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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.
Int J Clin Exp Pathol 2014; 7(2):552-64IJ

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+Show Affiliations

Lung Research Group, Institute of Science and Technology in Medicine, Keele University UK.Lung Research Group, Institute of Science and Technology in Medicine, Keele University UK ; Department of Cellular Pathology, University Hospital of North Staffordshire UK.Lung Research Group, Institute of Science and Technology in Medicine, Keele University UK.Lung Research Group, Institute of Science and Technology in Medicine, Keele University UK ; Heart & Lung Directorate, University Hospital of North Staffordshire UK.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24551275

Citation

Akram, Khondoker M., et al. "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." International Journal of Clinical and Experimental Pathology, vol. 7, no. 2, 2014, pp. 552-64.
Akram KM, Lomas NJ, Forsyth NR, et al. 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. Int J Clin Exp Pathol. 2014;7(2):552-64.
Akram, K. M., Lomas, N. J., Forsyth, N. R., & Spiteri, M. A. (2014). 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. International Journal of Clinical and Experimental Pathology, 7(2), pp. 552-64.
Akram KM, et al. 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. Int J Clin Exp Pathol. 2014;7(2):552-64. PubMed PMID: 24551275.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Akram,Khondoker M, AU - Lomas,Nicola J, AU - Forsyth,Nicholas R, AU - Spiteri,Monica A, Y1 - 2014/01/15/ PY - 2013/12/19/received PY - 2014/01/10/accepted PY - 2014/2/20/entrez PY - 2014/2/20/pubmed PY - 2014/10/15/medline KW - DR4 KW - DR5 KW - Idiopathic pulmonary fibrosis KW - TRAIL KW - immunohistochemistry KW - p21WAF1 KW - p53 SP - 552 EP - 64 JF - International journal of clinical and experimental pathology JO - Int J Clin Exp Pathol VL - 7 IS - 2 N2 - 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. SN - 1936-2625 UR - https://www.unboundmedicine.com/medline/citation/24551275/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_ L2 - https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24551275/ DB - PRIME DP - Unbound Medicine ER -