Niri Pakter, Saha Achintya, Polopalli Subramanyam, Kumar Mohit, Das Sanghita, Saha Bidisha, Goyary Danswrang, Bhutia Yangchen Doma, Karmakar Sanjeev, Kishor Sumit, Rahaman Saidur, Chattopadhyay Pronobesh
Division of Pharmaceutical Technology, Defence Research Laboratory, DRDO, Tezpur, Assam, 784001, India; Department of Chemical Technology, University of Calcutta, Kolkata, 700009, India.
Department of Chemical Technology, University of Calcutta, Kolkata, 700009, India.
Biochem Biophys Res Commun. 2025 Feb;746:151286. doi: 10.1016/j.bbrc.2024.151286. Epub 2025 Jan 2.
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.
急性肺损伤（ALI）及其严重形式急性呼吸窘迫综合征（ARDS）是一种可导致肺水肿、炎症、氧化应激和免疫失调的临床综合征。β-石竹烯（BCP）是一种天然的双环倍半萜，具有多种药理特性，有成为治疗剂的潜力。本研究旨在了解BCP对脂多糖（LPS）诱导的ALI大鼠模型中Nrf2/HO-1/NF-κB和ACE2/MasR轴的影响以及该过程中的潜在机制。该研究还检测了肺水肿、支气管肺泡灌洗液（BALF）和细胞因子产生情况，以研究炎症和氧化应激。在LPS组中，蛋白质免疫印迹分析显示Nrf2/HO-1和ACE2/MasR减少，包括肺水肿增加、血管通透性升高、BALF中中性粒细胞浸润、细胞因子水平升高以及组织学变化。与LPS组相比，BCP显著减轻了肺水肿、血管通透性和组织学变化。此外，通过降低肺组织中的丙二醛和髓过氧化物酶活性，它还减轻了氧化应激。BCP促进了IL-10的产生，降低了促炎细胞因子水平和中性粒细胞浸润。给予BCP可降低血管内皮生长因子-A（VEGF-A）和表面活性蛋白-D（SP-D）的表达，随后降低NF-κB的激活和细胞因子的产生。此外，BCP改变了ACE2的表达，表明其通过激活ACE2/血管紧张素（1-7）/MasR轴发挥作用。另外，BCP可刺激Nrf2/HO-1抗氧化轴以抑制NF-κB并减轻炎症。BCP对ACE2/MasR和Nrf2/HO-1/NF-κB轴的调节通过影响免疫反应（包括但不限于氧化应激、中性粒细胞流入和细胞因子产生）来阻碍ALI的进程。因此，BCP可能是治疗ALI的潜在候选药物。
