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Neuroprotective Effects of Annexin A1 Tripeptide after Deep Hypothermic Circulatory Arrest in Rats.

ABSTRACT: Resolution agonists, including lipid mediators and peptides such as annexin A1 (ANXA1), are providing novel approaches to treat inflammatory conditions. Surgical trauma exerts a significant burden on the immune system that can affect and impair multiple organs. Perioperative cerebral injury after cardiac surgery is associated with significant adverse neurological outcomes such as delirium and postoperative cognitive dysfunction. Using a clinically relevant rat model of cardiopulmonary bypass (CPB) with deep hypothermic circulatory arrest (DHCA), we tested the pro-resolving effects of a novel bioactive ANXA1 tripeptide (ANXA1sp) on neuroinflammation and cognition. Male rats underwent 2?h CPB with 1?h DHCA at 18°C, and received vehicle or ANXA1sp followed by timed reperfusion up to postoperative day 7. Immortalized murine microglial cell line BV2 were treated with vehicle or ANXA1sp and subjected to 2?h oxygen-glucose deprivation followed by timed reoxygenation. Microglial activation, cell death, neuroinflammation, and NF-?B activation were assessed in tissue samples and cell cultures. Rats exposed to CPB and DHCA had evident neuroinflammation in various brain areas. However, in ANXA1sp-treated rats, microglial activation and cell death (apoptosis and necrosis) were reduced at 24?h and 7?days after surgery. This was associated with a reduction in key pro-inflammatory cytokines due to inhibition of NF-?B activation in the brain and systemically. Treated rats also had improved neurologic scores and shorter latency in the Morris water maze. In BV2 cells treated with ANXA1sp, similar protective effects were observed including decreased pro-inflammatory cytokines and cell death. Notably, we also found increased expression of ANXA1, which binds to NF-?B p65 and thereby inhibits its transcriptional activity. Our findings provide evidence that treatment with a novel pro-resolving ANXA1 tripeptide is neuroprotective after cardiac surgery in rats by attenuating neuroinflammation and may prevent postoperative neurologic complications.

SUBMITTER: Zhang Z

PROVIDER: S-EPMC5582068 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Neuroprotective Effects of Annexin A1 Tripeptide after Deep Hypothermic Circulatory Arrest in Rats.

Zhang Zhiquan Z Ma Qing Q Shah Bijal B Mackensen G Burkhard GB Lo Donald C DC Mathew Joseph P JP Podgoreanu Mihai V MV Terrando Niccolò N

Frontiers in immunology 20170830

Resolution agonists, including lipid mediators and peptides such as annexin A1 (ANXA1), are providing novel approaches to treat inflammatory conditions. Surgical trauma exerts a significant burden on the immune system that can affect and impair multiple organs. Perioperative cerebral injury after cardiac surgery is associated with significant adverse neurological outcomes such as delirium and postoperative cognitive dysfunction. Using a clinically relevant rat model of cardiopulmonary bypass (CP ...[more]

PMID: 28912778

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Project description:Cardiac surgery, especially when employing cardiopulmonary bypass and deep hypothermic circulatory arrest, is associated with systemic inflammatory responses that significantly affect morbidity and mortality. Intestinal perfusion abnormalities have been implicated in such responses, but the mechanisms linking local injury and systemic inflammation remain unclear. Intestinal mast cells are specialized immune cells that secrete various preformed effectors in response to cellular stress. We hypothesized that mast cells are activated in a microenvironment shaped by intestinal ischemia/reperfusion, and investigated local and systemic consequences.Rat model of deep hypothermic circulatory arrest.University research laboratory.Twelve- to 14-week-old male Sprague-Dawley rats.Rats were anesthetized and cooled to 16°C to 18°C on cardiopulmonary bypass before instituting deep hypothermic circulatory arrest for 45 minutes. Specimens were harvested following rewarming and 2 hours of recovery.Significant intestinal barrier disruption was found, together with macro- and microscopic evidence of ischemia/reperfusion injury in ileum and colon, but not in the lungs or kidneys. Immunofluorescence and toluidine blue staining revealed increased numbers of mast cells and their activation in the gut. In animals pretreated with the mast cell stabilizer, cromolyn sodium, mast cell degranulation was blocked, and intestinal morphology and barrier function were preserved following deep hypothermic circulatory arrest. Furthermore, cromolyn sodium treatment was associated with reduced intestinal neutrophil influx and blunted systemic release of proinflammatory cytokines.Our data provide primary evidence that intestinal ischemia/reperfusion is a leading pathophysiologic process in a rat model of deep hypothermic circulatory arrest, and that intestinal injury, and local and systemic inflammatory responses are critically dependent on mast cell activation. This identifies intestinal mast cells as central players in deep hypothermic circulatory arrest-associated responses, and opens novel therapeutic possibilities for patients undergoing this procedure.

Project description:BackgroundThis study aimed to evaluate whether the use of mild hypothermic circulatory arrest (HCA) with selective cerebral perfusion (SCP) in open arch procedure provides comparable perioperative results to moderate HCA for patients with dissected or degenerative arch pathologies.MethodsBetween January 2017 and September 2020, a total of 88 consecutive patients (mean age 47±11 years, 71 males) underwent open arch repair under a single surgeon at our institution with mild or moderate systemic hypothermia assisted by unilateral or bilateral SCP. Patients were divided into groups according to the nasopharyngeal temperature at the beginning of HCA: a moderate HCA group (n=47, 53.4%) and a mild HCA group (n=41, 46.6%). The postoperative mortality, morbidity, and visceral organ functions between these groups were analyzed retrospectively.ResultsCompared to the moderate HCA group, the mild HCA group had a significantly higher core temperature (nasopharynx: 24.4±0.8 vs. 28.5±2, P<0.001; bladder 25.9±0.9 vs. 30±1.2, P<0.001), and the incidence of major adverse events (MAE) in this group was markedly lower (21.3% vs. 4.9%, P=0.031). No differences were identified between the two groups refer to in-hospital mortality, permanent neurological deficit (PND), temporary neurological deficit (TND), and paraplegia (8.5% vs. 2.4%, P=0.366; 8.5% vs. 0, P=0.120; 6.4% vs. 7.3%, P=1.0; 4.3% vs. 2.4%, P=1.0, respectively). In the moderate HCA group, 6 patients (12.8%) developed acute renal failure needing replacement therapy, which did not occur in the mild HCA group (P=0.028). The duration of ventilator support and intensive care unit stay was shorter in the mild HCA group, as well as a decreased volume of drainage during the first 24 h and reduced platelet transfusion.ConclusionsThe preliminary results of the mild HCA group with SCP applied in open arch repair, mainly in total arch replacement (TAR) and stented elephant trunk (SET) implantation for aortic dissection, were satisfactory. Furthermore, comparable inferior outcomes were obtained with mild HCA compared with that of the conventional moderate HCA strategy. These encouraging surgical and postoperative results favor this more aggressive hypothermia strategy in open arch repair.

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Neuroprotective Effects of Annexin A1 Tripeptide after Deep Hypothermic Circulatory Arrest in Rats.

Publications

Neuroprotective Effects of Annexin A1 Tripeptide after Deep Hypothermic Circulatory Arrest in Rats.

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