Role of necroptosis in the pathogenesis of solid organ injury.
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ABSTRACT:
SUBMITTER: Zhao H
PROVIDER: S-EPMC4670925 | biostudies-other | 2015 Nov
REPOSITORIES: biostudies-other
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Project description:Histone deacetylase 3 (HDAC3) plays a crucial role in chromatin remodeling, which, in turn, regulates gene transcription. Hence, HDAC3 has been implicated in various diseases, including ischemic injury, fibrosis, neurodegeneration, infections, and inflammatory conditions. In addition, HDAC3 plays vital roles under physiological conditions by regulating circadian rhythms, metabolism, and development. In this review, we summarize the current knowledge of the physiological functions of HDAC3 and its role in organ injury. We also discuss the therapeutic value of HDAC3 in various diseases.
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Project description:Although nonoperative management has become the standard of care for solid organ injury, variability exists in the care patients receive, and there are limited data regarding nonoperative management in patients with high grades of organ injury and substantial overall injury. We aimed to evaluate operative intervention frequency, including splenectomy, and patient outcomes before and after institution of the pediatric solid organ injury pathway at Harborview Medical Center (HMC) in 2005.This is a retrospective cohort study conducted at HMC for all pediatric solid organ injury patients from 2001 to 2012. Patients were identified in the Harborview Trauma Registry via DRG International Classification of Diseases-9th Rev. (ICD-9) codes for the presence of liver and spleen injuries. Demographic information, clinical characteristics, and ICD-9 procedure codes were also obtained from the trauma registry. Outcomes including splenectomy, a related abdominal surgery (exploratory laparotomy, spleen or liver repair, or splenectomy), mortality, and length of stay were compared between periods before and after 2005, adjusted for Injury Severity Score (ISS).The pediatric solid organ injury population at HMC (n = 712) has a high frequency of high-grade injury (35% Grade IV or V) and a high level of overall injury severity (median ISS, 21). Splenectomy was rare and remained stable over time despite an increase in severity of injury (from 2.4% to 0.8%, p = 0.44, among patients with isolated injury and from 4.0% to 3.3%, p = 0.78, among patients with nonisolated injury). Other abdominal surgeries also remained stable over time. Mortality decreased among patients with nonisolated injury (from 11.2% to 4.8%, p = 0.01). Length of stay decreased among patients with isolated organ injury, from a median of 4 days (interquartile range, 3-5 days) to 2 days (interquartile range, 2-3 days) (p < 0.0005) as well as within the lower ISS strata among patients with nonisolated organ injury (from a median of 4 days to 2 days among ISS < 12, p = 0.007; from 5 days to 3 days among ISS of 12-20, p = 0.0001; and from 7 days to 4 days among ISS of 21-33, p = 0.003).Care in the recent period (2005-2012) was associated with a stable, low frequency of splenectomy; decreased mortality for patients with nonisolated injury; and decreased hospital length of stay among most subsets of patients, suggesting improved care despite an increase in patients' severity of injury.Therapeutic study, level IV; epidemiologic study, level III.
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Project description:Severe acute respiratory disease coronavirus 2 (SARS-CoV-2, formerly 2019-nCoV) is a novel coronavirus that has rapidly disseminated worldwide, causing the coronavirus disease 2019 (COVID-19) pandemic. As of January 6th, 2021, there were over 86 million global confirmed cases, and the disease has claimed over 1.87 million lives (a ∼2.2% case fatality rate). SARS-CoV-2 is able to infect human cells by binding its spike (S) protein to angiotensin-conversing enzyme 2 (ACE2), which is expressed abundantly in several cell types and tissues. ACE2 has extensive biological activities as a component of the renin-angiotensin-aldosterone system (RAAS) and plays a pivotal role as counter-regulator of angiotensin II (Ang II) activity by converting the latter to Ang (1-7). Virion binding to ACE2 for host cell entry leads to internalization of both via endocytosis, as well as activation of ADAM17/TACE, resulting in downregulation of ACE2 and loss of its protective actions in the lungs and other organs. Although COVID-19 was initially described as a purely respiratory disease, it is now known that infected individuals can rapidly progress to a multiple organ dysfunction syndrome. In fact, all human structures that express ACE2 are susceptible to SARS-CoV-2 infection and/or to the downstream effects of reduced ACE2 levels, namely systemic inflammation and injury. In this review, we aim to summarize the major features of SARS-CoV-2 biology and the current understanding of COVID-19 pathogenesis, as well as its clinical repercussions in the lung, heart, kidney, bowel, liver, and brain. We also highlight potential therapeutic targets and current global efforts to identify safe and effective therapies against this life-threatening condition.
