Division of Nephrology, Department of Internal Medicine, Chi-Mei Hospital, Liouying, Tainan, Taiwan; Department of Environmental and Occupational Health, National Cheng Kung University, College of Medicine, Tainan, Taiwan.
Pharmacy Department, Wei-Gong Memorial Hospital, Miaoli, Taiwan.
Toxicology. 2021 May 30;456:152750. doi: 10.1016/j.tox.2021.152750. Epub 2021 Mar 15.
Paraquat, an herbicide used extensively worldwide, can cause severe toxicity in humans and animals, leading to irreversible, lethal lung fibrosis. The potential of CO-releasing molecules (CORMs), substances that release CO (Carbon monoxide) within animal tissues, for treating paraquat-induced ROS generation and inflammation is investigated here. Our results show that the fast CO releaser CORM-3 (4-20 μM) acts as a potential scavenger of free radicals and decreases fibrosis progression by inhibiting paraquat-induced overexpression of connective tissue growth factor and angiotensin II in MRC-5 cells. The slow CO releaser CORM-A1 (5 mg/kg) clearly decreased expression of the lung profibrogenic cytokines COX-2, TNF-α, and α-SMA and serum hydroxyproline, resulting in a lower mortality rate in paraquat-treated mice. Mice treated with higher-dose CORM-A1 (10 mg/kg) had relatively intact lung lobes and fewer fibrotic patches by gross observation, with less collagen deposition, mesangial matrix accumulation, and pulmonary fibrosis resulting from the mitigation of TGF-β overexpression. In conclusion, our data demonstrate for the first time that CORM-A1 alleviated the development of the fibrotic process and improved survival rate in mice exposed to PQ, would be an attractive therapeutic approach to attenuate the progression of pulmonary fibrosis following PQ exposure.
百草枯是一种在世界范围内广泛使用的除草剂，可导致人类和动物严重中毒，引起不可逆转的致命性肺纤维化。本研究旨在探讨一氧化碳释放分子（CORMs）——在动物组织中释放一氧化碳（Carbon monoxide）的物质——治疗百草枯诱导的活性氧生成和炎症的潜力。我们的结果表明，快速 CO 释放剂 CORM-3（4-20 μM）可作为自由基的潜在清除剂，通过抑制百草枯诱导的结缔组织生长因子和血管紧张素 II 在 MRC-5 细胞中的过度表达，抑制纤维化进展。慢 CO 释放剂 CORM-A1（5mg/kg）可明显降低肺纤维化细胞因子 COX-2、TNF-α和α-SMA 的表达以及血清羟脯氨酸水平，从而降低百草枯处理小鼠的死亡率。通过大体观察，用较高剂量 CORM-A1（10mg/kg）处理的小鼠的肺叶相对完整，纤维化斑块较少，胶原沉积、肾小球基质积聚和 TGF-β过表达减轻导致肺纤维化减少。总之，我们的数据首次表明，CORM-A1 可减轻 PQ 暴露小鼠的纤维化过程发展并提高其存活率，是一种有吸引力的治疗方法，可减轻 PQ 暴露后肺纤维化的进展。
