The Involvement of RIPK-3/Caspase-8 Inhibition and Nrf2/HO-1 Upregulation in the Protective Effect of Umbelliferone Against Chlorpyrifos-Induced Pulmonary Toxicity

Chlorpyrifos (CPF) is a pesticide commonly used for pest management. Regretfully, there is evidence that pesticides can cause pulmonary toxicity. The phytochemical umbelliferone (UMB) possesses anti-inflammatory and antioxidant bioactivities. This investigation aimed to determine whether UMB protects against pulmonary toxicity induced by CPF. Rats were divided into four groups: group I (control), group II (30 mg/kg of UMB), group III (10 mg/kg of untreated CPF), and group IV (30 mg/kg of CPF + UMB). Interestingly, UMB reduced pulmonary intoxication, as evidenced by the attenuation of CPF-induced histopathological alterations and the lowering of ALP, LDH, and CRP levels. Furthermore, UMB decreased CPF-induced pulmonary oxidative damage by reducing malondialdehyde (MDA) content and increasing GSH and SOD levels, which was mediated by the upregulation of Nrf2, HO-1, PPAR-γ, and cytoglobin expression. UMB decreased CPF-induced lung inflammation by lowering MPO, TNF-α, and IL-1β levels, as well as NF-κB expression. Additionally, UMB counteracted lung necroptosis by downregulating RIPK-1, RIPK3, mixed-lineage kinase domain-like pseudokinase (MLKL), and Caspase-8, as confirmed by in silico studies. Accordingly, UMB could be a sound therapeutic strategy for mitigating CPF-induced lung intoxication, as it balances antioxidants and oxidants, reduces cellular inflammation, and prevents lung tissue necroptosis.