Our immune system is based on the close collaboration of the innate and adaptive immune systems for the rapid detection of any threats to the host. Recognition of pathogen-derived molecules is entrusted to specific germline-encoded signaling receptors. The same receptors have now also emerged as efficient detectors of misplaced or altered self-molecules that signal tissue damage and cell death following, for example, disruption of the blood supply and subsequent hypoxia. Many types of endogenous molecules have been shown to provoke such sterile inflammatory states when released from dying cells. However, a group of proteins referred to as alarmins have both intracellular and extracellular functions which have been the subject of intense research. Indeed, alarmins can either exert beneficial cell housekeeping functions, leading to tissue repair, or provoke deleterious uncontrolled inflammation. This group of proteins includes the high-mobility group box 1 protein (HMGB1), interleukin (IL)-1α, IL-33 and the Ca2+-binding S100 proteins. These dual-function proteins share conserved regulatory mechanisms, such as secretory routes, post-translational modifications and enzymatic processing, that govern their extracellular functions in time and space. Release of alarmins from mesenchymal cells is a highly relevant mechanism by which immune cells can be alerted of tissue damage, and alarmins play a key role in the development of acute or chronic inflammatory diseases and in cancer development.

/pdf/hmgb1-il-1a-il-33-and-s100-proteins-dual-function-alarmins-yaxjhzql8p.pdf

HMGB1, IL-1α, IL-33 and S100 proteins: dual-function alarmins.

Uric acid (UA) is a risk factor for endothelial dysfunction, a process in which inflammation may play an important role. UA increases high mobility group box chromosomal protein 1 (HMGB1) expression and extracellular release in endothelial cells. HMGB1 is an inflammatory cytokine that interacts with the receptor for advanced glycation end products (RAGE), inducing an oxidative stress and inflammatory response, which leads to endothelial dysfunction. In this study, human umbilical vein endothelial cells (HUVECs) were incubated with a high concentration of UA (20 mg/dL) after which endothelial function and the expression of HMGB1, RAGE, nuclear factor kappa B (NF-κB), inflammatory cytokines, and adhesion molecules were evaluated. UA inhibited endothelial nitric oxide synthase (eNOS) expression and nitric oxide (NO) production in HUVECs, increased intracellular HMGB1 expression and extracellular HMGB1 secretion, and upregulated RAGE expression. UA also activated NF-κB and increased the level of inflammatory cytokines. Blocking RAGE significantly suppressed the upregulation of RAGE and HMGB1 and prevented the increase in DNA binding activity of NF-κB and the levels of inflammatory cytokines. It also blocked the decrease in eNOS expression and NO production induced by UA. Our results suggest that high concentrations of UA cause endothelial dysfunction via the HMGB1/RAGE signaling pathway.

/pdf/uric-acid-induces-endothelial-dysfunction-by-activating-the-4h7bhj0hef.pdf

Uric Acid Induces Endothelial Dysfunction by Activating the HMGB1/RAGE Signaling Pathway.

Chronic lung allograft dysfunction (CLAD) is the major limitation of long-term survival after lung transplantation. Chronic lung allograft dysfunction manifests as bronchiolitis obliterans syndrome or the recently described restrictive allograft syndrome. Although numerous risk factors have been identified so far, the physiopathological mechanisms of CLAD remain poorly understood. We investigate here the immune mechanisms involved in the development of CLAD after lung transplantation. We explore the innate or adaptive immune reactions induced by the allograft itself or by the environment and how they lead to allograft dysfunction. Because current literature suggests bronchiolitis obliterans syndrome and restrictive allograft syndrome as 2 distinct entities, we focus on the specific factors behind one or the other syndromes. Chronic lung allograft dysfunction is a multifactorial disease that remains irreversible and unpredictable so far. We thus finally discuss the potential of systems-biology approach to predict its occurrence and to better understand its underlying mechanisms.

/pdf/chronic-lung-allograft-dysfunction-a-systematic-review-of-205qh22hs2.pdf

Chronic Lung Allograft Dysfunction: A Systematic Review of Mechanisms.

