title: Alveolar epithelial cells in idiopathic pulmonary fibrosis display upregulation of TRAIL, DR4 and DR5 expression with simultaneous preferential over-expression of pro-apoptotic marker p53.
abstract: Idiopathic pulmonary fibrosis (IPF) is a progressive, debilitating, and fatal lung disease of unknown aetiology with no current cure. The pathogenesis of IPF remains unclear but repeated alveolar epithelial cell (AEC) injuries and subsequent apoptosis are believed to be among the initiating/ongoing triggers. However, the precise mechanism of apoptotic induction is hitherto elusive. In this study, we investigated expression of a panel of pro-apoptotic and cell cycle regulatory proteins in 21 IPF and 19 control lung tissue samples. We reveal significant upregulation of the apoptosis-inducing ligand TRAIL and its cognate receptors DR4 and DR5 in AEC within active lesions of IPF lungs. This upregulation was accompanied by pro-apoptotic protein p53 overexpression. In contrast, myofibroblasts within the fibroblastic foci of IPF lungs exhibited high TRAIL, DR4 and DR5 expression but negligible p53 expression. Similarly, p53 expression was absent or negligible in IPF and control alveolar macrophages and lymphocytes. No significant differences in TRAIL expression were noted in these cell types between IPF and control lungs. However, DR4 and DR5 upregulation was detected in IPF alveolar macrophages and lymphocytes. The marker of cellular senescence p21(WAF1) was upregulated within affected AEC in IPF lungs. Cell cycle regulatory proteins Cyclin D1 and SOCS3 were significantly enhanced in AEC within the remodelled fibrotic areas of IPF lungs but expression was negligible in myofibroblasts. Taken together these findings suggest that, within the remodelled fibrotic areas of IPF, AEC can display markers associated with proliferation, senescence, and apoptotosis, where TRAIL could drive the apoptotic response. Clear understanding of disease processes and identification of therapeutic targets will direct us to develop effective therapies for IPF.
authors.affiliation: Lung Research Group, Institute of Science and Technology in Medicine, Keele University UK.
authors.forename: Khondoker M
authors.initials: KM
authors.lastname: Akram
authors.affiliation: Lung Research Group, Institute of Science and Technology in Medicine, Keele University UK ; Department of Cellular Pathology, University Hospital of North Staffordshire UK.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Lomas
authors.affiliation: Lung Research Group, Institute of Science and Technology in Medicine, Keele University UK.
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Forsyth
authors.affiliation: Lung Research Group, Institute of Science and Technology in Medicine, Keele University UK ; Heart & Lung Directorate, University Hospital of North Staffordshire UK.
authors.forename: Monica A
authors.initials: MA
authors.lastname: Spiteri
mesh_terms: D017209:Apoptosis; D015415:Biomarkers / Q000032:analysis; D016022:Case-Control Studies; D049109:Cell Proliferation; D016922:Cellular Senescence; D019938:Cyclin D1 / Q000032:analysis; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis; D004847:Epithelial Cells / Q000737:chemistry* / Q000473:pathology; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000378:metabolism* / Q000473:pathology; D008214:Lymphocytes / Q000737:chemistry / Q000473:pathology; D016676:Macrophages, Alveolar / Q000737:chemistry / Q000473:pathology; D058628:Myofibroblasts / Q000737:chemistry / Q000473:pathology; D011650:Pulmonary Alveoli / Q000737:chemistry* / Q000473:pathology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000032:analysis*; D018124:Receptors, Tumor Necrosis Factor / Q000032:analysis*; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000032:analysis; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000032:analysis*; D016159:Tumor Suppressor Protein p53 / Q000032:analysis*; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; C530104:CCND1 protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C114109:TNFRSF21 protein, human; C505653:TNFSF10 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1
keywords: DR4; DR5; Idiopathic pulmonary fibrosis; TRAIL; immunohistochemistry; p21WAF1; p53