| S-EPMC7876335 | biostudies-literature
Project description:BackgroundPrevious studies have demonstrated protective effects of anti-receptor interacting protein kinase 1 (RIP1), a key necroptosis molecule. However, it is uncertain whether necroptosis has a crucial role in hepatic IR injury. Therefore, we evaluated the role of necroptosis in hepatic IR injury.MethodThe IR mice underwent 70% segmental IR injury induced by the clamping of the hepatic artery and portal vein for 1 hr followed by reperfusion for 4 hr. The key necroptosis molecules (RIP1, RIP3, and MLKL) and other key molecules of regulated necrosis (PGAM5 and caspase-1) were evaluated in the warm IR injury model. A RIP1 inhibitor (necrostain-1s) and/or an anti-mitochondrial permeability transition (MPT)-mediated necrosis mediator (cyclosporine A, CyA) were administered before clamping. Necrotic injury was quantified using Suzuki's scoring system. qRT-PCR and western blot were performed to evaluate RIP1, RIP3, MLKL and PGAM5 expressions.ResultsRIP1, RIP3, MLKL and PGAM5 expression did not change in the hepatic IR injury model. Moreover, Nec1s pretreatment did not improve histology or biochemical markers. The overall Suzuki score (cytoplasmic vacuolization, sinusoidal congestion and hepatocytes necrosis) was increased in the RIP3(-/-) mice compared to the IR group (3.5 vs. 5, p = 0.026). CyA pretreatment and/or RIP3(-/-) mice decreased Bax/Bcl2 expression; however, it did lead to an overall change in the levels of AST, ALT and LDH or necrotic injury. The Bax/Bcl2 ratio and the expression of caspase-1 and caspase-3 did not increase in our hepatic IR injury model.ConclusionKey necroptosis molecules did not increase in the necrosis-dominant hepatic IR injury model. Anti-necroptosis and/or cyclosporine-A treatment did not have an overall protective effect on necrosis-dominant hepatic IR injury.
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Project description:Impaired invasion of extravillous trophoblasts and severe oxidative stress manifest the poor placentation in preeclampsia, which is life-threatening and more than a hypertensive disease of pregnancy. Previous studies have reported that G protein-coupled receptor kinases (GRKs) play a key role in initiating hypertension and hypertensive renal damage, yet little evidence so far suggests a link between GRKs and preeclampsia-related hypertension. Here, we demonstrate GRK2 expression is significantly downregulated (P < 0.0001) in preeclamptic placentae compared to normotensive controls. Knockdown or inhibition of GRK2 in placentae caused insufficient arterial remodeling and elevated trophoblast necroptosis in vivo. These further induced preeclampsia-like phenotype in mice: hypertension, proteinuria, and elevated pro-angiogenic cytokines. By human extra-villous invasive trophoblast cell line (HTR8/SVneo cells), we revealed the knockdown or inhibition of GRK2 triggered excessive death with typical necroptotic characteristics: nuclear envelope rupture and the activation of RIPK1, RIPK3, and MLKL. Necrostatin-1, an inhibitor of RIPK1, is able to restore the survival of trophoblasts. Together, our findings demonstrated that insufficient GRK2 activity compromises spiral artery remodeling and initiates necrotic events in placentae, thereby leading to preeclampsia. These findings advance our understanding of GRK2 in the pathogenesis of preeclampsia and could shed light on a potential treatment for preeclampsia.
