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Functional recovery and survival rates after cardiac arrest and cardiopulmonary resuscitation (CA/CPR) in young and aged mice. A through C, Aged mice exhibited worse functional recovery after CA/ CPR compared with young mice. Assessments of neurologic score (A), rotarod (B), and spontaneous locomotor activity (10-minute period; C) were performed on day 1 after CA/CPR. D, Survival rates during the first 3 days after CA/CPR. n=7 per group. *P<0.05.
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Background
The mechanisms underlying worse outcome at advanced age after cardiac arrest (CA) and resuscitation are not well understood. Because protein homeostasis (proteostasis) is essential for cellular and organismal health, but is impaired after CA, we investigated the effects of age on proteostasis‐related prosurvival pathways activated after...
Contexts in source publication
Context 1
... After 8.5 minutes CA, 3 mice (1 in 8 young and 2 in 9 aged mice) were not successfully resuscitated and, therefore, excluded. During the 3-day observation, 40% of aged mice died, whereas all young mice survived ( Figure 1). Thus, functional recovery was evaluated only at 24 hours after surgery, when all experimental mice were still alive ( Figure 1). ...
Context 2
... the 3-day observation, 40% of aged mice died, whereas all young mice survived ( Figure 1). Thus, functional recovery was evaluated only at 24 hours after surgery, when all experimental mice were still alive ( Figure 1). In all behavioral tests (neurologic score, rotarod, and spontaneous locomotor activity), aged mice exhibited significantly worse performance compared with young mice ( Figure 1A-C). ...
Context 3
... functional recovery was evaluated only at 24 hours after surgery, when all experimental mice were still alive ( Figure 1). In all behavioral tests (neurologic score, rotarod, and spontaneous locomotor activity), aged mice exhibited significantly worse performance compared with young mice ( Figure 1A-C). On day 3 after CA, survived mice were analyzed for brain and kidney damage. ...
Citations
... Metabolic interventions HBP Glucose Increase [7,8] Glutamine Increase [9,10] Glucosamine Increase [22,23] N-acetylglucosamine Increase [15,16] Pharmacological interventions GFAT DON Decrease [24,25] Azaserine Decrease [9,26] OGT Alloxan Decrease [21,27] Ac 4 -5SGlcNAc Decrease [28,29] ST045849 Decrease [30,31] OSMI-1, − 2, − 3, and − 4 Decrease [32,33] OGA STZ Increase [34,35] PUGNAc Increase [36,37] NButGT Increase [38,39] GlcNAcstatin Increase [40,41] NAG-thiazoline Increase [42,43] thiamet G Increase [44,45] Genetic interventions OGT siRNA Decrease [46,47] Adenoviral overexpression Increase [46,47] Transgenic mouse models Increase [48] OGA siRNA Increase [49,50] Adenoviral overexpression Decrease [47,51] Transgenic mouse models Decrease [48] for functional studies on HBP/O-GlcNAcylation are listed in Table 1. ...
... In a transient forebrain ischaemia model, Liu et al. analysed the activation of proteostasis-related pathways in young and aged mice and found that the most prominent change in the ageing brain was the inactivation of the O-GlcNAc modification, suggesting that this pathway might be a promising target for stroke therapy [132]. In addition to the brain, impaired age-related activation of O-GlcNAcylation has also been confirmed in the kidney and spinal cord after cardiac arrest and cardiopulmonary resuscitation (CA/CPR) [45], signifying the importance of O-GlcNAcylation as a potential mechanism underlying the impairment of functional recovery in ageing organs/tissues in response to ischaemic challenge. LC-MS/MS analysis showed that the availability of UDP-GlcNAc in the aged brain was impaired both at baseline and after I/R, while metabolic intervention with glucosamine significantly improved the acute outcomes in young and elderly mice [130]. ...
O-GlcNAcylation is a unique monosaccharide modification that is ubiquitously present in numerous nucleoplasmic and mitochondrial proteins. The hexosamine biosynthesis pathway (HBP), which is a key branch of glycolysis, provides the unique sugar donor UDP-GlcNAc for the O-GlcNAc modification. Thus, HBP/O-GlcNAcylation can act as a nutrient sensor to perceive changes in nutrient levels and trigger O-GlcNAc modifications of functional proteins in cellular (patho-)physiology, thereby regulating diverse metabolic processes. An imbalance in O-GlcNAcylation has been shown to be a pathogenic contributor to dysfunction in metabolic diseases, including type 2 diabetes, cancer, and neurodegeneration. However, under acute stress conditions, protein O-GlcNAc modification exhibits rapid and transient upregulation, which is strongly correlated with stress tolerance and cell survival. In this context, we discuss the metabolic, pharmacological and genetic modulation of HBP/O-GlcNAc modification in the biological system, the beneficial role of O-GlcNAcylation in regulating stress tolerance for cardioprotection, and neuroprotection, which is a novel and rapidly growing field. Current evidence suggests that transient activation of the O-GlcNAc modification represents a potent pro-survival signalling pathway and may provide a promising strategy for stress-related disorder therapy.
