Daniel J. Weber

The HMGB1-RAGE axis mediates traumatic brain injury–induced pulmonary dysfunction in lung transplantation

Traumatic brain injury induces acute lung injury that negatively impacts the physiology of the donor lung before and after lung transplantation. Sounding the Alarm for RAGE Only 20% of lungs are transplantable because traumatic brain injury, a major cause of death in organ doors, may induce acute lung injury. High-mobility group box-1 (HMGB1) release from the injured brain likely contributes to acute lung injury in donors by preferentially interacting with receptor for advanced glycation end products (RAGE) in the lung. Blocking the HMGB1-RAGE axis improves lung function in murine donors with traumatic brain injury and after transplant. In translational studies, lungs sourced from donors with high HMGB1 levels had worse pulmonary function after transplant. Targeting the HMGB1-RAGE axis may increase the number of lungs available for transplantation and improve patient outcomes. Traumatic brain injury (TBI) results in systemic inflammatory responses that affect the lung. This is especially critical in the setting of lung transplantation, where more than half of donor allografts are obtained postmortem from individuals with TBI. The mechanism by which TBI causes pulmonary dysfunction remains unclear but may involve the interaction of high-mobility group box-1 (HMGB1) protein with the receptor for advanced glycation end products (RAGE). To investigate the role of HMGB1 and RAGE in TBI-induced lung dysfunction, RAGE-sufficient (wild-type) or RAGE-deficient (RAGE−/−) C57BL/6 mice were subjected to TBI through controlled cortical impact and studied for cardiopulmonary injury. Compared to control animals, TBI induced systemic hypoxia, acute lung injury, pulmonary neutrophilia, and decreased compliance (a measure of the lungs’ ability to expand), all of which were attenuated in RAGE−/− mice. Neutralizing systemic HMGB1 induced by TBI reversed hypoxia and improved lung compliance. Compared to wild-type donors, lungs from RAGE−/− TBI donors did not develop acute lung injury after transplantation. In a study of clinical transplantation, elevated systemic HMGB1 in donors correlated with impaired systemic oxygenation of the donor lung before transplantation and predicted impaired oxygenation after transplantation. These data suggest that the HMGB1-RAGE axis plays a role in the mechanism by which TBI induces lung dysfunction and that targeting this pathway before transplant may improve recipient outcomes after lung transplantation.

Role of Complement Activation in Obliterative Bronchiolitis Post–Lung Transplantation

Obliterative bronchiolitis (OB) post-lung transplantation involves IL-17–regulated autoimmunity to type V collagen and alloimmunity, which could be enhanced by complement activation. However, the specific role of complement activation in lung allograft pathology, IL-17 production, and OB is unknown. The current study examines the role of complement activation in OB. Complement-regulatory protein (CRP) (CD55, CD46, complement receptor 1–related protein y/CD46) expression was downregulated in human and murine OB; and C3a, a marker of complement activation, was upregulated locally. IL-17 differentially suppressed complement receptor 1–related protein y expression in airway epithelial cells in vitro. Neutralizing IL-17 recovered CRP expression in murine lung allografts and decreased local C3a production. Exogenous C3a enhanced IL-17 production from alloantigen- or autoantigen (type V collagen)-reactive lymphocytes. Systemically neutralizing C5 abrogated the development of OB, reduced acute rejection severity, lowered systemic and local levels of C3a and C5a, recovered CRP expression, and diminished systemic IL-17 and IL-6 levels. These data indicated that OB induction is in part complement dependent due to IL-17–mediated downregulation of CRPs on airway epithelium. C3a and IL-17 are part of a feed-forward loop that may enhance CRP downregulation, suggesting that complement blockade could be a therapeutic strategy for OB.

The role of autoimmunity in obliterative bronchiolitis after lung transplantation

First performed in the 1960s with long-term successes achieved in the 1980s, lung transplantation remains the only definitive treatment option for end-stage lung disease. Chronic lung rejection, pathologically classified as obliterative bronchiolitis (OB) with its clinical correlate referred to as bronchiolitis obliterans syndrome, is the limiting factor than keeps 5-yr survival rates for lung transplant significantly worse than for other solid organ transplants. Initially, OB was largely attributed to immune responses to donor antigens, alloimmunity. However, more recent work has demonstrated the role of autoimmunity in the process of lung transplant rejection. IL-17 and autoantigens such as collagen type V and K-α1 tubulin have been implicated in the development of chronic rejection. Ultimately, this translational review discusses the role that autoimmunity plays in the development of OB and lung transplant rejection and then discusses options for therapeutic intervention.

Refractory bleeding from a chest wall sarcoma: a rare indication for palliative resection

We report a case of a 57-year-old male who presented with an inoperable chest wall sarcoma due to numerous pulmonary metastases and was treated with chemotherapy and radiation therapy. The patient subsequently developed refractory bleeding from the chest wall tumor requiring palliative chest wall resection and reconstruction. The patient made an uneventful recovery however died from metastatic disease 8 months later. This case represents a very rare indication for palliative chest wall resection.

Institutional Cost of Unplanned 30-Day Readmission Following Open and Endovascular Surgery

Background: Vascular surgical patients have a high rate of readmission, and the cost of readmission for these patients has not been described. Herein, we characterize and compare institutional index hospitalization and 30-day readmission cost following open and endovascular vascular procedures. Methods: The American College of Surgeons National Surgical Quality Improvement Program database was used to identify inpatient open and endovascular procedures at a single institution, from January 2011 through June 2012. Variable and fixed costs for index hospitalization and unplanned 30-day readmissions were obtained using SAP BusinessObjects. Patient characteristics and outcome variables were analyzed using Student t tests or Wilcoxon rank-sum nonparametric tests for continuous variables and Fisher exact tests for categorical variables. Results: One thousand twenty-six inpatient procedures were included in the analysis. There were 605 (59%) open and 421 (41%) endovascular procedures with a 30-day unplanned readmission rate of 16.9% and 17.8%, respectively (P = .679). The mean index hospitalization costs for open and endovascular procedures were US

Stability of DNA/Anti-DNA Complexes

27 653 and US

PS138. The Excess Cost of Unplanned Thirty-Day Readmission Following Vascular Surgery

23 999, respectively (P = .146). The mean costs for 30-day unplanned readmission for open and endovascular procedures were US

The "cut-in patch-out" technique for Pancoast tumor resections results in postoperative pain reduction: a case control study

19 117 and US

Academic versus clinical productivity of cardiac surgeons in the state of New York: Who publishes more and who operates more

17 887, respectively (P = .635). Among open procedures, the mean cost for patients not readmitted was US

The HMGB1-RAGE Inflammatory Pathway: Implications for Brain Injury-Induced Pulmonary Dysfunction

28 321 compared to US