Targeting the proline-glycine-proline-protease feed-forward loop attenuates primary graft dysfunction after lung...

Area of Science:

• Immunology
• Transplantation Biology
• Biochemistry

Background:

• Primary graft dysfunction (PGD) is a major cause of early mortality following lung transplantation.
• Currently, no targeted therapies exist for PGD.
• The role of collagen-derived matrikines in PGD pathogenesis is not fully understood.

Purpose of the Study:

• To investigate if proline-glycine-proline (PGP) drives neutrophil-mediated injury in PGD.
• To determine if neutralizing PGP can protect against PGD.

Main Methods:

• Collected bronchoalveolar lavage (BAL) fluid from human lung transplant recipients with and without PGD.
• Utilized a murine lung transplant model to induce PGD.
• Administered L-arginine-threonine-arginine (RTR), a PGP-sequestering peptide, or vehicle (PBS) to mice.
• Assessed histologic injury, neutrophil infiltration, and levels of acetyl-PGP (acPGP), MMP-9, and prolyl endopeptidase (PE) in human and murine samples.

Main Results:

• Human PGD BAL fluid showed significantly higher levels of acPGP, MMP-9, and PE compared to controls.
• Murine PGD allografts exhibited increased neutrophil infiltration and elevated acPGP, MMP-9, and PE.
• RTR treatment reduced PGD-related histologic injury, neutrophil accumulation, and improved allograft lung function and oxygenation.

Conclusions:

• A PGP-protease circuit, involving extracellular matrix degradation and neutrophil recruitment, contributes to PGD.
• Neutralization of PGP using RTR effectively disrupts this circuit, mitigating graft injury.
• This study expands the understanding of PGD immunopathology by linking matrix-derived signals to innate immune activation.