Systems Biology and Medicine Center for Complex Diseases, the Affiliated Hospital of Qingdao University, Qingdao 266003, China; College of Food Science and engineering, Northwest A&F University, 712100, China.
Systems Biology and Medicine Center for Complex Diseases, the Affiliated Hospital of Qingdao University, Qingdao 266003, China; School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
Int J Biol Macromol. 2020 Oct 1;160:319-327. doi: 10.1016/j.ijbiomac.2020.05.087. Epub 2020 May 16.
Bleomycin is a clinically used anticancer drug, but it induces lung fibrosis in certain cancer patients with unknown mechanism. Glycosaminoglycans (GAGs) are required for lung morphogenesis during animal development. In current study, GAG disaccharides including heparan sulfate (HS) and chondroitin sulfate (CS) from bleomycin-induced and control lung tissues in lung fibrosis mouse model were tagged with 1-phenyl-3-methyl-5-pyrazolone (PMP) and deuterated PMP, respectively. The differentially isotope-tagged disaccharides were quantitatively compared by LC-MS. At day 10, the amount of CS disaccharides (U0a0, U0a6, and U0a4) and non-sulfated HS disaccharide (U0A0) were increased by 1.3-, 1.6-, 11.7-, and 2.2-fold, respectively, whereas the amount of CS disaccharide (U0a2), hyaluranan disaccharide (UβA0), and six HS disaccharides (U0A6, U2A0, U0H6, U0S0, U2S0, and U2S6) were decreased from1.1- to 14.3-fold compared to that of the controls. At day 15, under-sulfation of both HS and CS disaccharides was persisted. At day 30, the CS disaccharide compositions were recovered to that of the control levels whereas the HS were still remarkably under-sulfated. In conclusion, GAGs, especially HS, from fibrotic lungs induced by a single injection of bleomycin were significantly under-sulfated up to 30 days, suggesting GAGs might be another class of defective signaling molecules involved in bleomycin-induced lung fibrosis.
博来霉素是一种临床使用的抗癌药物，但它会在某些癌症患者中引起肺纤维化，其机制尚不清楚。糖胺聚糖 (GAGs) 是动物发育过程中肺形态发生所必需的。在本研究中，从博来霉素诱导的肺纤维化小鼠模型和对照肺组织中分离出的肝素硫酸盐 (HS) 和软骨素硫酸盐 (CS) 的 GAG 二糖分别用 1-苯基-3-甲基-5-吡唑啉酮 (PMP) 和氘代 PMP 标记。通过 LC-MS 对差异同位素标记的二糖进行定量比较。第 10 天，CS 二糖 (U0a0、U0a6 和 U0a4) 和非硫酸化 HS 二糖 (U0A0) 的含量分别增加了 1.3 倍、1.6 倍、11.7 倍和 2.2 倍，而 CS 二糖 (U0a2)、透明质酸二糖 (UβA0) 和六个 HS 二糖 (U0A6、U2A0、U0H6、U0S0、U2S0 和 U2S6) 的含量则降低了 1.1 至 14.3 倍。第 15 天，HS 和 CS 二糖的低硫酸化仍持续存在。第 30 天，CS 二糖的组成恢复到对照水平，而 HS 仍显著低硫酸化。总之，单次注射博来霉素诱导的纤维化肺中的 GAGs，尤其是 HS，其硫酸化程度显著降低，持续至 30 天，这表明 GAGs 可能是另一种参与博来霉素诱导的肺纤维化的缺陷信号分子。
