Targeting TGF-βeta for the Treatment of Pulmonary Fibrosis Following Radiotherapy

Kayla Daniels

Introduction: Following intense radiation treatment for lung cancer, damage to lung tissue can occur as a side effect. Radiation treatments will cause damage due to the release of free radicals. This damage causes the body to release cytokines that will recruit inflammatory cells. The main cytokines that are released and cause damage are TGF- β and platelet derived growth factor (PDGF). TGF- β will activate a variety of intracellular processes which will lead to varying results such as release of more inflammatory signals, accumulation of complexes, and chronically- scarring of pulmonary tissue. Experiments that hope to decrease the amount cytokines like TGF-β, lactate, and PDGF are hypothesized to decreased inflammation. Methods: It is hypothesized that TGF-b is one the main signaling molecules that will stimulate inflammation in pulmonary tissue that chronically will lead to pulmonary fibrosis.2  Latent TGF-β binding proteins (LTBP) will block TGF-β from binding to the extracellular matrix through proteins called latent). Results: LTPB will first bind to covalently bind to a TGF-β propeptide (LAP) and form a complex by disulfide bonds in the endoplasmic reticulum (ER).7  Integrin αvβ6 (located on the C terminus of the LAP) plays a role in both in the activation of TGF-β in late stages of pulmonary fibrosis.6 Two set of TGF-α transgenic mice were induced to have pulmonary fibrosis; one with an anti-αvβ6 antibody. At the end of 8 weeks, the group that was given anti-αvβ6 antibody showed significantly less pleural thickening as well as less damage to pleural tissue.6 A fall in lactate levels would result in a decrease in TGF-β and therefore, a decrease in pulmonary tissue damage.4 After blocking PDGF, epithelial cells and fibroblasts within the mice treated with the PDGF antibody were less damaged than those treated with the control.5 Mice treated with TGF- β or PDGF inhibitors individually showed signs of a decrease in pulmonary damage but combination therapy showed a significant decrease in radiation induced damage to the lung.3 Conclusion: Based on these results, it can be hypothesized that a reduction in LDHA could result in a decrease in the harmful effects of pulmonary fibrosis in humans as well. Blocking of TGF-β and PDGF trials should be considered for testing in human clinical trials next.

  1. Ballester B, Milara J, Cortijo J. Idiopathic Pulmonary Fibrosis and Lung Cancer: Mechanisms and Molecular Targets. Int J Mol Sci. 2019;20(3):593. Published 2019 Jan 30. doi:10.3390/ijms20030593 PDGF; use of anti PDGf drug
  2. Chen Z, Wu Z, Ning W. Advances in Molecular Mechanisms and Treatment of Radiation-Induced Pulmonary Fibrosis. Transl Oncol. 2018;12(1):162-169.
  3. Dadrich M, Nicolay NH, Flechsig P, et al. Combined inhibition of TGFβ and PDGF signaling attenuates radiation-induced pulmonary fibrosis. Oncoimmunology. 2015;5(5):e1123366. Published 2015 Dec 29. doi:10.1080/2162402X.2015.1123366
  4. Judge JL, Lacy SH, Ku WY, et al. The Lactate Dehydrogenase Inhibitor Gossypol Inhibits Radiation-Induced Pulmonary Fibrosis. Radiat Res. 2017;188(1):35–43. doi:10.1667/RR14620.1
  5. Kishi M, Aono Y, Sato S, et al. Blockade of platelet-derived growth factor receptor-β, not receptor-α ameliorates bleomycin-induced pulmonary fibrosis in mice. PLoS One. 2018;13(12):e0209786. Published 2018 Dec 31. doi:10.1371/journal.pone.0209786
  6. Madala SK, Korfhagen TR, Schmidt S, et al. Inhibition of the αvβ6 integrin leads to limited alteration of TGF-α-induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2014;306(8):L726–L735. doi:10.1152/ajplung.00357.2013
  7. Robertson IB, Horiguchi M, Zilberberg L, Dabovic B, Hadjiolova K, Rifkin DB. Latent TGF-β-binding proteins. Matrix Biol. 2015;47:44–53. doi:10.1016/j.matbio.2015.05.005