Judge Jennifer L, Lacy Shannon H, Ku Wei-Yao, Owens Kristina M, Hernady Eric, Thatcher Thomas H, Williams Jacqueline P, Phipps Richard P, Sime Patricia J, Kottmann R Matthew
a Department of Environmental Medicine, University of Rochester, Rochester, New York.
b Lung Biology and Disease Program, University of Rochester, Rochester, New York.
Radiat Res. 2017 Jul;188(1):35-43. doi: 10.1667/RR14620.1. Epub 2017 May 2.
Exposure of the lung to ionizing radiation that occurs in radiotherapy, as well as after accidental or intentional mass casualty incident can result in pulmonary fibrosis, which has few treatment options. Pulmonary fibrosis is characterized by an accumulation of extracellular matrix proteins that create scar tissue. Although the mechanisms leading to radiation-induced pulmonary fibrosis remain poorly understood, one frequent observation is the activation of the profibrotic cytokine transforming growth factor-beta (TGF-β). Our laboratory has shown that the metabolite lactate activates latent TGF-β by a reduction in extracellular pH. We recently demonstrated that lactate dehydrogenase-A (LDHA), the enzyme that produces lactate, is upregulated in patients with radiation-induced pulmonary fibrosis. Furthermore, genetic silencing of LDHA or pharmacologic inhibition using the LDHA inhibitor gossypol prevented radiation-induced extracellular matrix secretion in vitro through inhibition of TGF-β activation. In the current study, we hypothesized that LDHA inhibition in vivo prevents radiation-induced pulmonary fibrosis. To test this hypothesis, C57BL/6 mice received 5 Gy total-body irradiation plus 10 Gy thoracic irradiation from a Cs source to induce pulmonary fibrosis. Starting at 4 weeks postirradiation, mice were treated with 5 mg/kg of the LDHA inhibitor gossypol or vehicle daily until sacrifice at 26 weeks postirradiation. Exposure to radiation resulted in pulmonary fibrosis, characterized by an increase in collagen content, fibrosis area, extracellular matrix gene expression and TGF-β activation. Irradiated mice treated with gossypol had significantly reduced fibrosis outcomes, including reduced collagen content in the lungs, reduced expression of active TGF-β, LDHA and the transcription factor hypoxia-inducible factor-1 alpha (HIF-1α). These findings suggest that inhibition of LDHA protects against radiation-induced pulmonary fibrosis, and may be a novel therapeutic strategy for radiation-induced pulmonary fibrosis.
在放射治疗过程中，以及在意外或故意的大规模伤亡事件之后，肺部暴露于电离辐射会导致肺纤维化，而针对肺纤维化的治疗选择很少。肺纤维化的特征是细胞外基质蛋白积累，从而形成瘢痕组织。尽管导致辐射诱导的肺纤维化的机制仍知之甚少，但一个常见的现象是促纤维化细胞因子转化生长因子-β（TGF-β）的激活。我们实验室已经表明，代谢产物乳酸通过降低细胞外pH值来激活潜伏的TGF-β。我们最近证明，产生乳酸的酶乳酸脱氢酶-A（LDHA）在辐射诱导的肺纤维化患者中上调。此外，通过使用LDHA抑制剂棉酚对LDHA进行基因沉默或药理抑制，可在体外通过抑制TGF-β激活来防止辐射诱导的细胞外基质分泌。在本研究中，我们假设体内抑制LDHA可预防辐射诱导的肺纤维化。为了验证这一假设，C57BL / 6小鼠接受了5 Gy的全身照射以及来自Cs源的10 Gy胸部照射，以诱导肺纤维化。从照射后4周开始，每天用5 mg / kg的LDHA抑制剂棉酚或赋形剂处理小鼠，直至在照射后26周处死。暴露于辐射会导致肺纤维化，其特征是胶原蛋白含量增加、纤维化面积增加、细胞外基质基因表达增加以及TGF-β激活。用棉酚处理的受辐照小鼠的纤维化结果明显降低，包括肺中胶原蛋白含量降低、活性TGF-β、LDHA和转录因子缺氧诱导因子-1α（HIF-1α）的表达降低。这些发现表明，抑制LDHA可预防辐射诱导的肺纤维化，并且可能是治疗辐射诱导的肺纤维化的一种新策略。
