Luteolin Alleviates Oxidative Stress in Chronic Obstructive Pulmonary Disease Induced by Cigarette Smoke via Modulation of the TRPV1 and CYP2A13/NRF2 Signaling Pathways

Abstract

The current study aims to investigate the therapeutic potential of luteolin (Lut), a naturally occurring flavonoid found in various medicinal plants, for treating chronic obstructive pulmonary disease (COPD) through both in vitro and in vivo studies. The results demonstrated that Lut increased body weight, reduced lung tissue swelling and lung damage indices, mitigated systemic oxidative stress levels, and decreased alveolar fusion in cigarette smoke (CS)- and lipopolysaccharide (LPS)-induced COPD mice. Additionally, Lut was observed to downregulate the expression of the TRPV1 and CYP2A13 proteins while upregulating SIRT6 and NRF2 protein expression in CS + LPS-induced COPD mice and cigarette smoke extract (CSE)-treated A549 cells. The concentrations of total reactive oxygen species (ROS) and mitochondrial ROS in A549 cells induced by CSE significantly increased. Moreover, CSE caused a notable elevation of intracellular Ca2+ levels in A549 cells. Importantly, Lut exhibited inhibitory effects on the inward flow of Ca2+ and attenuated the overproduction of mitochondrial and intracellular ROS in A549 cells treated with CSE. In conclusion, Lut demonstrated a protective role in alleviating oxidative stress and inflammation in CS + LPS-induced COPD mice and CSE-treated A549 cells by regulating TRPV1/SIRT6 and CYP2A13/NRF2 signaling pathways.

Silencing KLF6 Alleviates Cigarette Smoke Extract-Induced Mitochondrial Dysfunction in Bronchial Epithelial Cells by SIRT4 Upregulation

“… 20 When cigarette smoke is inhaled into the lungs, it first causes oxidative stress and inflammation in the lungs, activates the inflammatory signaling pathway of airway epithelial cells and alveolar macrophages, recruits more immune cells to the lungs, secretes a large number of inflammatory factors and proteases and then further amplifies inflammation, accompanied by imbalance between oxidative stress and proteinase-antiprotease. 21 Besides, cigarette smoke has been elucidated to be a predominant source of ROS, and excessive ROS production contributes to oxidative stress, thereby triggering the development of pathological changes in the lungs of COPD patients 22 In addition, CSE can activate molecules involved in the cell cycle and mediate cell apoptosis. 23 Moreover, the abnormal inflammation in the lungs caused by the inhalation of cigarette smoke has close association with COPD.…”

Nrf-2 as a novel target in radiation induced lung injury

“…Impaired Nrf-2 has been shown to contribute potentially to the development of COPD [ 41 ]; this could be due to the Nrf-2 pathway's role in increasing antioxidant defense and decreasing lung inflammation and alveolar apoptosis. These mechanisms help protect alveolar cells from the harmful effects of tobacco smoke [ [42] , [43] , [44] ]. At the same time, recent studies have also shown that activation of the Nrf-2 pathway can balance redox reactions in COPD and restore macrophage function, thus playing a protective role [ 45 ].…”