John Dark

The hemodynamic mechanisms of lung injury and systemic inflammatory response following brain death in the transplant donor.

Brain‐dead donors are the major source of lungs for transplantation. Brain death is characterized by two hemodynamic phases. Initially, massive sympathetic discharge results in a hypertensive crisis. This is followed by neurogenic hypotension. Up‐regulation of pro‐inflammatory mediators occurs in all organs and lung injury develops; this can adversely affect graft function post‐transplantation. The mechanisms of the systemic and lung inflammation are unknown. We hypothesized that the hemodynamic changes are responsible for these inflammatory phenomena. Brain death was induced by intra‐cranial balloon inflation in rats. This resulted in hypertensive crisis, followed by hypotension. There was a significant increase in blood neutrophil CD11b/CD18 expression and pro‐inflammatory cytokine levels in serum and bronchoalveolar lavage, compared with control animals. Rupture of the capillary‐alveolar membrane was demonstrated by electron microscopy. Elimination of the hypertensive response by α‐adrenergic antagonist pre‐treatment prevented inflammatory lung injury, reduced the systemic inflammatory markers and preserved capillary‐alveolar membrane integrity. Correction of the neurogenic hypotension with noradrenaline ameliorated the systemic inflammatory response and improved oxygenation. We conclude that the sympathetic discharge triggers systemic and lung inflammation, which can be further enhanced by neurogenic hypotension. Management of the brain‐dead donor with early anti‐inflammatory treatment and vasoconstrictors is warranted.

The safety and efficacy of total lymphoid irradiation in progressive bronchiolitis obliterans syndrome after lung transplantation

Total lymphoid irradiation (TLI) has been used to control renal and cardiac allograft rejection. Data evaluating TLI in bronchiolitis obliterans syndrome (BOS), the physiological manifestation of chronic lung allograft rejection, is very limited. We present our single center experience of the safety and efficacy of TLI in controlling progressive BOS in a retrospective study.

Examination of the mechanism by which heparin antagonizes activation of a model endothelium by interferon‐gamma (IFN‐γ)

IFN‐γ increases the potential immunogenicity of vascular endothelial cells by up‐regulation of intercellular adhesion molecule‐1 (ICAM‐1) and class I MHC antigen expression and by induction of class II MHC antigens and certain chemokines. In this study the mechanism by which the glycosaminoglycan (GAG) heparin antagonizes the activation of a model endothelium by IFN‐γ was investigated. Radioligand binding assays demonstrated that total binding of 125I‐IFN‐γ to the EAhy.926 endothelial hybridoma cell line was reduced in the presence of heparin or heparan sulphate (HS); the structurally dissimilar GAG chondroitin sulphate had no effect. Treatment of the cells with chlorate, a metabolic inhibitor of GAG sulphation, was found to reduce both the subsequent binding of IFN‐γ and its ability to induce expression of class II MHC antigens. Treatment with heparinase II dramatically reduced the binding of IFN‐γ, while chondroitin ABC lyase had no effect. A cationic peptide from the C‐terminal region of IFN‐γ was also found to reduce binding of intact IFN‐γ to the cells. These results appear to demonstrate that IFN‐γ is sequestered at the surface of endothelial cells by electrostatic interaction between specific basic amino acid residues and sulphated domains on HS, the most abundant endothelial GAG. This interaction is competitively inhibited by heparin, which is structurally related to HS. These observations are consistent with the model that IFN‐γ is bound by membrane‐associated HS before engagement with the high‐affinity receptor and signal transduction. Inhibition of the interaction between proinflammatory cytokines and membrane‐associated GAG molecules may provide a mechanism for inducing clinically useful immunosuppression.

Role of glycosaminoglycans (GAGs) in regulation of the immunogenicity of human vascular endothelial cells

Heparan sulphate is a common glycosaminoglycan component of proteoglycans present on the luminal surface of vascular endothelium. It has been proposed that an important function of these molecules is the sequestration of a range of proinflammatory and proadhesive cytokines. Such cytokines play a vital role during lymphocyte recruitment from the blood at sites of inflammation. In this study it is shown that the effects of interferon‐gamma (IFN‐γ), but not of tumour necrosis factor‐alpha (TNF‐α), are inhibited by treatment with soluble heparin. Specifically, heparin was shown to inhibit the induction of class II MHC antigens and the up‐regulation of intercellular adhesion molecule‐1 (ICAM‐1) produced by treatment of cultured human endothelial cells with IFN‐γ. Furthermore, it was shown that heparin blocked the enhanced adhesion of T lymphocytes to IFN‐γ‐treated endothelial cells. Investigation of the inhibitory effects of other GAG molecules demonstrated a requirement for heparin‐like structural domains as chondroitin sulphate was unable to inhibit the function of IFN‐γ. These results may explain reported immunosuppressive properties of heparin, and are consistent with the model that heparin may compete with cell surface GAGs to bind IFN‐γ, thereby reducing effective biological activity.

