Role of defensins in the pathogenesis of chronic lung allograft rejection

Chronic rejection predominantly manifested as bronchiolitis obliterans syndrome (BOS), still remains a major problem affecting long-term outcomes in human lung transplantation (LTx). Donor specific antibodies (DSA) and infiltration of neutrophils in the graft have been associated with the development of BOS. This study determines the role of defensins, produced by neutrophils, and its interaction with α-1-antitrypsin (AAT) towards induction of airway inflammation and fibrosis which are characteristic hallmarks of BOS. Bronchoalveolar lavage (BAL) and serum from LTx recipients, BOS+ (n=28), BOS− (n=26) and normal healthy controls (n=24) were analyzed. Our results show that BOS+ LTx recipients had higher α-defensins (HNP1–3) and β-defensin2 HBD2 concentration in BAL and serum compared to BOS-DSA-recipients and normal controls (p=0.03). BOS+ patients had significantly lower serum AAT along with higher circulating concentration of HNP–AAT complexes in BAL (p=0.05). Stimulation of primary small airway epithelial cells (SAECs) with HNPs induced expression of HBD2, adhesion molecules (ICAM and VCAM), cytokines (IL-6, IL-1β, IL-13, IL-8 and MCP-1) and growth-factor (VEGF and EGF). In contrast, anti-inflammatory cytokine, IL-10 expression decreased 2-fold (p=0.002). HNPs mediated SAEC activation was completely abrogated by AAT. In conclusion, our results demonstrates that neutrophil secretory product, α-defensins, stimulate β-defensin production by SAECs causing upregulation of pro-inflammatory and pro-fibrotic signaling molecules. Hence, chronic stimulation of airway epithelial cells by defensins can lead to inflammation and fibrosis the central events in the development of BOS following LTx

Effect of development of antibodies to hla and cytomegalovirus mismatch on lung transplantation survival and development of bronchiolitis obliterans syndrome

AbstractObjective: A retrospective analysis was performed to examine the role of HLA antibodies and cytomegalovirus mismatch on the development of bronchiolitis obliterans syndrome and survival after lung transplantation. Methods: Of 339 consecutive lung transplantations performed over a 102-month interval, 301 patients survived at least 3 months. There was a minimum follow-up period of 13 months. Bronchiolitis obliterans syndrome was defined as a decline in forced expiratory volume in 1 second less than 80% of posttransplantation baseline and/or histologic presence of obliterative bronchiolitis and was defined as occurring “early” if documented within 3 years of transplantation. Variables analyzed included preoperative donor and recipient cytomegalovirus status and the development of antibodies to human leukocyte antigens after transplantation. Microcytotoxicity was used to determine the presence of antibodies to human leukocyte antigens. Variables were subjected to Kaplan-Meier analysis to determine their impact on freedom from bronchiolitis obliterans syndrome and survival. Results: The development of antibodies to human leukocyte antigens after transplantation correlated significantly with bronchiolitis obliterans syndrome (P = .02). The development of antibodies to human leukocyte antigens did not affect survival (P = .33) unless they were detected within 2 years of transplantation (P = .04). There was greater frequency of early bronchiolitis obliterans syndrome in cytomegalovirus seronegative patients who received allografts from seropositive donors compared with all other combinations (P = .02). There was also a trend toward worse survival of cytomegalovirus seronegative patients who received allografts from seropositive donors (P = .13). Conclusion: These data suggest that bronchiolitis obliterans syndrome is the result of an immune-mediated process in which HLA antibodies and cytomegalovirus may play a significant role. (J Thorac Cardiovasc Surg 1998;116:812-20

Fatal thrombosis after administration of activated prothrombin complex concentrates in a patient supported by extracorporeal membrane oxygenation who had received activated recombinant factor VII

AbstractJ Thorac Cardiovasc Surg 2002;124:852-

Pediatric And Adult Lung Transplantation For Cystic Fibrosis

AbstractObjective: This paper was undertaken to review the experience at our institution with bilateral sequential lung transplantation for cystic fibrosis.Methods: Since 1989, 103 bilateral sequential lung transplants for cystic fibrosis have been performed (46 pediatric, 48 adult, 9 redo); the mean age was 21 ± 10 years. Cardiopulmonary bypass was used in all but one pediatric (age <18) transplant, and in 15% of adults.Results: Hospital mortality was 4.9%, with 80% of early deaths related to infection. Bronchial anastomotic complications occurred with equal frequency in the pediatric and the adult populations (7.3%). One- and 3-year actuarial survival are 84% and 61%, respectively (no significant difference between pediatric and adult age groups; average follow-up 2.1 ± 1.6 years). Mean forced expiratory volume in 1 second increased from 25% ± 9% before transplantation to 79% ± 35% 1 year after transplantation. Acute rejection occurred 1.7 times per patient-year, with most episodes taking place within the first 6 months after transplantation. The need for treatment of lower respiratory tract infections occurred 1.2 times per patient in the first year after transplantation. Actuarial freedom from bronchiolitis obliterans was 63% at 2 years and 43% at 3 years. Redo transplantation was performed only in the pediatric population and was associated with an early mortality of 33%. Eight living donor transplants (four primary transplants, four redo transplants) were performed with an early survival of 87.5%.Conclusion: Patients with end-stage cystic fibrosis can undergo bilateral lung transplantation with morbidity and mortality comparable to that seen in pulmonary transplantation for other disease entities. (J Thorac Cardiovasc Surg 1998;115:404-14

Economic evaluation of the specialized donor care facility for thoracic organ donor management

Background: Over the last decade two alternative models of donor care have emerged in the United States: the conventional model, whereby donors are managed at the hospital where brain death occurs, and the specialized donor care facility (SDCF), in which brain dead donors are transferred to a SDCF for medical optimization and organ procurement. Despite increasing use of the SDCF model, its cost-effectiveness in comparison to the conventional model remains unknown. Methods: We performed an economic evaluation of the SDCF and conventional model of donor care from the perspective of U.S. transplant centers over a 2-year study period. In this analysis, we utilized nationwide data from the Scientific Registry of Transplant Recipients and controlled for donor characteristics and patterns of organ sharing across the nation\u27s organ procurement organizations (OPOs). Subgroup analysis was performed to determine the impact of the SDCF model on thoracic organ transplants. Results: A total of 38,944 organ transplants were performed in the U.S. during the study period from 13,539 donors with an observed total organ cost of $1.36 billion. If every OPO assumed the cost and effectiveness of the SDCF model, a predicted 39,155 organ transplants (+211) would have been performed with a predicted total organ cost of$1.26 billion (-$100 million). Subgroup analysis of thoracic organs revealed that the SDCF model would lead to a predicted 156 additional transplants with a cost saving of$24.6 million. Conclusions: The U.S. SDCF model may be a less costly and more effective means of multi-organ donor management, particularly for thoracic organ donors, compared to the conventional hospital-based model

Neurobehavioral Functioning and Survival Following Lung Transplantation

Neurobehavioral functioning is widely recognized as being an important consideration in lung transplant candidates, but little is known about whether these factors are related to clinical outcomes. The present study examined the relationship of neurobehavioral functioning, including measures of executive function and memory, depression, and anxiety, to long-term survival among lung transplant recipients