Impact of Human Interleukin-10 on Vector-Induced Inflammation and Early Graft Function in Rat Lung Transplantation

Abstract

This study was undertaken to examine the time course of human interleukin (hIL)-10 gene expression after transtracheal administration of adenoviral (Ad)hIL-10 and its effect on the early adenoviral proinflammatory cytokine response and on post-transplant lung function. Using a rat lung transplant model, we observed that lungs retrieved 12 h after the administration of AdhIL-10 were associated with significant improvement in post-transplant lung function. Shorter periods of transfection were associated with significantly elevated levels of tumor necrosis factor-alpha and macrophage inflammatory protein-2 in lung tissue, leading to an increased degree of injury. The release of proinflammatory cytokines secondary to the adenoviral vector was reduced by high-dose methylprednisolone (30 mg/kg) administered 3 h before transfection. Reduction in the early adenoviral inflammatory response was associated with significant improvement in post-transplant lung function when lungs were retrieved 6 or 12 h after transtracheal administration of AdhIL-10. Transtracheal administration of adenoviral-mediated hIL-10 to donor lungs is associated with a significant early inflammatory response that may enhance ischemia-reperfusion injury if insufficient hIL-10 is expressed in lung tissue before retrieval. The period between delivery of AdhIL-10 and lung retrieval can be reduced if the early inflammatory response is suppressed with methylprednisolone.

CXCR2/CXCR2 Ligand Biology during Lung Transplant Ischemia-Reperfusion Injury

“…This rat model of clinically relevant cold ischemia-reperfusion injury related to lung transplantation was used to further evaluate the role of ELR ϩ CXC chemokines during the pathogenesis of ischemia-reperfusion lung injury (26,27,36,37). This rat model consisted of a cold (i.e., donor lung ischemia time of 6 h at 4 o C) orthotopic single left lung transplantation followed by reperfusion with lung injury evaluated at multiple time points.…”

“…This rat model consisted of a cold (i.e., donor lung ischemia time of 6 h at 4 o C) orthotopic single left lung transplantation followed by reperfusion with lung injury evaluated at multiple time points. Lewis rats received a lung transplantation from either donor Brown Norway (allograft) or Lewis (isograft) rats as previously described (26,27,36,37). Sham-operated matched controls consisted of a left side thoracotomy with dissection of the pulmonary artery, vein, and left main stem bronchus followed by closure of the chest wall thoracotomy site.…”

Obesity and Primary Graft Dysfunction after Lung Transplantation

“…Primary graft dysfunction (PGD), defined as the occurrence of acute lung injury (ALI) in the allograft within 72 hours of transplantation (1), is a leading cause of death early after lung transplantation (2) and is a risk factor for chronic allograft rejection (3,4). Although PGD is typically attributed to ischemia-reperfusion injury of the allograft, systemic inflammation plays a critical role (5)(6)(7).…”

In Vivo Molecular Imaging Characterizes Pulmonary Gene Expression During Experimental Lung Transplantation

“…Furthermore, therapeutic gene transfer can markedly reduce these injuries. Recent experimental evidence (27,31) indicates that gene transfer to the donor prior to harvest, as performed in this study, may be the most feasible method to prevent reperfusion injury in a clinical setting. While donor-directed transfection may not be the optimal strategy to prevent acute allograft rejection, our laboratory has demonstrated the efficacy of this approach, as well as gene transfer to the recipient, in preventing experimental acute rejection (32,33).…”

“…As shown in Figure 8 cold preservation used to induce I/R injury was excluded from time after gene transfer as we and others have shown that there is no significant gene expression activity that occurs during cold preservation of lung grafts (8,27). Similarly, as shown in Figure 8, uptake of [ 18 F]FHBG in lungs undergoing acute allograft rejection was comparable to normally transplanted controls.…”