Candesartan Attenuates Cisplatin-Induced Lung Injury by Modulating Oxidative Stress, Inflammation, and TLR-4/NF-κB, JAK1/STAT3, and Nrf2/HO-1 Signaling

Cisplatin (CIS) is an effective chemotherapeutic agent against different cancers. The use of CIS is associated with acute lung injury (ALI) and other adverse effects, and oxidative stress and inflammation were implicated in its toxic effects. Candesartan (CAN), an angiotensin II (Ang II) receptor blocker, showed beneficial effects against oxidative stress and inflammation. Therefore, this study investigated the potential of CAN to prevent CIS-induced oxidative stress, inflammation, and lung injury in rats, pointing to the involvement of TLR4/NF-kappa B, JAK1/STAT3, PPAR gamma, and Nrf2/HO-1 signaling. The rats received CAN (5 mg/kg) for 10 days and were challenged with a single dose of CIS (7 mg/kg) on day 7. CIS caused injury to the alveoli and the bronchial tree, increased lipid peroxidation, nitric oxide, myeloperoxidase, TLR-4, NF-kappa B p65, iNOS, TNF-alpha, IL-6, IL-1 beta, and caspase-3, and decreased cellular antioxidants and IL-6 in the lungs of rats. CAN effectively prevented tissue injury, suppressed TLR-4/ NF-kappa B signaling, and ameliorated oxidative stress, inflammatory markers, and caspase-3 in CIS-administered rats. CAN enhanced antioxidants and IL-10, decreased Ang II, increased Ang (1-7), suppressed the phosphorylation of JAK1 and STAT3, and upregulated SOCS3 in CIS-administered rats. These effects were associated with the downregulation of Keap1 and enhanced Nrf2, GCLC, HO-1, and PPAR gamma. In conclusion, CAN prevented CIS-induced lung injury by attenuating oxidative stress, suppressing TLR-4/NF-kappa B and JAK1/STAT3 signaling, Ang II, and pro-inflammatory mediators, and upregulating PPAR gamma, and Nrf2/HO-1 signaling.

Automated summary

This study found that candesartan can prevent oxidative stress, inflammation, and lung injury induced by cisplatin. Candesartan can suppress the activity of TLR-4/NF-κB and JAK1/STAT3 signaling pathways, alleviating cisplatin-induced oxidative stress and inflammation.