Alruhaimi Reem S, Alnasser Sulaiman M, Althagafy Hanan S, Mansour Sherif M A, Abd El-Ghafar Omnia A M, Mahmoud Ayman M, Hassanein Emad H M
Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, 11671, Saudi Arabia.
Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraydah, 52571, Saudi Arabia.
J Mol Histol. 2025 Sep 15;56(5):314. doi: 10.1007/s10735-025-10599-w.
Cyclophosphamide (CP) is an effective chemotherapeutic agent whose clinical efficacy is often limited by toxicity, including intestinal injury. Oxidative stress and inflammation are central to CP-induced tissue damage and represent a valuable target to attenuate intestinal injury. Ambroxol (ABX), a clinically approved mucolytic agent, has demonstrated antioxidant, anti-inflammatory, and mucoregulatory properties that may confer multi-organ protection. This study investigated the protective effects of ABX against CP-induced intestinal injury in rats, exploring the involvement of oxidative stress, inflammation and Keap-1/Nrf2/HO-1 signaling. Adult male rats received ABX (20 mg/kg/day) orally for seven consecutive days, with CP (100 mg/kg, i.p.) administered on the fifth day. CP induced significant intestinal injury manifested by intestinal mucosal atrophy, decreased length of villi and goblet cell depletion. CP triggered oxidative stress characterized by increased MDA and decreased GSH, SOD, and catalase, upregulated NF-κB, IL-6, and TNF-α, and increased caspase-3 expression in the intestine. ABX attenuated histopathological alterations, mitigated oxidative stress, suppressed NF-κB and cytokines, and downregulated caspase-3. In addition, ABX preserved intestinal goblet cells while modulating the Keap-1/Nrf2/HO-1 pathway in intestinal tissue. These findings demonstrate the protective role of ABX against CP-induced intestinal injury via antioxidant, anti-inflammatory, and mucoprotective mechanisms, supporting its potential repurposing as an adjuvant during CP chemotherapy. The protective mechanism of ABX involves its ability to modulate the Keap-1/Nrf2/HO-1 signaling pathway.
环磷酰胺（CP）是一种有效的化疗药物，但其临床疗效常常受到毒性的限制，包括肠道损伤。氧化应激和炎症是CP诱导组织损伤的核心因素，也是减轻肠道损伤的一个有价值的靶点。氨溴索（ABX）是一种临床批准的黏液溶解剂，已证明具有抗氧化、抗炎和黏液调节特性，可能对多器官起到保护作用。本研究调查了ABX对CP诱导的大鼠肠道损伤的保护作用，探讨了氧化应激、炎症以及Keap-1/Nrf2/HO-1信号通路的参与情况。成年雄性大鼠连续7天口服ABX（20毫克/千克/天），在第5天腹腔注射CP（100毫克/千克）。CP诱导了明显的肠道损伤，表现为肠黏膜萎缩、绒毛长度缩短和杯状细胞减少。CP引发了氧化应激，其特征是丙二醛增加，谷胱甘肽、超氧化物歧化酶和过氧化氢酶减少，肠道中核因子κB、白细胞介素-6和肿瘤坏死因子-α上调，半胱天冬酶-3表达增加。ABX减轻了组织病理学改变，减轻了氧化应激，抑制了核因子κB和细胞因子，并下调了半胱天冬酶-3。此外，ABX在调节肠道组织中Keap-1/Nrf2/HO-1通路的同时，保留了肠道杯状细胞。这些发现证明了ABX通过抗氧化、抗炎和黏液保护机制对CP诱导的肠道损伤具有保护作用，支持其作为CP化疗辅助药物的潜在重新用途。ABX的保护机制涉及其调节Keap-1/Nrf2/HO-1信号通路的能力。
