNNB1 protein, human; D011518:Proto-Oncogene Proteins; C085389:WNT5A protein, human; C435831:WNT5B protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D051176:beta Catenin
keywords: ICAT; Wnt signaling; Wnt5a; idiopathic pulmonary fibrosis; β‐catenin