Browse > Article
http://dx.doi.org/10.14348/molcells.2018.2307

Increased Primary Cilia in Idiopathic Pulmonary Fibrosis  

Lee, Junguee (Department of Pathology, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea)
Oh, Dong Hyun (Department of Radiology, Konyang University Hospital)
Park, Ki Cheol (Clinical Research Institute, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea)
Choi, Ji Eun (Department of Pathology, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea)
Kwon, Jong Beom (Department of Thoracic and Cardiovascular Surgery, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea)
Lee, Jongho (Department of Thoracic and Cardiovascular Surgery, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea)
Park, Kuhn (Department of Thoracic and Cardiovascular Surgery, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea)
Sul, Hae Joung (Department of Pathology, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea)
Publication Information
Molecules and Cells / v.41, no.3, 2018 , pp. 224-233 More about this Journal
Abstract
Primary cilia are solitary, non-motile, axonemal microtubule-based antenna-like organelles that project from the plasma membrane of most mammalian cells and are implicated in transducing hedgehog signals during development. It was recently proposed that aberrant SHH signaling may be implicated in the progression of idiopathic pulmonary fibrosis (IPF). However, the distribution and role of primary cilia in IPF remains unclear. Here, we clearly observed the primary cilia in alveolar epithelial cells, fibroblasts, and endothelial cells of human normal lung tissue. Then, we investigated the distribution of primary cilia in human IPF tissue samples using immunofluorescence. Tissues from six IPF cases showed an increase in the number of primary cilia in alveolar cells and fibroblasts. In addition, we observed an increase in ciliogenesis related genes such as IFT20 and IFT88 in IPF. Since major components of the SHH signaling pathway are known to be localized in primary cilia, we quantified the mRNA expression of the SHH signaling components using qRT-PCR in both IPF and control lung. mRNA levels of SHH, the coreceptor SMO, and the transcription factors GLI1 and GLI2 were upregulated in IPF compared with control. Furthermore, the nuclear localization of GLI1 was observed mainly in alveolar epithelia and fibroblasts. In addition, we showed that defective KIF3A-mediated ciliary loss in human type II alveolar epithelial cell lines leads to disruption of SHH signaling. These results indicate that a significant increase in the number of primary cilia in IPF contributes to the upregulation of SHH signals.
Keywords
Idiopathic pulmonary fibrosis; primary cilia; Sonic Hedgehog signaling pathway;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Lancaster, M.A., Schroth, J., and Gleeson, J.G. (2011). Subcellular spatial regulation of canonical Wnt signalling at the primary cilium. Nat. Cell Biol. 13, 700-707.   DOI
2 Litingtung, Y., Lei, L., Westphal, H., and Chiang, C. (1998). Sonic hedgehog is essential to foregut development. Nat. Genet. 20, 58-61.   DOI
3 Marszalek, J.R., Liu, X., Roberts, E.A., Chui, D., Marth, J.D., Williams, D.S., and Goldstein, L.S. (2000). Genetic evidence for selective transport of opsin and arrestin by kinesin-II in mammalian photoreceptors. Cell 102, 175-187.   DOI
4 Cigna, N., Farrokhi Moshai, E., Brayer, S., Marchal-Somme, J., Wemeau-Stervinou, L., Fabre, A., Mal, H., Leseche, G., Dehoux, M., Soler, P., et al. (2012). The hedgehog system machinery controls transforming growth factor-beta-dependent myofibroblastic differentiation in humans: involvement in idiopathic pulmonary fibrosis. Am. J. Pathol. 181, 2126-2137.   DOI
5 Corbit, K.C., Aanstad, P., Singla, V., Norman, A.R., Stainier, D.Y., and Reiter, J.F. (2005). Vertebrate Smoothened functions at the primary cilium. Nature 437, 1018-1021.   DOI
6 Ding, H., Zhou, D., Hao, S., Zhou, L., He, W., Nie, J., Hou, F.F., and Liu, Y. (2012). Sonic hedgehog signaling mediates epithelialmesenchymal communication and promotes renal fibrosis. J. Am. Soc. Nephrol. 23, 801-813.   DOI
7 Eggenschwiler, J.T., and Anderson, K.V. (2007). Cilia and developmental signaling. Annu. Rev. Cell Dev. Biol. 23, 345-373.   DOI
8 Fitch, P.M., Howie, S.E., and Wallace, W.A. (2011). Oxidative damage and TGF-beta differentially induce lung epithelial cell sonic hedgehog and tenascin-C expression: implications for the regulation of lung remodelling in idiopathic interstitial lung disease. Int. J. Exp. Pathol. 92, 8-17.   DOI
9 Hamamoto, N., Ashizawa, N., Niigaki, M., Kaji, T., Katsube, T., Endoh, H., Watanabe, M., Sumi, S., and Kinoshita, Y. (2002). Morphological changes in the rat exocrine pancreas after pancreatic duct ligation. Histol. Histopathol. 17, 1033-1041.
