Alteration of canonical and non-canonical WNT-signaling by crystalline silica in human lung epithelial cells.
Growth and development of the mature lung is a complex process orchestrated by a number of intricate developmental signaling pathways. Wingless-type MMTV-integration site (WNT) signaling plays critical roles in controlling branching morphogenesis cell differentiation, and formation of the conducting and respiratory airways. In addition, WNT pathways are often re-activated in mature lungs during repair and regeneration. WNT- signaling has been elucidated as a crucial contributor to the development of idiopathic pulmonary fibrosis as well as other hyper-proliferative lung diseases. Silicosis, a detrimental occupational lung disease caused by excessive inhalation of crystalline silica dust, is hallmarked by repeated cycles of damaging inflammation, epithelial hyperplasia, and formation of dense, hyalinized nodules of whorled collagen. However, mechanisms of epithelial cell hyperplasia and matrix deposition are not well understood, as most research efforts have focused on the pronounced inflammatory response. Microarray data from our previous studies has revealed a number of WNT-signaling and WNT-target genes altered by crystalline silica in human lung epithelial cells. In the present study, we utilize pathway analysis to designate connections between genes altered by silica in WNT-signaling networks. Furthermore, we confirm microarray findings by QRT-PCR and demonstrate both activation of canonical (β-catenin) and down-regulation of non-canonical (WNT5A) signaling in immortalized (BEAS-2B) and primary (PBEC) human bronchial epithelial cells. These findings suggest that WNT-signaling and cross-talk with other pathways (e.g. Notch), may contribute to proliferative, fibrogenic and inflammatory responses to silica in lung epithelial cells.
Department of Respiratory Medicine, Maastricht University Medical Centre +, Maastricht University Maastricht, The Netherlands.
Timothy N
TN
Perkins
Department of Respiratory Medicine, Maastricht University Medical Centre +, Maastricht University Maastricht, The Netherlands.
Mieke A
MA
Dentener
Department of Medical Microbiology, Maastricht University Medical Centre +, Maastricht University Maastricht, The Netherlands.
Frank R
FR
Stassen
Department of Respiratory Medicine, Maastricht University Medical Centre +, Maastricht University Maastricht, The Netherlands.
Gernot G
GG
Rohde
Department of Pathology, University of Vermont College of Medicine, Burlington, VT, USA.
Brooke T
BT
Mossman
Department of Respiratory Medicine, Maastricht University Medical Centre +, Maastricht University Maastricht, The Netherlands.
Emiel F M
EF
Wouters
Department of Respiratory Medicine, Maastricht University Medical Centre +, Maastricht University Maastricht, The Netherlands. Electronic address: n.reynaert@maastrichtuniversity.nl.
Niki L
NL
Reynaert
D002460:Cell Line; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000166:cytology; D020411:Oligonucleotide Array Sequence Analysis; D012822:Silicon Dioxide / Q000633:toxicity*; D059467:Transcriptome; D060449:Wnt Signaling Pathway / Q000187:drug effects*
D012822:Silicon Dioxide
Epithelium; Fibrosis; Pathway-analysis; Pneumoconiosis; Silica; WNT