Susskind Herbert, Hymowitz Michelle H, Lau Yat Hong, Atkins Harold L, Hurewitz Adam N, Valentine Edward S, Meek Allen G, Zucker Stanley
Clinical Research Center, Brookhaven National Laboratory, Upton, NY 11973, USA.
Int J Radiat Oncol Biol Phys. 2003 Jul 15;56(4):1161-9. doi: 10.1016/s0360-3016(03)00161-5.
Does the release of plasma matrix metalloproteinase-9 (MMP-9) by radiation-activated airway epithelial cells and infiltrating inflammatory cells play a role in the radiation damage or repair process in the lungs? We evaluated lung damage by ionizing radiation using plasma levels of MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), and MMP-3 as biologic markers of tissue damage, and also their relationship to changes in pulmonary epithelial permeability, clinical signs and symptoms, and lung structural changes.
Seven serial studies were conducted in each of 8 patients undergoing chest radiotherapy (RT) for lung or breast cancer, beginning before the first treatment (baseline) and then biweekly to approximately 100 days during and after RT. Chest radiographs were monitored for each patient. Sandwich enzyme-linked immunoassays (ELISA) were used to measure plasma MMP-3, MMP-9, and TIMP-1 levels. Lung permeability was evaluated by measuring the rate of epithelial clearance of approximately 150 microCi ( approximately 5.6 MBq) inhaled (99m)Tc diethylenetriamine pentaacetate aerosol (DTPA).
Lung and breast cancer resulted in very high plasma levels of MMP-9 (126-893 ng/mL) and TIMP-1 (496-8985 ng/mL) in all subjects studied before initiation of RT. This compares with plasma MMP-9 and TIMP-1 values in healthy volunteers of 29 +/- 11 ng/mL and 436 +/- 86 ng/mL, respectively. RT was followed by a sharp decrease in plasma MMP-9 within the first 2 weeks, but without a corresponding change in TIMP-1. In contrast, plasma MMP-3 levels, which are generally increased with inflammation, were elevated in only 1 of 5 subjects.
Lung and breast cancer are associated with high plasma levels of MMP-9 and TIMP-1. These high baseline plasma levels of MMP-9 were reduced in the first 2 weeks of RT in 7 of 8 subjects, and TIMP-1 plasma levels remained high in all subjects. The decrease in plasma MMP-9 after initiation of chest RT appears to reflect a suppressive effect on cancer-induced cellular responses rather than a primary role for MMP-9 in radiation-induced lung damage. Likewise, the lack of a rise in plasma MMP-3 levels does not support a role for MMP-3 in tissue injury or repair in the lung. It remains to be determined whether plasma MMP-9 measurements will serve as a useful parameter in predicting cancer relapse.
辐射激活的气道上皮细胞和浸润的炎性细胞释放的血浆基质金属蛋白酶-9（MMP-9）在肺部辐射损伤或修复过程中起作用吗？我们通过使用MMP-9、金属蛋白酶组织抑制剂-1（TIMP-1）和MMP-3的血浆水平作为组织损伤的生物学标志物来评估电离辐射对肺的损伤，以及它们与肺上皮通透性变化、临床症状体征和肺结构变化的关系。
对8例因肺癌或乳腺癌接受胸部放疗（RT）的患者进行了7项系列研究，从首次治疗前（基线）开始，然后在放疗期间及放疗后每两周进行一次，持续约100天。对每位患者进行胸部X光片监测。采用夹心酶联免疫吸附测定法（ELISA）测量血浆MMP-3、MMP-9和TIMP-1水平。通过测量吸入的约150微居里（约5.6兆贝克勒尔）（99m）锝二乙三胺五乙酸气雾剂（DTPA）的上皮清除率来评估肺通透性。
在所有放疗开始前研究的受试者中，肺癌和乳腺癌导致血浆MMP-9（126 - 893纳克/毫升）和TIMP-1（496 - 8985纳克/毫升）水平非常高。相比之下，健康志愿者的血浆MMP-9和TIMP-1值分别为29±11纳克/毫升和436±86纳克/毫升。放疗后，血浆MMP-9在最初2周内急剧下降，但TIMP-1没有相应变化。相反，通常随炎症增加的血浆MMP-3水平仅在5名受试者中的1名中升高。
肺癌和乳腺癌与血浆MMP-9和TIMP-1高水平相关。在8名受试者中的７名中，这些MMP-9的高基线血浆水平在放疗的前2周内降低，而所有受试者的TIMP-1血浆水平仍然很高。胸部放疗开始后血浆MMP-9的下降似乎反映了对癌症诱导的细胞反应的抑制作用，而不是MMP-9在辐射诱导的肺损伤中的主要作用。同样，血浆MMP-3水平没有升高不支持MMP-3在肺组织损伤或修复中的作用。血浆MMP-9测量是否将作为预测癌症复发的有用参数还有待确定。