Pseudomembranous colitis in four patients with cystic fibrosis following lung transplantation

Pseudomembranous colitis is an uncommon complication in patients with cystic fibrosis, despite the use of multiple high-dose antibiotic regimens and the frequency of hospital admissions. Four patients from a total of 137 patients with cystic fibrosis undergoing lung transplantation are described who developed fulminant pseudomembranous colitis. Initial presentation was variable and the mortality rate was 50% despite urgent colectomy. In one case the presenting abdominal distension was thought to be due to meconium ileus equivalent. It is concluded that Clostridium difficile colitis may be a difficult diagnosis in patients with cystic fibrosis and follows a fulminant course after lung transplantation.

Pulmonary transplantation for cystic fibrosis: Pre-transplant recipient characteristics in patients dying of peri-operative sepsis

BACKGROUND Pulmonary transplantation has emerged as a successful treatment for end-stage cystic fibrosis. Despite the chronic bronchial sepsis and often multi-resistant organisms seen in this group of recipients, death due to post-operative sepsis is relatively scarce. Identifying potential recipient risk factors for poor outcome may further improve the utilization of a scarce donor pool. METHODS We assessed the role of pre-operative clinical measures of sepsis, microbial characteristics and recipient characteristics on post-transplant outcome in 85 cystic fibrosis patients who underwent pulmonary transplantation. Ten percent of patients died in the early post-operative period due to sepsis. The prognostic role of recipient factors including markers of sepsis, such as white cells and C-reactive protein (CRP), and the influence of multi-resistant organisms, in particular organisms from the Burkholderia cepacia complex, on outcomes were investigated. RESULTS We found no prognostic effect of gender, pre-transplant CRP, forced expiratory volume in 1 second (FEV(1)), weight, diabetic status or infection with multi-resistant Pseudomonas organisms. A raised white cell count or temperature or a pre-transplant infection with B cepacia was, however, associated with a significantly poorer prognosis at p = 0.03, 0.03 and 0.001, respectively. CONCLUSIONS Pre-operative B cepacia complex infection, leukocytosis and pyrexia, but not CRP, weight, diabetes or lung function, were found to be associated with poorer post-transplant outcome. The most clinically relevant of these to the subsequent risk of post-operative death from sepsis appear to be B cepacia infection and pyrexia.

Ameliorated reperfusion injury in lung transplantation after reduction of brain death induced inflammatory graft damage in the donor

AMELIORATED REPERFUSION INJURY IN LUNG TRANSPLANTATION AFTER REDUCTION OF BRAIN DEATH INDUCED INFLAMMATORY GRAFT DAMAGE IN THE DONOR C.H. Wigfield, H.D. Golledge, B.K. Shenton, J.A. Kirby, J.H. Dark, Department of Cardiothoracic Surgery and Transplantation, Freeman Hospital, Newcastle upon Tyne, United Kingdom; Comparative Biology Centre, University of Newcastle, Newcastle upon Tyne, United Kingdom; Department of Surgery, University of Newcastle, Newcastle upon Tyne, United Kingdom

Longitudinal changes in gastro-oesophageal reflux from 3 months to 6 months after lung transplantation.

Gastro-oesophageal reflux (GOR) and microaspiration are implicated in the pathophysiology of asthma, chronic obstructive pulmonary disease, interstitial lung disease and chronic lung allograft dysfunction.1 2 Aspiration, which is often asymptomatic, has been identified as a treatable allograft injury that may affect mortality.1 2 The potential for thoracic mechanical changes caused by advanced lung disease to predispose to reflux has been highlighted.2 Although aspiration could cause lung damage, alternatively reflux might represent a secondary event. Longitudinal data are lacking,2 so we have undertaken a prospective study of reflux in lung transplantation. This allowed investigations in patients where thoracic mechanical changes associated with advanced lung disease had improved. We hypothesised that reflux was prevalent and could develop at different times following transplantation in patients with good allograft function. ### Methods Between …

What's new in pulmonary transplantation: Finding the right lung for every patient.

From the Institute of Cellular Medicine, University of Newcastle, Newcastle upon Tyne, United Kingdom. Disclosures: Author has nothing to disclose with regard to commercial support. Received for publication Sept 2, 2015; accepted for publication Sept 3, 2015. Address for reprints: John H. Dark, FRCS, Cardiothoracic Centre, Freeman Hospital, Newcastle upon Tyne NE7 7DN, United Kingdom (E-mail: j.h.dark@ncl.ac.uk). J Thorac Cardiovasc Surg 2016;151:315-6 0022-5223/

The effect of ex vivo lung perfusion on proinflammatory and anti-inflammatory cytokines in the human lung

36.00 Copyright 2016 by The American Association for Thoracic Surgery http://dx.doi.org/10.1016/j.jtcvs.2015.09.024