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Updated: Jun 21, 2025
Assessment of Respiratory Function in Conscious Mice by Double-chamber Plethysmography
Published on: July 10, 2018
Bongkrekic acid alleviates airway inflammation via breaking the mPTP/mtDAMPs/RAGE feedback loop in a
Ying Chen1, Junwen Huang1, Yuemao Li1
1Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
Abstract:
Mitochondrial dysfunction is critical in the pathogenesis of asthma. Mitochondrial permeability transition pore (mPTP) regulates the release of mitochondrial damage-associated molecular patterns (mtDAMPs) to maintain mitochondrial homeostasis. Bongkrekic acid (BKA) is a highly selective inhibitor of mPTP opening, participates the progression of various diseases. This research investigated the exact roles of BKA and mPTP in the pathogenesis of asthma and elucidated its underlying mechanisms. In the present study, cytochrome c, one of the mtDAMPs, levels were elevated in asthmatic patients, and associated to airway inflammation and airway obstruction. BKA, the inhibitor of mPTP markedly reversed TDI-induced airway hyperresponsiveness, airway inflammation, and mitochondrial dysfunction. Pretreatment with mitochondrial precipitation, to simulate the release of mtDAMPs, further increased TDI-induced airway inflammation and the expression of RAGE in mice. Administration of the inhibitor of RAGE, FPS-ZM1, alleviated the airway inflammation, the abnormal open of mPTP and mitochondrial dysfunction induced by mtDAMPs and TDI. Furthermore, stimulation with different mtDAMPs activated RAGE signaling in human bronchial epithelial cells. Accordingly, our study indicated that mPTP was important and BKA was efficient in alleviating inflammation in TDI-induced asthma. A positive feedback loop involving mPTP, mtDAMPs and RAGE was present in TDI-induced asthma, indicating that mPTP might serve as a potential therapeutic target for asthma.
Insights
Mitochondrial permeability transition pore (mPTP) inhibition with Bongkrekic acid (BKA) reduces asthma symptoms. This study reveals a positive feedback loop involving mPTP, mitochondrial damage-associated molecular patterns (mtDAMPs), and RAGE in asthma pathogenesis.
Area of Science:
- Respiratory Medicine
- Cell Biology
- Immunology
Background:
- Mitochondrial dysfunction is a key factor in asthma development.
- Mitochondrial permeability transition pore (mPTP) controls the release of mitochondrial damage-associated molecular patterns (mtDAMPs).
- Bongkrekic acid (BKA) selectively inhibits mPTP opening and is implicated in various disease processes.
Purpose of the Study:
- To investigate the role of BKA and mPTP in asthma pathogenesis.
- To elucidate the underlying mechanisms of mPTP and BKA in asthma.
- To explore the therapeutic potential of targeting mPTP in asthma.
Main Methods:
- Measured cytochrome c levels in asthmatic patients.
- Administered BKA to reverse toluene diisocyanate (TDI)-induced asthma in a mouse model.
- Utilized mitochondrial precipitation to simulate mtDAMP release.
- Administered RAGE inhibitor FPS-ZM1.
- Stimulated human bronchial epithelial cells with mtDAMPs.
Main Results:
- Elevated cytochrome c levels in asthmatic patients correlated with airway inflammation and obstruction.
- BKA treatment significantly reduced airway hyperresponsiveness, inflammation, and mitochondrial dysfunction in TDI-induced asthma.
- mtDAMPs exacerbated TDI-induced airway inflammation and RAGE expression.
- FPS-ZM1 alleviated inflammation and mitochondrial dysfunction.
- mtDAMPs activated RAGE signaling in bronchial epithelial cells.
Conclusions:
- mPTP plays a significant role in TDI-induced asthma.
- BKA is effective in alleviating asthma-related inflammation.
- A positive feedback loop exists between mPTP, mtDAMPs, and RAGE in asthma.
- mPTP represents a potential therapeutic target for asthma.
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