Tong Zhang: Department of Occupational Health, College of Public Health, Harbin Medical University, Harbin, Heilongjiang Province 150086, PR China.
Yue Wang: Department of Occupational Health, College of Public Health, Harbin Medical University, Harbin, Heilongjiang Province 150086, PR China.
Wenxue Yao: Department of Occupational Health, College of Public Health, Harbin Medical University, Harbin, Heilongjiang Province 150086, PR China.
Yangyang Chen: Department of Occupational Health, College of Public Health, Harbin Medical University, Harbin, Heilongjiang Province 150086, PR China.
Dan Zhang: Department of Occupational Health, College of Public Health, Harbin Medical University, Harbin, Heilongjiang Province 150086, PR China.
Ying Gao: Department of Occupational Health, College of Public Health, Harbin Medical University, Harbin, Heilongjiang Province 150086, PR China.
Shuo Jin: Department of Occupational Health, College of Public Health, Harbin Medical University, Harbin, Heilongjiang Province 150086, PR China.
Lina Li: Department of Occupational Health, College of Public Health, Harbin Medical University, Harbin, Heilongjiang Province 150086, PR China.
Shikuan Yang: Department of Occupational Health, College of Public Health, Harbin Medical University, Harbin, Heilongjiang Province 150086, PR China.
Yonghui Wu: Department of Occupational Health, College of Public Health, Harbin Medical University, Harbin, Heilongjiang Province 150086, PR China. Electronic address: wuyonghui777@163.com.
Nickel compounds, an international carcinogen in the industrial environment, increased the risk of lung inflammation even lung cancer in Ni refinery workers. Metformin has displayed the intense anti-inflammation and anti-cancer properties through regulating pyroptosis. This study was designed to explore whether Nickel-refining fumes (NiRF) can induce cell pyroptosis and how AMPK/CREB/Nrf2 mediated the protection afforded by metformin against Ni particles-induced lung impairment. Our results represented that Ni fumes exposure evoked pyroptosis via GOLPH3 and induced oxidative stress, while, metformin treatment alleviated Ni particles-mediated above changes. Moreover, nuclear factor erythroid 2-related factor 2 (Nrf2) involved in the protection of metformin, and the deficiency of Nrf2 attenuated the beneficial protection. We also determined that Nrf2 was a downstream molecule of AMPK/CREB pathway. Furthermore, male C57BL/6 mice were administered with Ni at a dose of 2 mg/kg by non-exposed endotracheal instillation and metformin (100, 200 and 300 mg/kg) via oral gavage for 4 weeks. The results indicated that NiRF promoted GOLPH3 and pyroptosis by stimulating NLRP3, caspase-1, N-GSDMD, IL-18 and IL-1β expression. However, various doses of metformin reduced GOLPH3 and the above protein levels of pyroptosis, also improved AMPK/CREB/Nrf2 expression. In summary, we found that metformin suppressed NiRF-connected GOLPH3-prompted pyroptosis via AMPK/CREB/Nrf2 signaling pathway to confer pulmonary protection.
