Clinical significance of mTOR, ZEB1, ROCK1 expression in lung tissues of pulmonary fibrosis patients

BMC Pulmonary Medicine

Young Whan Kim²  Sung Koo Han²  Chul-Gyu Yoo²  Jae-Joon Yim²  Sang-Min Lee²  Young Sik Park²  Hyo Jin Park¹  Jong Sun Park³ 

[1] Department of Pathology, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, Korea;Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea;Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, Korea

关键词: Survival;    ROCK1;    ZEB1;    mTOR;    Usual interstitial pneumonia;    Immunohistochemical analysis;    Pulmonary fibrosis;   

Others  :  1091634
DOI  :  10.1186/1471-2466-14-168

 received in 2013-07-20, accepted in 2014-10-15,  发布年份 2014

【 摘 要 】

Background

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease of unknown causes. Three proteins (mammalian target of rapamycin, mTOR; zinc finger E-box-binding homeobox 1, ZEB1; Rho-associated, coiled-coil containing protein kinase 1, ROCK1) may be related to pulmonary fibrosis. However, they have not been assessed in human pulmonary fibrosis. We assessed the clinical significance of mTOR, ZEB1, and ROCK1 expression in human pulmonary fibrosis of usual interstitial pneumonia (UIP) pattern.

Methods

The mTOR, ZEB1, and ROCK1 expression was evaluated by immunohistochemical staining of 30 surgical lung biopsy tissues from 26 IPF and 4 UIP pattern connective tissue disease related interstitial lung disease (CTD-ILD) patients. The expression scores correlated with the clinical features.

Results

The mTOR, ZEB1 and ROCK1 mainly expressed in alveolar epithelial cells of UIP lungs. The histological fibrosis scores and lung function decline in the strong mTOR expression group were higher than those in the weak and intermediate expression group. Patients with positive ZEB1 expression had higher fibrosis scores and greater decline in carbon monoxide diffusion capacity (DL_CO) than patients with negative ZEB1 expression. Patients with positive mTOR or ZEB1 expression had poorer prognosis than that of patients with negative mTOR or ZEB1 expression, although it was not statistically significant. ROCK1 was not associated with the studied clinicopathological features.

Conclusions

The mTOR and ZEB1 expression in pulmonary fibrosis patients significantly correlated with the fibrosis score and lung function decline, indicating that it may be related to the prognosis of pulmonary fibrosis. Further studies involving large numbers of homogeneous IPF patients are warranted.

