Title: Role of transforming growth factor and vascular endothelial growth factor and their receptors in the pathogenesis of bleomycin induced lung fibrosis

Authors: Apoorva Pandey, Ritu Kulshrestha, Himani Singh, Shilpi Bhardwaj, Surendra K Bansal

 DOI:  https://dx.doi.org/10.18535/jmscr/v5i6.146

Abstract

Several growth factors including transforming growth factor, vascular endothelial growth factor receptor, fibroblast growth factor etc. are known to play critical roles in the pathogenesis of pulmonary fibrosis. While these growth factors stimulate the proliferation of lung fibroblasts in vitro, their altered expression and release during angiogenesis, aberrant vascular and parenchymal remodeling in lung fibrosis remains controversial. These factors act via receptor tyrosine kinases (vascular endothelial growth factor receptor and fibroblast growth factor receptor), and serine threonine kinase receptors (transforming growth factor receptor) which in turn regulate their availability and modulate cell functions. Therefore protein kinase inhibitors are gaining popularity in the treatment of diseases due to hyperactive protein kinases (including mutant or over expressed kinases in cancer) and other chronic inflammatory diseases. Recently the tyrosine kinase inhibitors such as nintedanib have shown anti-fibrotic and anti-inflammatory effects in animal models of pulmonary fibrosis. Here, we summarise the evidence for involvement of transforming growth factor, vascular endothelial growth factor and their receptors in the pathogenesis of parenchymal and vascular remodeling in pulmonary fibrosis.

Keywords: Pulmonary fibrosis, bleomycin, Transforming growth factor-β, vascular endothelial growth factor, receptor tyrosine kinases, serine threonine kinase receptors.

References

1.      Alonso, A., Sasin, J., Bottini, N., Friedberg, I., Friedberg, I., Osterman, A., Godzik, A., Hunter, T., Dixon, J., Mustelin, T., 2004. Protein Tyrosine Phosphatases in the Human Genome. Cell 117, 699–711. doi:10.1016/j.cell.2004.05.018

2.      Attisano, L., Wrana, J.L., 2002. Signal transduction by the TGF-beta superfamily. Science 296, 1646–7. doi:10.1126/science.1071809

3.      Ball, S.G., Shuttleworth, C.A., Kielty, C.M., 2007. Vascular endothelial growth factor can signal through platelet-derived growth factor receptors. J. Cell Biol. 177.

4.      Chen, S.J., Yuan, W., Lo, S., Trojanowska, M., Varga, J., 2000. Interaction of smad3 with a proximal smad-binding element of the human alpha2(I) procollagen gene promoter required for transcriptional activation by TGF-beta. J. Cell. Physiol. 183, 381–92. doi:10.1002/(SICI)1097-4652(200006)183:3<381::AID-JCP11>3.0.CO;2-O

5.      Chua, F., Gauldie, J., Laurent, G.J., 2005. Pulmonary Fibrosis. Am. J. Respir. Cell Mol. Biol. 33, 9–13. doi:10.1165/rcmb.2005-0062TR

6.      Cosgrove, G.P., Brown, K.K., Schiemann, W.P., Serls, A.E., Parr, J.E., Geraci, M.W., Schwarz, M.I., Cool, C.D., Worthen, G.S., 2004. Pigment epithelium-derived factor in idiopathic pulmonary fibrosis: a role in aberrant angiogenesis. Am. J. Respir. Crit. Care Med. 170, 242–51. doi:10.1164/rccm.200308-1151OC

7.      Datta, P.K., Blake, M.C., Moses, H.L., 2000. Regulation of plasminogen activator inhibitor-1 expression by transforming growth factor-beta -induced physical and functional interactions between smads and Sp1. J. Biol. Chem. 275, 40014–9. doi:10.1074/jbc.C000508200

8.      Derynck, R., Zhang, Y.E., 2003. Smad-dependent and Smad-independent path-ways in TGF-β family signalling. Nature 425, 577–584. doi:10.1038/nature02006

