Metformin attenuates chronic lung allograft dysfunction: evidence in rat models

Area of Science:

• Immunology
• Pharmacology
• Transplantation

Background:

• Chronic lung allograft dysfunction (CLAD) significantly worsens long-term outcomes after lung transplantation (LTx).
• Currently, no effective and safe drugs are available to treat CLAD.
• Metformin possesses potential antifibrotic and immunomodulatory properties, but its efficacy in CLAD is unknown.

Purpose of the Study:

• To investigate the therapeutic effect of metformin on chronic lung allograft dysfunction (CLAD) in a rat model.
• To evaluate the antifibrotic and immunomodulatory effects of metformin in lung allografts.

Main Methods:

• Allogeneic lung transplant (LTx) rats were treated with Cyclosporin A (CsA) initially, followed by metformin, CsA, or vehicle.
• Lung graft, spleen, and thymus pathology, fibrosis extent, cytokine activity, adaptive immunity, and AMPK activity were assessed at post-transplant week 4.
• Syngeneic LTx rats received only vehicle treatment.

Main Results:

• Metformin treatment prevented CLAD pathological characteristics in allogeneic recipients.
• Metformin suppressed lung graft fibrosis and profibrotic cytokine expression.
• Metformin reduced immune cell infiltration, modulated lymphoid organ weights and areas, and activated AMPK in lung allografts.

Conclusions:

• Metformin demonstrates efficacy in attenuating CLAD in rat models.
• Antifibrotic and immunomodulatory effects, potentially mediated by AMPK activation, contribute to metformin's therapeutic action.
• This research provides a basis for future clinical trials investigating metformin for CLAD treatment.