10 Hassounah, N.B., Bunch, T.A., and McDermott, K.M. (2012). Molecular pathways: the role of primary cilia in cancer progression and therapeutics with a focus on Hedgehog signaling. Clin. Cancer Res. 18, 2429-2435.   DOI
11 Harari, S., and Caminati, A. (2010). IPF: new insight on pathogenesis and treatment. Allergy 65, 537-553.   DOI
12 Cardoso, W.V., and Lu, J. (2006). Regulation of early lung morphogenesis: questions, facts and controversies. Development 133, 1611-1624.   DOI
13 Adams, M., Smith, U.M., Logan, C.V., and Johnson, C.A. (2008). Recent advances in the molecular pathology, cell biology and genetics of ciliopathies. J. Med. Genet. 45, 257-267.   DOI
14 Ashizawa, N., Niigaki, M., Hamamoto, N., Niigaki, M., Kaji, T., Katsube, T., Sato, S., Endoh, H., Hidaka, K., Watanabe, M., et al. (1999). The morphological changes of exocrine pancreas in chronic pancreatitis. Histol. Histopathol. 14, 539-552.
15 Bolanos, A.L., Milla, C.M., Lira, J.C., Ramirez, R., Checa, M., Barrera, L., Garcia-Alvarez, J., Carbajal, V., Becerril, C., Gaxiola, M., et al. (2012). Role of Sonic Hedgehog in idiopathic pulmonary fibrosis. Am. J. Physiol. Lung Cell. Mol. Physiol. 303, L978-990.   DOI
16 Chang, M.Y., Parker, E., Ibrahim, S., Shortland, J.R., Nahas, M.E., Haylor, J.L., and Ong, A.C. (2006). Haploinsufficiency of Pkd2 is associated with increased tubular cell proliferation and interstitial fibrosis in two murine Pkd2 models. Nephrol. Dial. Transplant. 21, 2078-2084.   DOI
17 Wilson, C.W., and Chuang, P.T. (2010). Mechanism and evolution of cytosolic Hedgehog signal transduction. Development 137, 2079-2094.
