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Melatonin ameliorates PM2.5-induced airway inflammation and apoptosis by PERK/eIF2α/ATF4/CHOP in chronic obstructive
1The First school of Clinical Medicine, Lanzhou University, Lanzhou 730000, China.
Abstract:
Fine particulate matter (PM2.5) has been reported to exacerbate chronic airway inflammation, contributing to progression and acute exacerbation of chronic obstructive pulmonary disease (COPD). Persistent activated endoplasmic reticulum (ER) stress-related PERK/eIF2α/ATF4/CHOP pathway is critical in driving inflammation and cell death in a variety of inflammatory diseases. Melatonin (MEL) is well-recognized for its broad biological activities, such as anti-oxidative and anti-inflammatory effects However, the exact role of ER stress-related pathway and MEL in PM2.5-induced airway inflammation and apoptosis in COPD has not yet been elucidated. Therefore, we constructed the COPD mice model by cigarette smoke (CS) exposure to evaluate the mechanism by which PM2.5 exacerbate the development of COPD and the protective role of MEL. Results indicated that PM2.5 significantly impair lung function, disrupt emphysema, exacerbate inflammation and apoptosis and intensify the PERK/eIF2α/ATF4/CHOP pathway in COPD mice. Moreover, these changes caused by PM2.5 could be mitigated by MEL. In vitro, PM2.5 exposure notably reduced cell viability and triggered inflammation and apoptosis in BEAS-2B cells induced by cigarette smoke extract (CSE). These effects were reversed by the ER stress inhibitor 4-phenylbutyric acid (4-PBA), with MEL demonstrating similar effect. These findings demonstrate that PM2.5 aggravates airway inflammation and apoptosis via activating ER stress-related PERK/eIF2α/ATF4/CHOP pathways in COPD, which could be significantly restored by MEL.
Insights
Fine particulate matter (PM2.5) worsens chronic obstructive pulmonary disease (COPD) by activating endoplasmic reticulum (ER) stress pathways. Melatonin (MEL) effectively mitigates PM2.5-induced airway inflammation and cell death in COPD models.
Area of Science:
- Environmental Health
- Pulmonary Medicine
- Molecular Biology
Background:
- Fine particulate matter (PM2.5) exacerbates chronic airway inflammation and COPD progression.
- Endoplasmic reticulum (ER) stress, specifically the PERK/eIF2α/ATF4/CHOP pathway, is implicated in inflammatory diseases.
- The role of ER stress and melatonin (MEL) in PM2.5-induced COPD remains unclear.
Purpose of the Study:
- To investigate the mechanism of PM2.5 in exacerbating COPD.
- To evaluate the protective effects of melatonin (MEL) against PM2.5-induced lung injury.
- To elucidate the involvement of the ER stress pathway in PM2.5-induced COPD.
Main Methods:
- A COPD mouse model was established using cigarette smoke (CS) exposure.
- Mice were exposed to PM2.5 to assess its impact on lung function, emphysema, inflammation, and apoptosis.
- In vitro studies used BEAS-2B cells exposed to cigarette smoke extract (CSE) and PM2.5, with or without MEL or ER stress inhibitor (4-PBA).
Main Results:
- PM2.5 significantly impaired lung function, worsened emphysema, and increased inflammation and apoptosis in COPD mice.
- PM2.5 exposure activated the PERK/eIF2α/ATF4/CHOP pathway in COPD mouse lungs.
- In vitro, PM2.5 reduced cell viability and induced inflammation and apoptosis, effects reversed by MEL and 4-PBA.
Conclusions:
- PM2.5 aggravates airway inflammation and apoptosis in COPD by activating ER stress-related PERK/eIF2α/ATF4/CHOP pathways.
- Melatonin (MEL) demonstrates a protective role by mitigating PM2.5-induced lung damage and ER stress.
- Targeting ER stress pathways may offer therapeutic strategies for PM2.5-related COPD exacerbations.
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