9.      Ebina, M., Shimizukawa, M., Shibata, N., Kimura, Y., Suzuki, T., Endo, M., Sasano, H., Kondo, T., Nukiwa, T., 2004. Heterogeneous Increase in CD34-positive Alveolar Capillaries in Idiopathic Pulmonary Fibrosis. Am. J. Respir. Crit. Care Med. 169, 1203–1208. doi:10.1164/rccm.200308-1111OC

10.  Gharaee-Kermani, M., Ullenbruch, M., Phan, S.H., 2005. Animal models of pulmonary fibrosis. Methods Mol. Med. 117, 251–9. doi:10.1385/1-59259-940-0:251

11.  Gong, F., Gu, W., Tang, H., Lin, Y., Wang, W., Kang, M., 2005. [Pathophys-iology of bleomycin-induced pulmonary hypertension in immature rabbits]. Zhejiang Da Xue Xue Bao. Yi Xue Ban 34, 237–42.

12.  Gu, L., Zhu, Y.-J., Yang, X., Guo, Z.-J., Xu, W.-B., Tian, X.-L., 2007. Effect of TGF-beta/Smad signaling pathway on lung myofibroblast differentiation. Acta Pharmacol. Sin. 28, 382–91. doi:10.1111/j.1745-7254.2007.00468.x

13.  Gueders, M.M., Foidart, J.M., Noel, A., Cataldo, D.D., 2006. Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs in the respiratory tract: Potential implications in asthma and other lung diseases. Eur. J. Pharmacol. 533, 133–144. doi:10.1016/j.ejphar.2005.12.082

14.  Hanks, S.K., Quinn, A.M., Hunter, T., 1988. The protein kinase family: conse-rved features and deduced phylogeny of the catalytic domains. Science 241, 42–52.

15.  Huang, F., Chen, Y.-G., 2012. Regulation of TGF-β receptor activity. Cell Biosci. 2, 9. doi:10.1186/2045-3701-2-9

16.  Jakobsson, L., Kreuger, J., Holmborn, K., Lundin, L., Eriksson, I., Kjellén, L., Claesson-Welsh, L., 2006. Heparan sulfate in trans potentiates VEGFR-mediated angiogenesis. Dev. Cell 10, 625–34. doi:10.1016/j.devcel.2006.03.009

17.  Koch, S., Tugues, S., Li, X., Gualandi, L., Claesson-Welsh, L., 2011. Signal transduction by vascular endothelial growth factor receptors. Biochem. J. 437, 169–83. doi:10.1042/BJ20110301

18.  Lu, Y., Azad, N., Wang, L., Iyer, A.K. V, Castranova, V., Jiang, B.-H., Rojanasakul, Y., 2010. Phosphatidylinositol-3-kinase/-akt regulates bleomycin-induced fibroblast proliferation and collagen production. Am. J. Respir. Cell Mol. Biol. 42, 432–41. doi:10.1165/rcmb.2009-0002OC

19.  Maharaj, A.S.R., Saint-Geniez, M., Maldonado, A.E., D’Amore, P.A., 2006. Vascular endothelial growth factor localization in the adult. Am. J. Pathol. 168, 639–48. doi:10.2353/ajpath.2006.050834

20.  Massagué, J., Chen, Y.G., 2000. Controlling TGF-beta signaling. Genes Dev. 14, 627–44.

21.  McMahon, S., Charbonneau, M., Grandmont, S., Richard, D.E., Dubois, C.M., 2006. Transforming growth factor beta1 induces hypoxia-inducible factor-1 stabilization through selective inhibition of PHD2 expression. J. Biol. Chem. 281, 24171–81. doi:10.1074/jbc.M604507200

22.  Meadows, K.N., Bryant, P., Pumiglia, K., 2001. Vascular endothelial growth factor induction of the angiogenic phenotype requires Ras activation. J. Biol. Chem. 276, 49289–98. doi:10.1074/jbc.M108069200