18 Zhou, D., Li, Y., Zhou, L., Tan, R.J., Xiao, L., Liang, M., Hou, F.F., and Liu, Y. (2014). Sonic hedgehog is a novel tubule-derived growth factor for interstitial fibroblasts after kidney injury. J. Am. Soc. Nephrol. 25, 2187-2200.   DOI
19 Wong, S.Y., Seol, A.D., So, P.L., Ermilov, A.N., Bichakjian, C.K., Epstein, E.H., Jr., Dlugosz, A.A., and Reiter, J.F. (2009). Primary cilia can both mediate and suppress Hedgehog pathway-dependent tumorigenesis. Nat. Med. 15, 1055-1061.   DOI
20 Yang, I.V., Coldren, C.D., Leach, S.M., Seibold, M.A., Murphy, E., Lin, J., Rosen, R., Neidermyer, A.J., McKean, D.F., Groshong, S.D., et al. (2013). Expression of cilium-associated genes defines novel molecular subtypes of idiopathic pulmonary fibrosis. Thorax 68, 1114-1121.   DOI
21 Visscher, D.W., and Myers, J.L. (2006). Histologic spectrum of idiopathic interstitial pneumonias. Proc. Am. Thorac. Soc. 3, 322-329.   DOI
22 Pepicelli, C.V., Lewis, P.M., and McMahon, A.P. (1998). Sonic hedgehog regulates branching morphogenesis in the mammalian lung. Curr. Biol. 8, 1083-1086.   DOI
23 Ocbina, P.J., and Anderson, K.V. (2008). Intraflagellar transport, cilia, and mammalian Hedgehog signaling: analysis in mouse embryonic fibroblasts. Dev. Dyn. 237, 2030-2038.   DOI
24 Piontek, K., Menezes, L.F., Garcia-Gonzalez, M.A., Huso, D.L., and Germino, G.G. (2007). A critical developmental switch defines the kinetics of kidney cyst formation after loss of Pkd1. Nat. Med. 13, 1490-1495.   DOI
25 Raghu, G., Collard, H.R., Egan, J.J., Martinez, F.J., Behr, J., Brown, K.K., Colby, T.V., Cordier, J.F., Flaherty, K.R., Lasky, J.A., et al. (2011). An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am. J. Respir. Crit. Care Med. 183, 788-824.   DOI
26 Rohatgi, R., Milenkovic, L., and Scott, M.P. (2007). Patched1 regulates hedgehog signaling at the primary cilium. Science 317, 372-376.   DOI
27 Seeger-Nukpezah, T., and Golemis, E.A. (2012). The extracellular matrix and ciliary signaling. Curr. Opin. Cell Biol. 24, 652-661.   DOI
28 Verghese, E., Weidenfeld, R., Bertram, J.F., Ricardo, S.D., and Deane, J.A. (2008). Renal cilia display length alterations following tubular injury and are present early in epithelial repair. Nephrol. Dial. Transplant. 23, 834-841.
29 Trempus, C.S., Song, W., Lazrak, A., Yu, Z., Creighton, J.R., Young, B.M., Heise, R.L., Yu, Y.R., Ingram, J.L., Tighe, R.M., et al. (2017). A novel role for primary cilia in airway remodeling. Am. J. Physiol. Lung Cell. Mol. Physiol. 313, L328-L338.   DOI
30 Verghese, E., Ricardo, S.D., Weidenfeld, R., Zhuang, J., Hill, P.A., Langham, R.G., and Deane, J.A. (2009). Renal primary cilia lengthen after acute tubular necrosis. J. Am. Soc. Nephrol. 20, 2147-2153.   DOI
31 Haycraft, C.J., Banizs, B., Aydin-Son, Y., Zhang, Q., Michaud, E.J., and Yoder, B.K. (2005). Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. PLoS Genet. 1, e53.   DOI
32 Hellman, N.E., Liu, Y., Merkel, E., Austin, C., Le Corre, S., Beier, D.R., Sun, Z., Sharma, N., Yoder, B.K., and Drummond, I.A. (2010). The zebrafish foxj1a transcription factor regulates cilia function in response to injury and epithelial stretch. Proc. Natl. Acad. Sci. USA 107, 18499-18504.   DOI
33 Horowitz, J.C., and Thannickal, V.J. (2006). Epithelial-mesenchymal interactions in pulmonary fibrosis. Semin. Respir. Crit. Care Med. 27, 600-612.   DOI
34 Hu, Q., Wu, Y., Tang, J., Zheng, W., Wang, Q., Nahirney, D., Duszyk, M., Wang, S., Tu, J.C., and Chen, X.Z. (2014). Expression of polycystins and fibrocystin on primary cilia of lung cells. Biochem. Cell Biol. 92, 547-554.   DOI
35 Jain, R., Pan, J., Driscoll, J.A., Wisner, J.W., Huang, T., Gunsten, S.P., You, Y. and Brody, S.L. (2010). Temporal relationship between primary and motile ciliogenesis in airway epithelial cells. Am. J. Respir. Cell Mol. Biol. 43, 731-739.   DOI
36 Huangfu, D., and Anderson, K.V. (2005). Cilia and Hedgehog responsiveness in the mouse. Proc. Natl. Acad. Sci. USA 102, 11325-11330.   DOI