【 授权许可】

   
2014 Park et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]King TE Jr, Pardo A, Selman M: Idiopathic pulmonary fibrosis. Lancet 2011, 378(9807):1949-1961.
• [2]Hartford CM, Ratain MJ: Rapamycin: something old, something new, sometimes borrowed and now renewed. Clin Pharmacol Ther 2007, 82(4):381-388.
• [3]Korfhagen TR, Le Cras TD, Davidson CR, Schmidt SM, Ikegami M, Whitsett JA, Hardie WD: Rapamycin prevents transforming growth factor-alpha-induced pulmonary fibrosis. Am J Respir Cell Mol Biol 2009, 41(5):562-572.
• [4]Buschhausen L, Kamm M, Arns W, Schulze-Lohoff E, Weber M: [Successful treatment of a severe case of idiopathic pulmonary fibrosis with rapamycin]. Med Klin (Munich) 2005, 100(3):161-164.
• [5]Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, Vadas MA, Khew-Goodall Y, Goodall GJ: The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol 2008, 10(5):593-601.
• [6]Cho JH, Gelinas R, Wang K, Etheridge A, Piper MG, Batte K, Dakhallah D, Price J, Bornman D, Zhang S, March C, Galas D: Systems biology of interstitial lung diseases: integration of mRNA and microRNA expression changes. BMC Med Genomics 2011, 4:8. BioMed Central Full Text
• [7]Shimizu Y, Dobashi K, Iizuka K, Horie T, Suzuki K, Tukagoshi H, Nakazawa T, Nakazato Y, Mori M: Contribution of small GTPase Rho and its target protein rock in a murine model of lung fibrosis. Am J Respir Crit Care Med 2001, 163(1):210-217.
• [8]American Thoracic Society/European Respiratory Society : American Thoracic Society/European respiratory society international multidisciplinary consensus classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med 2002, 165(2):277-304.
• [9]Park YS, Park CM, Lee HJ, Goo JM, Chung DH, Lee SM, Yim JJ, Kim YW, Han SK, Yoo CG: Clinical implication of protease-activated receptor-2 in idiopathic pulmonary fibrosis. Respir Med 2013, 107(2):256-262.
• [10]Ashcroft T, Simpson JM, Timbrell V: Simple method of estimating severity of pulmonary fibrosis on a numerical scale. J Clin Pathol 1988, 41(4):467-470.
• [11]Akira M, Sakatani M, Ueda E: Idiopathic pulmonary fibrosis: progression of honeycombing at thin-section CT. Radiology 1993, 189(3):687-691.
• [12]Sarbassov DD, Ali SM, Sabatini DM: Growing roles for the mTOR pathway. Curr Opin Cell Biol 2005, 17(6):596-603.
• [13]Lloberas N, Cruzado JM, Franquesa M, Herrero-Fresneda I, Torras J, Alperovich G, Rama I, Vidal A, Grinyo JM: Mammalian target of rapamycin pathway blockade slows progression of diabetic kidney disease in rats. J Am Soc Nephrol 2006, 17(5):1395-1404.
• [14]Wu MJ, Wen MC, Chiu YT, Chiou YY, Shu KH, Tang MJ: Rapamycin attenuates unilateral ureteral obstruction-induced renal fibrosis. Kidney Int 2006, 69(11):2029-2036.
• [15]Kramer S, Wang-Rosenke Y, Scholl V, Binder E, Loof T, Khadzhynov D, Kawachi H, Shimizu F, Diekmann F, Budde K, Neumayer HH, Peters H: Low-dose mTOR inhibition by rapamycin attenuates progression in anti-thy1-induced chronic glomerulosclerosis of the rat. Am J Physiol Renal Physiol 2008, 294(2):F440-449.
• [16]Patsenker E, Schneider V, Ledermann M, Saegesser H, Dorn C, Hellerbrand C, Stickel F: Potent antifibrotic activity of mTOR inhibitors sirolimus and everolimus but not of cyclosporine A and tacrolimus in experimental liver fibrosis. J Hepatol 2011, 55(2):388-398.
• [17]Mehrad B, Burdick MD, Strieter RM: Fibrocyte CXCR4 regulation as a therapeutic target in pulmonary fibrosis. Int J Biochem Cell Biol 2009, 41(8–9):1708-1718.
• [18]Simler NR, Howell DC, Marshall RP, Goldsack NR, Hasleton PS, Laurent GJ, Chambers RC, Egan JJ: The rapamycin analogue SDZ RAD attenuates bleomycin-induced pulmonary fibrosis in rats. Eur Respir J 2002, 19(6):1124-1127.
• [19]Fernandez IE, Eickelberg O: New cellular and molecular mechanisms of lung injury and fibrosis in idiopathic pulmonary fibrosis. Lancet 2012, 380(9842):680-688.
• [20]Nair RV, Huang X, Shorthouse R, Adams B, Brazelton T, Braun-Dullaeus R, Morris RE: Antiproliferative effect of rapamycin on growth factor-stimulated human adult lung fibroblasts in vitro may explain its superior efficacy for prevention and treatment of allograft obliterative airway disease in vivo. Transplant Proc 1997, 29(1–2):614-615.
• [21]Gao Y, Xu X, Ding K, Liang Y, Jiang D, Dai H: Rapamycin inhibits transforming growth factor beta1-induced fibrogenesis in primary human lung fibroblasts. Yonsei Med J 2013, 54(2):437-444.
• [22]Clinicaltrials.gov, A service of the U.S. National Institutes of Health. http://clinicaltrials.gov/ct2/show/NCT01462006?term=mTOR%2C+idiopathic+pulmonary+fibrosis&rank=1 webcite
• [23]ten Dijke P, Hill CS: New insights into TGF-beta-Smad signalling. Trends Biochem Sci 2004, 29(5):265-273.
• [24]Aigner K, Descovich L, Mikula M, Sultan A, Dampier B, Bonne S, van Roy F, Mikulits W, Schreiber M, Brabletz T, Sommergruber W, Schweifer N, Wernitznig A, Beug H, Foisner R, Eger A: The transcription factor ZEB1 (deltaEF1) represses Plakophilin 3 during human cancer progression. FEBS Lett 2007, 581(8):1617-1624.
• [25]Bhowmick NA, Ghiassi M, Bakin A, Aakre M, Lundquist CA, Engel ME, Arteaga CL, Moses HL: Transforming growth factor-beta1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. Mol Biol Cell 2001, 12(1):27-36.
• [26]Das S, Becker BN, Hoffmann FM, Mertz JE: Complete reversal of epithelial to mesenchymal transition requires inhibition of both ZEB expression and the Rho pathway. BMC Cell Biol 2009, 10:94. BioMed Central Full Text