Non-apoptotic forms of cell death can trigger sterile inflammation through the release of danger-associated molecular patterns, which are recognized by innate immune receptors. However, despite years ...of investigation the mechanisms which initiate inflammatory responses after heart transplantation remain elusive. Here, we demonstrate that ferrostatin-1 (Fer-1), a specific inhibitor of ferroptosis, decreases the level of pro-ferroptotic hydroperoxy-arachidonoyl-phosphatidylethanolamine, reduces cardiomyocyte cell death and blocks neutrophil recruitment following heart transplantation. Inhibition of necroptosis had no effect on neutrophil trafficking in cardiac grafts. We extend these observations to a model of coronary artery ligation-induced myocardial ischemia reperfusion injury where inhibition of ferroptosis resulted in reduced infarct size, improved left ventricular systolic function, and reduced left ventricular remodeling. Using intravital imaging of cardiac transplants, we uncover that ferroptosis orchestrates neutrophil recruitment to injured myocardium by promoting adhesion of neutrophils to coronary vascular endothelial cells through a TLR4/TRIF/type I IFN signaling pathway. Thus, we have discovered that inflammatory responses after cardiac transplantation are initiated through ferroptotic cell death and TLR4/Trif-dependent signaling in graft endothelial cells. These findings provide a platform for the development of therapeutic strategies for heart transplant recipients and patients, who are vulnerable to ischemia reperfusion injury following restoration of coronary blood flow.
Size-matching donors to recipients in lung transplantation continues to be a clinical challenge. Predicted total lung capacity equations, or more simply, donor and recipient heights, while widely ...used, are imprecise and may not be representative of the pool of donors and recipients. These inherent limitations may result in size discrepancies. The advent of easily accessible software and the widespread availability of computed tomography (CT) imaging in donor assessments have made it possible to directly measure lung volumes in donors and recipients. As a result, there is a growing interest in adopting personalized CT volumetry as an alternative. This article explores both methods and underscores the potential benefits and precision offered by CT.
Birds and mammals independently evolved the highest metabolic rates among living animals
. Their metabolism generates heat that enables active thermoregulation
, shaping the ecological niches they ...can occupy and their adaptability to environmental change
. The metabolic performance of birds, which exceeds that of mammals, is thought to have evolved along their stem lineage
. However, there is no proxy that enables the direct reconstruction of metabolic rates from fossils. Here we use in situ Raman and Fourier-transform infrared spectroscopy to quantify the in vivo accumulation of metabolic lipoxidation signals in modern and fossil amniote bones. We observe no correlation between atmospheric oxygen concentrations
and metabolic rates. Inferred ancestral states reveal that the metabolic rates consistent with endothermy evolved independently in mammals and plesiosaurs, and are ancestral to ornithodirans, with increasing rates along the avian lineage. High metabolic rates were acquired in pterosaurs, ornithischians, sauropods and theropods well before the advent of energetically costly adaptations, such as flight in birds. Although they had higher metabolic rates ancestrally, ornithischians reduced their metabolic abilities towards ectothermy. The physiological activities of such ectotherms were dependent on environmental and behavioural thermoregulation
, in contrast to the active lifestyles of endotherms
. Giant sauropods and theropods were not gigantothermic
, but true endotherms. Endothermy in many Late Cretaceous taxa, in addition to crown mammals and birds, suggests that attributes other than metabolism determined their fate during the terminal Cretaceous mass extinction.
Valve selection in dialysis-dependent patients can be difficult because long-term survival is diminished and bleeding risks during anticoagulation treatment are greater in patients with renal ...failure. In this study we analyzed long-term outcomes of dialysis-dependent patients who underwent valve replacement to help guide optimal prosthetic valve type selection.
Dialysis-dependent patients who underwent aortic and/or mitral valve replacement at 3 institutions over 20 years were examined. The primary outcome was long-term survival. A Cox regression model was used to estimate survival according to 5 ages, presence of diabetes, and/or heart failure symptoms.
