Cystatin C protects against primary graft dysfunction after lung transplantation.

Lung transplantation (LTx) is the definitive treatment for end-stage lung diseases, but its success is hindered by donor lung scarcity, high waiting list mortality rates, and post-transplant complications such as Primary Graft Dysfunction (PGD). PGD, a major cause of early LTx rejection, is influenced by ischemia-reperfusion injury, inflammation, and immune responses. Recently, we have identified cysteine proteases, particularly Cathepsin B, as substantial contributors to these pathways. Here our study focuses on the role of cysteine proteases in early lung graft damage and their potential as therapeutic targets. We examined lung function and clinical stability in LTx patients, categorizing them into Bronchiolitis Obliterans Syndrome (BOS) stages based on the decline in Forced Expiratory Volume in 1 second (FEV1). Our findings highlighted a significant decline in Cystatin C (CysC) levels, an endogenous inhibitor of cysteine proteases, concurrent with increasing BOS stages and a notable increase in γ-H2AX expression, indicating DNA damage response early in transplanted lung tissue. Incorporating CysC in the preservation solution allowed for extended ischemic storage with improved transplant function (30% higher blood oxygenation in the left ventricle). Upon histological analysis lung tissue showed significantly cleared airspace with less endothelial damage, concurrent with reduced DNA damage and cell death 4h post-transplantation. Our results suggest that CysC represents a promising approach for improving lung transplant outcomes by enabling longer preservation times and mitigating early graft damage