Effects of cold or warm ischemia and ex-vivo lung perfusion on the release of damage associated molecular patterns and inflammatory cytokines in experimental lung transplantation

BACKGROUND: Lung transplantation (LTx) is associated with sterile inflammation, possibly related to the release of damage associated molecular patterns (DAMPs) by injured allograft cells. We have measured cellular damage and the release of DAMPs and cytokines in an experimental model of LTx after cold or warm ischemia and examined the effect of pretreatment with ex-vivo lung perfusion (EVLP). METHODS: Rat lungs were exposed to cold ischemia alone (CI group) or with 3h EVLP (CI-E group), warm ischemia alone (WI group) or with 3 hour EVLP (WI-E group), followed by LTx (2 hour). Bronchoalveolar lavage (BAL) was performed before (right lung) or after (left lung) LTx to measure LDH (marker of cellular injury), the DAMPs HMGB1, IL-33, HSP-70 and S100A8, and the cytokines IL-1 beta, IL-6, TNF alpha, and CXCL-1. Graft oxygenation capacity and static compliance after LTx were also determined. RESULTS: Compared to CI, WI displayed cellular damage and inflammation without any increase of DAMPs after ischemia alone, but with a significant increase of HMGB1 and functional impairment after LTx. EVLP promoted significant inflammation in both cold (CI-E) and warm (WI-E) groups, which was not associated with cell death or DAMP release at the end of EVLP, but with the release of S100A8 after LTx. EVLP reduced graft damage and dysfunction in warm ischemic, but not cold ischemic, lungs. CONCLUSIONS: The pathomechanisms of sterile lung inflammation during LTx are significantly dependent on the conditions. The release of HMGB1 (in the absence of EVLP) and S100A8 (following EVLP) may be important factors in the pathogenesis of LTx. (C) 2021 The Author(s). Published by Elsevier Inc. on behalf of International Society for Heart and Lung Transplantation.

Automated summary

This study found that the occurrence of sterile lung inflammation during lung transplantation is significantly dependent on the conditions, and EVLP may promote inflammation, while factors such as HMGB1 and S100A8 may play important roles in the pathogenesis of LTx.