Ursolic Acid Protected Lung of Rats From Damage Induced by Cigarette Smoke Extract

Abstract

Background: We found previously that ursolic acid (UA) administration could alleviate cigarette smoke-induced emphysema in rats partly through the unfolded protein response (UPR) PERK-CHOP and Nrf2 pathways, thus alleviating endoplasmic reticulum stress (ERS)-associated oxidative stress and cell apoptosis. We hypothesized that other UPR pathways may play similar roles in cigarette smoke extract (CSE)-induced emphysema. So, we sought to investigate the dynamic changes and effects of UPR and the downstream apoptotic pathways. Further, we investigated whether UA could alleviate CSE-induced emphysema and airway remodelling in rats, whether and when it exerts its effects through UPR pathways as well as Smads pathways. Methods: One hundred eight Sprague Dawley (SD) rats were randomly divided into three groups: Sham group, CSE group, and UA group, and each group was further divided into three subgroups, administered CSE (vehicle) for 2, 3, or 4 weeks; each subgroup had 12 rats. We examined pathological changes, analyzed the three UPR signaling pathways and subsequent ERS, intrinsic and extrinsic apoptotic pathway indicators, as well as activation of Smad2,3 molecules in rat lungs. Results: Exposure to CSE for 3 or 4 weeks could apparently induce emphysema and airway remodeling in rats, including gross and microscopic changes, alteration of mean alveolar number (MAN), mean linear intercept (MLI), and mean airway thickness in lung tissue sections. UA intervention could significantly alleviate CSE-induced emphysema and airway remodeling in rats. UA exerted its effects through ameliorating apoptosis by down regulating UPR signalling pathways and subsequent apoptosis pathways, as well as, downregulating p-Smad2 and p-Smad3 molecules. Conclusions: UA attenuated CSE-induced emphysema and airway remodeling, exerting its effects partly through regulation of three UPR pathways, amelioration downstream apoptotic pathways, and alleviating activation of Smad2 and Smad3.

Developmental Timing Determines the Protective Effect of Maternal Electroacupuncture on Perinatal Nicotine Exposure-Induced Offspring Lung Phenotype

“…e left lung was used for paraffin embedding, cut into 5 μm slices, which for lung morphometry were stained with hematoxylin and eosin (H&E). Subsequently, lung tissue morphology was assessed by determining mean linear intercepts (MLI) and mean alveolar numbers (MAN) using previously described methods [44].…”

Ursolic Acid Alleviates Mucus Secretion and Tissue Remodeling in Rat Model of Allergic Rhinitis After PM2.5 Exposure

“…These observations are important and warrant further studies. 26…”

The Impact of Endoplasmic Reticulum-Associated Protein Modifications, Folding and Degradation on Lung Structure and Function

“…Expanding on our understanding of ER stress and the UPR in disease, we investigated their roles in complex models of oxidative stress-induced airway injury in which ER stress was also induced. In vivo and in vitro exposure to cigarette smoke extract is known to induce both stress responses ( Lin et al, 2017b , 2019 ). Raising the protein folding capacity of lung cells by administering an ER stress inhibitor/chemical chaperone reduced cigarette smoke extract-induced airway remodeling and emphysema in the rat, which coincided with an augmentation in the antioxidant response ( Lin et al, 2019 ).…”

“…In vivo and in vitro exposure to cigarette smoke extract is known to induce both stress responses ( Lin et al, 2017b , 2019 ). Raising the protein folding capacity of lung cells by administering an ER stress inhibitor/chemical chaperone reduced cigarette smoke extract-induced airway remodeling and emphysema in the rat, which coincided with an augmentation in the antioxidant response ( Lin et al, 2019 ). In a bleomycin-induced model of fibrosis, the adoptive transfer of mesenchymal stem cells reduced airway fibrosis and attenuated ER stress through PERK-Nrf2, but not the PERK-eIF2α-ATF4-CHOP pathway, suggesting that the ER stress-induced activation of the non-canonical PERK-Nrf2 pathway of the UPR may have a protective role in complex airway diseases ( Ono et al, 2015 ; Lee et al, 2020 ).…”