Brain death that occurs in the setting of deceased organ donation for transplantation is associated with systemic inflammation of unknown origin. It has recently been recognized that mitochondria-derived damage-associated molecular patterns (mtDAMPs) released into the circulation in the setting of trauma and tissue injury are associated with a systemic inflammatory response. We examined the blood of deceased organ donors and found elevated levels of inflammatory cytokines and chemokines that correlated with levels of mtDAMPs. We also found that donor neutrophils are activated and that donor plasma contains a neutrophil-activating factor that is blocked by cyclosporin H, a formyl peptide receptor-1 antagonist. Examination of donor plasma by electron microscopy and flow cytometry revealed that free- and membrane-bound mitochondria are elevated in donor plasma. Interestingly, we demonstrated a correlation between donor plasma mitochondrial DNA levels and early allograft dysfunction in liver transplant recipients, suggesting a role for circulating mtDAMPs in allograft outcomes. Current approaches to prolong allograft survival focus on immune suppression in the transplant recipient; our data indicate that targeting inflammatory factors in deceased donors prior to organ procurement is another potential strategy for improving transplant outcomes.

/pdf/circulating-mitochondria-in-deceased-organ-donors-are-1nqqk09fbp.pdf

Circulating mitochondria in deceased organ donors are associated with immune activation and early allograft dysfunction.

Approximately 20–25% of traumatic brain injury (TBI) subjects develop acute lung injury (ALI), but the pathomechanisms of TBI-induced ALI remain poorly defined. Our previous work has shown...

Traumatic Brain Injury-Induced Acute Lung Injury: Evidence for Activation and Inhibition of a Neural-Respiratory-Inflammasome Axis.

Background

Data are limited regarding the influence of donor age on outcomes after heart transplantation. We sought to determine if advanced donor age is associated with differences in survival after heart transplantation and how this compares to waitlist survival.



Methods

All adult heart transplants from 2000 to 2012 were identified using the United Network for Organ Sharing database. Donors were stratified into four age groups: 18–39 (reference group), 40–49, 50–54, and 55 and above. Propensity scoring was used to compare status IA waitlist patients who did not undergo transplantation with IA recipients who received hearts from advanced age donors. The primary outcome of interest was recipient survival and this was analyzed with multivariate Cox regression analysis and the Kaplan–Meier method.



Results

A total of 22,960 adult heart transplant recipients were identified. Recipients of hearts from all three older donor groups had significantly increased risk of mortality (HR, 1.187–1.426, all p < 0.001) compared to recipients from donors age 18 to 39. Additionally, propensity-matched status IA patients managed medically without transplantation had significantly worse adjusted survival than status IA recipients who received hearts from older donors age ≥55 (HR, 1.362, p < 0.001).



Conclusions

Compared to donors aged 18–39, age 40 and above is associated with worse adjusted recipient survival in heart transplantation. This survival difference becomes more pronounced as age increases to above 55. However, the survival rate among status IA patients who receive hearts from advanced age donors (≥55) is significantly better compared to similar status IA patients who are managed without transplantation. doi: 10.1111/jocs.12406 (J Card Surg 2014;29:723–728)

The Impact of Donor Age on Survival After Heart Transplantation: An Analysis of the United Network for Organ Sharing (UNOS) Registry

Although recipient body mass index (BMI) and age are known risk factors for mortality after heart transplantation, how they interact to influence survival is unknown. Our study utilized the UNOS registry from 1997 to 2012 to define the interaction between BMI and age and its impact on survival after heart transplantation. Recipients were stratified by BMI: underweight (<18.5), normal weight (18.5-24.99), overweight (25-29.99), and either moderate (30-34.99), severe (35-39.99), or very severe (≥40) obesity. Recipients were secondarily stratified based on age: 18-40 (younger recipients), 40-65 (reference group), and ≥65 (advanced age recipients). Among younger recipients, being underweight was associated with improved adjusted survival (HR 0.902; p = 0.010) while higher mortality was seen in younger overweight recipients (HR 1.260; p = 0.005). However, no differences in adjusted survival were appreciated in underweight and overweight advanced age recipients. Obesity (BMI ≥ 30) was associated with increased adjusted mortality in normal age recipients (HR 1.152; p = 0.021) and even more so with young (HR 1.576; p < 0.001) and advanced age recipients (HR 1.292; p = 0.001). These results demonstrate that BMI and age interact to impact survival as age modifies BMI-mortality curves, particularly with younger and advanced age recipients.

Recipient body mass index and age interact to impact survival after heart transplantation.

The Role of Recipient BMI and Age on Survival after Heart Transplantation

The Role of Donor Age and Gender on Survival after Heart Transplantation

/pdf/erratum-the-hmgb1-rage-axis-mediates-traumatic-brain-injury-308kmpwk65.pdf

Erratum: The HMGB1-RAGE axis mediates traumatic brain injury-induced pulmonary dysfunction in lung transplantation (Science Translational Medicine (2018) 10:471 (eaaw2634) DOI:10.1126/scitranslmed.3009443)

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