Four hundred twenty-three available patients were analyzed; 341 patients had biological and 82 had mechanical valves. Overall complication and 30-day mortality rates were similar between the groups. Thirty-day readmission rates for biological and mechanical groups were 15% (50/341) and 28% (23/82; P = .005). Five-year survival was 23% and 33% for the biological and mechanical groups, respectively. After adjusting for age, New York Heart Association (NYHA) class, and diabetes using a multivariable Cox regression model, survival was similar between groups (hazard ratio, 0.93; 95% confidence interval, 0.66-1.29; P = .8). A Cox regression model on the basis of age, diabetes, and heart failure, estimated that patients only 30 or 40 years old, with NYHA class I-II failure without diabetes had a >50% estimated 5-year survival (P < .001).
Dialysis-dependent patients who underwent valve replacement surgery had poor long-term survival. Young patients without diabetes or NYHA III or IV symptoms might survive long enough to justify placement of a mechanical valve; however, a biological valve is suitable for most patients.
Innate immunity in lung transplantation Shepherd, Hailey M; Gauthier, Jason M; Li, Wenjun ...
The Journal of heart and lung transplantation,
07/2021, Letnik:
40, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Innate immune pathways early after pulmonary transplantation have been shown to cause primary graft dysfunction (PGD) and also predispose to late graft failure. Recent studies in animal models have ...elucidated critical mechanisms governing such innate immune responses. Here, we discuss pathways of inflammatory cell death, triggers for sterile and infectious inflammation, and signaling cascades that mediate lung injury early after transplantation. These studies highlight potential avenues for lung-specific therapies early following lung transplantation to dampen innate immune responses and improve outcomes.
Ischemia-reperfusion injury is an inevitable event during organ transplantation and represents a primary risk factor for the development of early graft dysfunction in lung, heart, liver, and kidney ...transplant recipients. Recent studies have implicated recipient neutrophils as key mediators of this process and also have found that early innate immune responses after transplantation can ultimately augment adaptive alloimmunity and affect late graft outcomes. Here, we discuss signaling pathways involved in neutrophil recruitment and activation after ischemia-mediated graft injury in solid organ transplantation with an emphasis on lung allografts, which have been the focus of recent studies. These findings suggest novel therapeutic interventions that target ischemia-reperfusion injury-mediated graft dysfunction in transplant recipients.
Hitting the target with lung perfusion Gauthier, Jason M.; Puri, Varun; Kreisel, Daniel
The Journal of thoracic and cardiovascular surgery,
November 2017, 2017-11-00, 20171101, Letnik:
154, Številka:
5
Journal Article
Aortic arch transplants have advanced our understanding of processes that contribute to progression and regression of atherosclerotic plaques. To characterize the dynamic behavior of monocytes and ...macrophages in atherosclerotic plaques over time, we developed a new model of cervical aortic arch transplantation in mice that is amenable to intravital imaging.
Vascularized aortic arch grafts were transplanted heterotropically to the right carotid arteries of recipient mice using microsurgical suture techniques. To image immune cells in atherosclerotic lesions during regression, plaque-bearing aortic arch grafts from B6 ApoE-deficient donors were transplanted into syngeneic CX
CR1 GFP reporter mice. Grafts were evaluated histologically, and monocytic cells in atherosclerotic plaques in ApoE-deficient grafts were imaged intravitally by 2-photon microscopy in serial fashion. In complementary experiments, CCR2
cells in plaques were serially imaged by positron emission tomography using specific molecular probes. Plaques in ApoE-deficient grafts underwent regression after transplantation into normolipidemic hosts. Intravital imaging revealed clusters of largely immotile CX
CR1
monocytes/macrophages in regressing plaques that had been recruited from the periphery. We observed a progressive decrease in CX
CR1
monocytic cells in regressing plaques and a decrease in CCR2
positron emission tomography signal during 4 months.
Cervical transplantation of atherosclerotic mouse aortic arches represents a novel experimental tool to investigate cellular mechanisms that contribute to the remodeling of atherosclerotic plaques.
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