Abstract
BackgroundPrimary graft dysfunction (PGD) is considered to be the end result of an inflammatory response targeting the new lung allograft after transplant. Previous research has indicated that MAPC cell therapy might attenuate this injury by its paracrine effects on the pro-/anti-inflammatory balance. This study aims to investigate the immunoregulatory capacities of MAPC cells in PGD when administered in the airways.MethodsLungs of domestic pigs (n = 6/group) were subjected to 90 minutes of warm ischemia. Lungs were cold flushed, cannulated on ice and placed on EVLP for 6 hours. At the start of EVLP, 40 ml of an albumin-plasmalyte mixture was distributed in the airways (CONTR group). In the MAPC cell group, 150 million MAPC cells (ReGenesys/Athersys, Cleveland, OH, USA) were added to this mixture. At the end of EVLP, a physiological evaluation (pulmonary vascular resistance, lung compliance, PaO2/FiO2), wet-to-dry weight ratio (W/D) sampling and a multiplex analysis of bronchoalveolar lavage (BAL) (2 × 30 ml) was performed.ResultsPulmonary vascular resistance, lung compliance, PaO2/FiO2 and W/D were not statistically different at the end of EVLP between both groups. BAL neutrophilia was significantly reduced in the MAPC cell group. Moreover, there was a significant decrease in TNF-α, IL-1β and IFN-γ in the BAL, but not in IFN-α; whereas IL-4, IL-10 and IL-8 were below the detection limit.ConclusionsAlthough no physiologic effect of MAPC cell distribution in the airways was detected during EVLP, we observed a reduction in pro-inflammatory cytokines and neutrophils in BAL in the MAPC cell group. This effect on the innate immune system might play an important role in critically modifying the process of PGD after transplantation. Further experiments will have to elucidate the immunoregulatory effect of MAPC cell administration on graft function after transplantation.
Highlights
Primary graft dysfunction (PGD) is considered to be the end result of an inflammatory response targeting the new lung allograft after transplant
Mordant et al recently published their results on mesenchymal stem cell (MSC) administration to a porcine donor lung on ex vivo lung perfusion (EVLP), which resulted in a reduction of interleukin (IL)-8, there was no effect on physiological parameters detected [13]
The immunoregulatory properties of multipotent adult progenitor cell (MAPC) cells have not been widely studied in preclinical large animal models and most preliminary theories of working mechanisms are based on in vitro and rodent models. In this large animal study, we aim to investigate if MAPC cell delivery in the airways during EVLP, can modulate the inflammatory process linked to ischemiareperfusion injury (IRI) by immunoregulatory effects
Summary
Primary graft dysfunction (PGD) is considered to be the end result of an inflammatory response targeting the new lung allograft after transplant. PGD is the end result of ischemiareperfusion injury (IRI) attacking the integrity of the capillary-alveolar membrane leading to pulmonary edema and impaired oxygenation [1, 2] It is based on an inflammatory cascade that is triggered by hypoxic stress and activation of donor macrophages, which attracts many recipient neutrophils to the donor lung upon reperfusion in the recipient chest. Bone marrow-derived mesenchymal cells possess immunoregulatory capabilities and could be of particular interest to attenuate PGD They are already found to be a successful treatment option for patients suffering from acute respiratory distress syndrome, which shares a similar inflammatory pathophysiology with PGD [3,4,5]. The role in a reduction of inflammatory cytokines in an acellular ex vivo perfusion set-up still has to be unraveled
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