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Project description:In recent decades, solid organ transplantation (SOT) has increased the survival and quality of life for patients with end-stage organ failure by providing a potentially long-term treatment option. Although the availability of organs for transplantation has increased throughout the years, the demand greatly outweighs the supply. One possible solution for this problem is to extend the potential donor pool by using extended criteria donors. However, organs from such donors are more prone to ischemia reperfusion injury (IRI) resulting in higher rates of delayed graft function, acute and chronic graft rejection and worse overall SOT outcomes. This can be overcome by further investigating donor preconditioning strategies, graft perfusion and storage and by finding novel therapeutic agents that could reduce IRI. relaxin (RLX) is a peptide hormone with antifibrotic, antioxidant, anti-inflammatory and cytoprotective properties. The main research until now focused on heart failure; however, several preclinical studies showed its potentials for reducing IRI in SOT. The aim of this comprehensive review is to overview currently available literature on the possible role of RLX in reducing IRI and its positive impact on SOT.
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Project description:Gestation and delivery can increase intra-abdominal pressure, which are well-known risk factors for Pelvic Organ Prolapse (POP). But the pathogenesis mechanism of POP remains unclear. Our previous research showed that the expression of glutathione peroxidase type 1 (GPX1) decreased in pelvic floor ligaments from POP patients, implying that oxidative stress (OS) may be related to POP. The aim of this study was to figure out the role of GPx1 regulation in the pathogenesis of POP. Women (>45 years) who received hysterectomy surgery were enrolled in this research, identified by screening. We applied mechanical strain of 0μ, 5333 μ to GPX1-overexpressing human uterosacral ligament fibroblasts (hUSLFs) isolated from menopausal women without POP respectively for 4 hours, in order to investigate the changes of cell apoptosis, oxidative status and ECM metabolism when cytomechanics model loaded on GPX1-overexpressing hUSLFs. Comparing with the non-transfection and mock-vehicle groups, we found that GPX1 not only protects hUSLFs from cell apoptosis, oxidative damage, but also improves the remodeling of ECM induced by mechanical stimulation. These results suggested that mechanical strain caused abnormalities of ECM metabolism via OS pathway in hUSLFs, which was involved in the pathogenesis of POP, and that GPx1 played a significant role in regulating mechanical strain induced POP.
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Project description:Graft rejection remains the major obstacle after vascularized solid organ transplantation. Endothelial cells, which form the interface between the transplanted graft and the host's immunity, are the first target for host immune cells. During acute cellular rejection endothelial cells are directly attacked by HLA I and II-recognizing NK cells, macrophages, and T cells, and activation of the complement system leads to endothelial cell lysis. The established forms of immunosuppressive therapy provide effective treatment options, but the treatment of chronic rejection of solid organs remains challenging. Chronic rejection is mainly based on production of donor-specific antibodies that induce endothelial cell activation-a condition which phenotypically resembles chronic inflammation. Activated endothelial cells produce chemokines, and expression of adhesion molecules increases. Due to this pro-inflammatory microenvironment, leukocytes are recruited and transmigrate from the bloodstream across the endothelial monolayer into the vessel wall. This mononuclear infiltrate is a hallmark of transplant vasculopathy. Furthermore, expression profiles of different cytokines serve as clinical markers for the patient's outcome. Besides their effects on immune cells, activated endothelial cells support the migration and proliferation of vascular smooth muscle cells. In turn, muscle cell recruitment leads to neointima formation followed by reduction in organ perfusion and eventually results in tissue injury. Activation of endothelial cells involves antibody ligation to the surface of endothelial cells. Subsequently, intracellular signaling pathways are initiated. These signaling cascades may serve as targets to prevent or treat adverse effects in antibody-activated endothelial cells. Preventive or therapeutic strategies for chronic rejection can be investigated in sophisticated mouse models of transplant vasculopathy, mimicking interactions between immune cells and endothelium.
