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Published on: July 6, 2019
Inhibition of mPTP and GSDME-mediated pyroptosis alleviates lung injury in septic mice
Na Lu1, Meng-Jie Yu2, Rui Zhang3
1Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Bengbu Medical University, Anhui Province Key Laboratory of Clinical and Preclinical Research in Respiratory Disease, Clinical Research Center for Respiratory Disease (tumor) in Anhui Province, Bengbu, Anhui, 233000, PR China; Department of Respiratory, Linyi Central Hospital, Yishui, Shandong, 276400, PR China.
Objective:
To explore the role of mitochondrial permeability transition pore (mPTP) and gasdermin E (GSDME) - mediated pyroptosis in septic lung injury in mice model.
Methods:
Adult male c57BL/6J mice were randomly assigned with 10 mice in each group. Sepsis model was established by cecal ligation and puncture (CLP) operation. Alisporivir (AL) was used to inhibit the opening of mPTP, plumbagin (PL) was used to open mPTP. Knockdown or overexpression of GSDME were done by Adeno associated virus 6 (AAV 6). The changes of lung tissue, ultrastructure, reactive oxygen species (ROS), GSDME-mediated pyroptosis related proteins, inflammatory factors and mitochondrial function were detected.
Results:
Compared with Sham group, the aggravating of lung injury, mitochondrial dysfunction, oxidative stress and inflammatory reaction were shown in CLP and GSDME high-expression groups, and the opening of mPTP, the mRNA levels of pyroptosis related genes were increased, the expressions of pyroptosis related proteins were increased. After inhibiting mPTP opening by AL or knockdown GSDME respectively, septic lung injury was alleviated, mitochondrial function was improved, oxidative stress and inflammatory response were reduced, the mRNA levels of GSDME and Caspase-3 were decreased, the protein expressions of GSDME, Caspase-3, IL-1β and IL-18 were reduced. In knockdown GSDME group, the application of PL to open mPTP still played the protective role.
Conclusion:
Inhibiting mPTP opening or GSDME-mediated pyroptosis both alleviated septic lung injury. The mPTP is the upstream of GSDME, GSDME-N can also positively promote mPTP opening, mPTP and GSDME regulates each other in the GSDME-mediated pyroptosis pathway.
Insights
Inhibiting mitochondrial permeability transition pore (mPTP) opening or gasdermin E (GSDME)-mediated pyroptosis alleviates septic lung injury. These pathways are interconnected, with mPTP acting upstream of GSDME and GSDME-N promoting mPTP opening.
Area of Science:
- Cellular Biology
- Immunology
- Pathophysiology
Background:
- Sepsis can lead to acute lung injury.
- Mitochondrial dysfunction and pyroptosis are implicated in sepsis-induced organ damage.
- The specific roles of mitochondrial permeability transition pore (mPTP) and gasdermin E (GSDME) in septic lung injury require further elucidation.
Purpose of the Study:
- To investigate the involvement of mPTP and GSDME-mediated pyroptosis in a mouse model of septic lung injury.
- To explore the regulatory relationship between mPTP and GSDME in this context.
Main Methods:
- A cecal ligation and puncture (CLP) model was used in adult male C57BL/6J mice.
- Alisporivir (AL) was employed to inhibit mPTP opening, while plumbagin (PL) was used to induce mPTP opening.
- Gasdermin E (GSDME) levels were manipulated using Adeno-associated virus 6 (AAV-6) for knockdown or overexpression.
Main Results:
- CLP and GSDME overexpression exacerbated lung injury, mitochondrial dysfunction, oxidative stress, and inflammation.
- Inhibition of mPTP opening (with AL) or GSDME knockdown alleviated these detrimental effects.
- The study observed a reciprocal regulatory relationship between mPTP and GSDME in the pyroptosis pathway.
Conclusions:
- Both mPTP inhibition and suppression of GSDME-mediated pyroptosis are protective against septic lung injury.
- mPTP acts upstream in the GSDME-mediated pyroptosis pathway.
- mPTP and GSDME exhibit a mutual regulatory interaction within the pyroptosis pathway.
