β-Caryophyllene attenuates oxidative stress and inflammatory response in LPS induced acute lung injury by targeting ACE2/MasR and Nrf2/HO-1/NF-κB axis

Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), is a clinical syndrome that can cause pulmonary edema, inflammation, oxidative stress, and immunological dysregulations. β-Caryophyllene (BCP), a natural bicyclic sesquiterpene, possesses a variety of pharmacological properties and has the potential to be a therapeutic agent. This study aimed to comprehend the effect of BCP on Nrf2/HO-1/NF-κB and ACE2/MasR axis in a rat model of ALI by lipopolysaccharide (LPS) and the underlying mechanisms during this process. The study also examined pulmonary edema, BALF, and cytokine production to investigate inflammation and oxidative stress. In the LPS group, Western blot analysis showed decreased Nrf2/HO-1 and ACE2/MasR, including increased lung edema, elevated vascular permeability, neutrophil infiltration in BALF, increased cytokine levels, and histological changes. In comparison to the LPS group, BCP dramatically reduced lung edema, vascular permeability, and histological changes. Additionally, by lowering malondialdehyde and myeloperoxidase activity in lung tissues, it also reduced oxidative stress. BCP boosted IL-10 production and decreased the levels of pro-inflammatory cytokines and neutrophil infiltration. BCP administration decreased VEGF-A and SP-D expression, subsequently lowering NF-κB activation and cytokine production. Further, BCP altered ACE2 expression, indicating its involvement by activating the ACE2/Angiotensin (1-7)/MasR axis. In addition, BCP could stimulate the Nrf2/HO-1 anti-oxidant axis to suppress NF-κB and reduce inflammation. BCP modulation of the ACE2/MasR and Nrf2/HO-1/NF-κB axis impedes the course of ALI by influencing immunological response including but not limited to oxidative stress, the influx of neutrophils, and cytokine production. Hence, BCP may act as a potential candidate for management of ALI.