International journal of chronic obstructive pulmonary disease · 2025
Cigarette Smoke Extract-Induced Necroptosis Causes Mitochondrial DNA Release and Inflammation of Bronchial Epithelial Cells.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
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Mizumura Kenji, Ozoe Ryosuke, Nemoto Yosuke, Furusho Naho, Kurosawa Yusuke, Kozu Yutaka, Oki Takashi, Maruoka Shuichiro, Gon Yasuhiro
Аннотация
PURPOSE: Chronic obstructive pulmonary disease (COPD) is characterized by airway inflammation and structural changes in the lungs, including emphysema. Cigarette smoke exposure induces mitochondrial damage, necroptosis-mediated pulmonary epithelial cell death, and emphysematous changes. However, the association between these events and airway inflammation remains unclear. Here, we focused on mitochondrial DNA (mtDNA) as a second messenger linking mitochondrial damage to airway inflammation, aiming to elucidate the mechanisms underlying extracellular mtDNA release and its role in airway inflammation.
METHODS: Human bronchial epithelial BEAS-2B cells were exposed to cigarette smoke extract and the release of mtDNA into the cytoplasm and extracellular space was examined. Real-time polymerase chain reaction was used to measure mtDNA levels. To examine the involvement of necroptosis, a necroptosis inhibitor (Nec-1) and mitochondria-targeted antioxidant (MitoQ) were used. To evaluate the inflammatory response induced by extracellular mtDNA, we quantified the levels of specific cytokines-interleukin (IL)-6 and IL-8-in the cell culture supernatants after mtDNA transfection, as these mediators are widely accepted as key markers of inflammation in bronchial epithelial cells.
RESULTS: Cigarette smoke extract treatment induced the translocation of mtDNA from the mitochondria to the cytoplasm in BEAS-2B cells, followed by its extracellular release. Nec-1 and MitoQ inhibited the extracellular release of mtDNA without affecting its cytoplasmic translocation. Introducing mtDNA into BEAS-2B cells markedly elevated IL-6 and IL-8 levels, indicating that mtDNA may play a pro-inflammatory role.
CONCLUSION: Necroptosis facilitated the release of extracellular mtDNA after cigarette smoke extract exposure, establishing a connection between mitochondrial damage and airway inflammation. mtDNA acted as a pro-inflammatory mediator by inducing cytokine production in pulmonary epithelial cells. These findings suggest that targeting necroptosis could offer a novel therapeutic strategy for COPD by addressing both airway inflammation and structural lung damage.
METHODS: Human bronchial epithelial BEAS-2B cells were exposed to cigarette smoke extract and the release of mtDNA into the cytoplasm and extracellular space was examined. Real-time polymerase chain reaction was used to measure mtDNA levels. To examine the involvement of necroptosis, a necroptosis inhibitor (Nec-1) and mitochondria-targeted antioxidant (MitoQ) were used. To evaluate the inflammatory response induced by extracellular mtDNA, we quantified the levels of specific cytokines-interleukin (IL)-6 and IL-8-in the cell culture supernatants after mtDNA transfection, as these mediators are widely accepted as key markers of inflammation in bronchial epithelial cells.
RESULTS: Cigarette smoke extract treatment induced the translocation of mtDNA from the mitochondria to the cytoplasm in BEAS-2B cells, followed by its extracellular release. Nec-1 and MitoQ inhibited the extracellular release of mtDNA without affecting its cytoplasmic translocation. Introducing mtDNA into BEAS-2B cells markedly elevated IL-6 and IL-8 levels, indicating that mtDNA may play a pro-inflammatory role.
CONCLUSION: Necroptosis facilitated the release of extracellular mtDNA after cigarette smoke extract exposure, establishing a connection between mitochondrial damage and airway inflammation. mtDNA acted as a pro-inflammatory mediator by inducing cytokine production in pulmonary epithelial cells. These findings suggest that targeting necroptosis could offer a novel therapeutic strategy for COPD by addressing both airway inflammation and structural lung damage.