Profiling Proteinic Changes Induced by Vildagliptin Treatment in a Mouse Lung Transplantation Model: The Role of
Zheng Tang1, Wei Zhai2, Zhiwei Wang1
1Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China (mainland).
Abstract:
BACKGROUND This study investigated the protective effects of pharmaceutical CD26/dipeptidylpeptidase-4 (CD26/DPP-4) inhibitor in lung transplantation (LTx). Changes in protein expression associated with the treatment were screened and identified to evaluate the role of kininogen-1 in early-term ischemia/reperfusion (I/R) injury after LTx. MATERIAL AND METHODS Orthotopic single LTx was performed in syngeneic C57BL/6 mice, with a pharmaceutical CD26/DPP-4 inhibitor (vildagliptin, subcutaneous injection, 10 mg/kg, every 12 h) administered to the investigational group. All donors were perfused and preserved with low potassium dextran (LPD). Grafts were harvested at 60 h post-transplantation after 8 h of cold ischemia. Myeloperoxidase activity and wet/dry weight ratio were measured, followed by histopathological examination. Proteins were separated, analyzed, and identified using proteomics and database searches. The target proteins were validated by Western blot. Immunohistochemical studies were performed in the same lung specimen locus. RESULTS Investigational group (IN) versus control group (CON) comparison showed decreased myeloperoxidase enzymatic activity, as well as decreased edema and interstitial-alveolar inflammation. Proteomics results revealed 78 spots with significant differences in abundance between the 2 groups. Fifteen proteins were identified. Kininogen-1 was up-regulated in CON and down-regulated in IN, with contrasting results for the heat shock protein 70. Immunohistochemical results revealed significantly different staining with kininogen-1 in alveolar macrophages and inflammatory cells. CONCLUSIONS Combined vildagliptin and LPD significantly ameliorated I/R injury after LTx. This treatment may change local pulmonary protein levels. Moreover, proper application of proteins such as kininogen-1 may enhance the protective effects against I/R injury during transplantation.
Insights
Vildagliptin, a CD26/dipeptidylpeptidase-4 inhibitor, combined with low potassium dextran (LPD) reduces lung ischemia/reperfusion injury after transplantation. This treatment impacts kininogen-1 levels, potentially enhancing protective effects against lung injury.
Area of Science:
- Transplantation immunology
- Proteomics
- Pharmacology
Background:
- Lung transplantation (LTx) is susceptible to ischemia/reperfusion (I/R) injury.
- CD26/dipeptidylpeptidase-4 (CD26/DPP-4) inhibitors are being investigated for protective effects.
- Kininogen-1's role in early-term I/R injury requires further elucidation.
Purpose of the Study:
- To investigate the protective effects of a pharmaceutical CD26/DPP-4 inhibitor in lung transplantation.
- To screen and identify protein expression changes associated with the treatment.
- To evaluate the role of kininogen-1 in early-term I/R injury after LTx.
Main Methods:
- Orthotopic single lung transplantation performed in C57BL/6 mice.
- Administration of vildagliptin (a CD26/DPP-4 inhibitor) to the investigational group.
- Graft preservation with low potassium dextran (LPD), followed by proteomics and Western blot analysis.
Main Results:
- Combined vildagliptin and LPD treatment significantly reduced myeloperoxidase activity, edema, and inflammation.
- Proteomics identified 15 differentially expressed proteins, with kininogen-1 down-regulated in the treatment group.
- Immunohistochemistry showed distinct kininogen-1 staining in alveolar macrophages and inflammatory cells.
Conclusions:
- Combined vildagliptin and LPD significantly ameliorates ischemia/reperfusion injury in lung transplantation.
- This therapeutic approach alters local pulmonary protein expression profiles.
- Targeting proteins like kininogen-1 may offer enhanced protection against transplantation-related I/R injury.