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Project description:To investigate the use of abdominal CT scanning in the management of pediatric blunt abdominal trauma in pediatric and non-pediatric departments.In this observational cohort study, anonymized data were extracted from 2 large German statutory health insurances (∼5.9 million clients) in a 7-year period (2010-2016). All patients with inpatient International Classification of Diseases (ICD) codes S36.- and S37.- (injury of intra-abdominal organs; injury of urinary and pelvic organs) aged ≤18 years were included. Demographic and clinical data were analyzed by logistic regression analysis for associations with the use of abdominal CT.A total of 524 children with blunt abdominal trauma (mean age 11.0 ± 5.2 years; 62.6% males) were included; 164 patients (31.3%) received abdominal CT-imaging. There were no significant differences in traumatic non-intraabdominal comorbidity patterns (injuries of external causes; injuries to the head or thorax). There was substantial variability in the rate of abdominal CT imaging among different medical disciplines ranging from 11.6% to 44.5%. Patients admitted to pediatric departments (Pediatrics and Pediatric Surgery) underwent abdominal CT imaging significantly less frequently (19.7%; N = 55) compared to patients treated in non-pediatric departments (General/Trauma Surgery: 44.5%; N = 109) irrespective of concomitant injuries. The estimated OR for the use of abdominal CT by General/Trauma Surgery was 6.2-fold higher (OR: 6.15 [95-%-CI:3.07-13.21]; P < .001) compared to Pediatric Surgery. Other risk factors associated with the use of abdominal CT were traumatic extra-abdominal comorbidities, increasing age, male gender, and admission to a university hospital.Abdominal CT imaging was significantly less frequently used in pediatric departments. The substantial variability of the abdominal CT rate among different medical disciplines and centers indicates a potential for reduction of CT imaging by implementation of evidence-based guidelines. Furthermore, our study underlines the need for centralization of pediatric trauma care in Germany not only to improve patient outcome but to avoid radiation-induced cancer mortality.
| S-EPMC7647522 | biostudies-literature
Project description:BackgroundThe optimal level of care for hemodynamically stable patients with isolated blunt hepatic, renal, or splenic injuries (solid organ injuries [SOIs]) is unknown. We sought to characterize interhospital variability in intensive care unit (ICU) admission of such patients and to determine whether greater hospital-level ICU use would be associated with improved outcomes.MethodsWe conducted a retrospective cohort study using the 2015 and 2016 National Trauma Data Bank. We included adult patients with blunt trauma with SOIs with an Abbreviated Injury Scale score of 2 to 4. We excluded patients with other significant injuries, hypotension, or another indication for ICU admission, and hospitals with less than 10 eligible patients. We categorized hospitals into quartiles based on the proportion of eligible patients admitted to an ICU. The primary outcome was a composite of organ failure (cardiac arrest, acute lung injury/acute respiratory failure, or acute kidney injury), infection (sepsis, pneumonia, or catheter-related blood stream infection), or death during hospitalization.ResultsAmong 14,312 patients at 444 facilities, 7,225 (50%), 5,050 (35%), and 3,499 (24%) had splenic, hepatic, and renal injuries, respectively. The median proportion of ICU use was 44% (interquartile range, 27-59%, range 0-95%). The composite outcome occurred in 180 patients (1.3%), with death in 76 (0.5%), organ failure in 97 (0.7%), and infection in 53 (0.4%). Relative to hospitals with the lowest ICU use (quartile 1), greater hospital-level ICU use was not associated with decreased likelihood of the composite outcome (adjusted odds ratios, 1.31; 95% confidence interval [95% CI], 0.88-1.95; 0.81; 95% CI, 0.52-1.26; and 0.94; 95% CI, 0.62-1.43 for quartiles 2-4, respectively) or its components. Unplanned ICU transfer was no more likely with lower hospital-level ICU use.ConclusionAdmission location of stable patients with isolated mild to moderate abdominal SOIs is variable across hospitals, but hospitalization at a facility with greater ICU use is not associated with substantially improved outcomes.Level of evidenceTherapeutic/care management, Level IV.
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