23.  Moustakas, A., Heldin, C.-H., 2005. Non-Smad TGF-β signals. J. Cell Sci. 118. 3573-84. doi: 10.1242/jcs.02554

24.  Murakami, M., Zheng, Y., Hirashima, M., Suda, T., Morita, Y., Ooehara, J., Ema, H., Fong, G.-H., Shibuya, M., 2008. VEGFR1 tyrosine kinase signaling promotes lymphangiogenesis as well as angiogenesis indirectly via macrophage recruitment. Arterioscler. Thromb. Vasc. Biol. 28, 658–64. doi:10.1161/ATVBAHA.107.150433

25.  Nobel, J.J., Norman, G.K., 2003. Emerging Information Management Technologies and the Future of Disease Management. Dis. Manag. 6, 219–231. doi:10.1089/109350703322682531

26.  Peão, M.N., Aguas, A.P., de Sá, C.M., Grande, N.R., 1994. Neoformation of blood vessels in association with rat lung fibrosis induced by bleomycin. Anat. Rec. 238, 57–67. doi:10.1002/ar.1092380108

27.  Piek, E., Heldin, C.H., Ten Dijke, P., 1999. Specificity, diversity, and regulation in TGF-beta superfamily signaling. FASEB J. 13, 2105–24.

28.  Radha, V., Nambirajan, S., Swarup, G., 1996. Association of Lyn tyrosine kinase with the nuclear matrix and cell-cycle-dependent changes in matrix-associated tyrosine kinase activity. Eur. J. Biochem. 236, 352–9.

29.  Renzoni, E.A., Walsh, D.A., Salmon, M., Wells, A.U., Sestini, P., Nicholson, A.G., Veeraraghavan, S., Bishop, A.E., Romanska, H.M., Pantelidis, P., Black, C.M., du Bois, R.M., 2003. Interstitial vascularity in fibrosing alveolitis. Am. J. Respir. Crit. Care Med. 167, 438–443. doi:10.1164/rccm.200202-135OC

30.  Shi, Y., Massagué, J., 2003. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113, 685–700.

31.  Shu, X., Wu, W., Mosteller, R.D., Broek, D., 2002. Sphingosine kinase mediates vascular endothelial growth factor-induced activation of ras and mitogen-activated protein kinases. Mol. Cell. Biol. 22, 7758–68.

32.  Steurer, M., Zoller, H., Augustin, F., Fong, D., Heiss, S., Strasser-Weippl, K., Gastl, G., Tzankov, A., 2007. Increased angiogenesis in chronic idiopathic myelofibrosis: vascular endothelial growth factor as a prominent angiogenic factor. Hum. Pathol. 38, 1057–64. doi:10.1016/j.humpath.2006.12.011

33.  Tuder, R.M., Yun, J.H., 2008. Vascular endothelial growth factor of the lung: friend or foe. Curr. Opin. Pharmacol. 8, 255–60. doi:10.1016/j.coph.2008.03.003

34.  Turner-Warwick, M., 1963. Precapillary systemic-pulmonary anastomoses. Thorax 18, 225–37. doi:10.1136/THX.18.3.225

35.  Verrecchia, F., Chu, M.-L., Mauviel, A., 2001. Identification of Novel TGF- /Smad Gene Targets in Dermal Fibroblasts using a Combined cDNA Microarray/Promoter Transactivation Approach. J. Biol. Chem. 276, 17058–17062. doi:10.1074/jbc.M100754200

36.  Wollin, L., Wex, E., Pautsch, A., Schnapp, G., Hostettler, K.E., Stowasser, S., Kolb, M., 2015. Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis. Eur. Respir. J. 45, 1434-45 doi: 10.1183/09031936.00174914

37.  Wrighton, K.H., Lin, X., Feng, X.-H., 2009. Phospho-control of TGF-β superfamily signaling. Cell Res. 19, 8–20. doi:10.1038/cr.2008.327 

Corresponding Author

Dr Ritu Kulshrestha

Tel No: +91 9891334373, Email: This email address is being protected from spambots. You need JavaScript enabled to view it.