... The consequence is a reduction in ER workload, which facilitates the restoration of ER homeostasis. An increase in phosphorylated eIF2α (p-eIF2α) and protein synthesis inhibition (PSI) has been found in the ischemic brain [21][22][23]. However, this observation alone does not necessarily indicate that the PERK branch is the cause of stroke-induced PSI, because four kinases-GCN2, PKR, HRI, and PERK-have been identified as eIF2α kinases [8]. ...
Many pathologic states can lead to the accumulation of unfolded/misfolded proteins in cells. This causes endoplasmic reticulum (ER) stress and triggers the unfolded protein response (UPR), which encompasses three main adaptive branches. One of these UPR branches is mediated by protein kinase RNA-like ER kinase (PERK), an ER stress sensor. The primary consequence of PERK activation is the suppression of global protein synthesis, which reduces ER workload and facilitates the recovery of ER function. Ischemic stroke induces ER stress and activates the UPR. Studies have demonstrated the involvement of the PERK pathway in stroke pathophysiology; however, its role in stroke outcomes requires further clarification. Importantly, considering mounting evidence that supports the therapeutic potential of the PERK pathway in aging-related cognitive decline and neurodegenerative diseases, this pathway may represent a promising therapeutic target in stroke. Therefore, in this review, our aim is to discuss the current understanding of PERK in ischemic stroke, and to summarize pharmacologic tools for translational stroke research that targets PERK and its associated pathways.
... Neurologic dysfunction was evaluated by a 9-point scoring system (Shen et al., 2018). Mice were scored based on their performance on the vertical screen, horizontal bar, and rope (0-3 points for each test), and then the overall neurologic score was obtained. ...
... More and longer time points for detection, like 7 and 14 days after ROSC, are needed to verify the prolonged treatment effects of AA147 for CA. Thirdly, worse post-CA neurological outcomes comes to aged mice (Shen et al., 2018), so the proposed drug dose of AA147 should vary in different age groups. The effects of AA147 on aged mice subjected to CA are also necessary to be elucidated. ...
Ischemia/reperfusion caused by cardiac arrest (CA) disturbs endoplasmic reticulum (ER) homeostasis and redox balance in neurons. AA147, originally developed as a pharmacologic activator of the activating transcription factor 6 (ATF6), can protect multiple tissues from ischemia/reperfusion injury (IRI) by decreasing reactive oxygen species (ROS) and restoring ER function. However, it is unclear whether pharmacologic treatment of AA147 could ameliorate post-CA cerebral IRI and whether it is associated with proteostasis regulation and anti-oxidative stress mechanism. In the present study, mice were subjected to 9 min-CA surgery followed by cardiopulmonary resuscitation (CPR). AA147 or vehicle was administered 1 day before the operation and 15 min after the return of spontaneous circulation. We found that AA147 restored neurological function and reduced dead neurons in mice suffering from CA. Moreover, AA147 inhibited CA/CPR-caused neuronal apoptosis and ER stress, indicated by reduced TUNEL-positive neurons, surged expression of Bcl-2/Bax, and down expression of cleaved caspase-3, caspase-12, C/EBP homologous protein (CHOP). The expression of ATF6 and its regulated gene glucose-regulated protein 78 (GRP78) increased significantly after the administration of AA147, suggesting the activation of the ATF6 pathway. In addition, AA147 also alleviated the upsurge of the ROS generation and MDA levels as well as increased SOD activity, accompanied by enhancement of the nuclear factor E2-related factor 2 (Nrf2) and its modulated heme-oxygenase-1 (HO-1) expressions. Cotreatment of AA147 with inhibitors of the ATF6 or Nrf2 significantly suppressed AA147-dependent reductions in ROS scavenging and neuronal death after CA/CPR. The results suggested that AA147 could confer neuroprotection against post-CA cerebral IRI through inhibition of oxidative stress along with ER stress-associated apoptosis, which is attributed to the coregulation of both ATF6 and Nrf2 signaling pathways activity. Our findings support the potential for AA147 as a therapeutic approach to improve post-CA brain injury.
... Such a decrease in O-GlcNAcylation suggests a shift away from non-oxidative glucose metabolism in the heart. Conversely, excessive protein O-GlcNAcylation is observed in multiple organs with increasing age in rat and mouse models, contributing to adverse clinical outcomes (35,36). For example, young mice subjected to cardiac arrest and resuscitation displayed increased unfolded protein response pathways and post-translational modifications including O-GlcNAcylation, which corresponded with improved recovery not observed in aged animals (36,37). ...
... Conversely, excessive protein O-GlcNAcylation is observed in multiple organs with increasing age in rat and mouse models, contributing to adverse clinical outcomes (35,36). For example, young mice subjected to cardiac arrest and resuscitation displayed increased unfolded protein response pathways and post-translational modifications including O-GlcNAcylation, which corresponded with improved recovery not observed in aged animals (36,37). The most accepted rationale behind this increase is the gradual shift into cellular senescence during the aging process and the subsequent decline of proteostasis (35,36). ...
... For example, young mice subjected to cardiac arrest and resuscitation displayed increased unfolded protein response pathways and post-translational modifications including O-GlcNAcylation, which corresponded with improved recovery not observed in aged animals (36,37). The most accepted rationale behind this increase is the gradual shift into cellular senescence during the aging process and the subsequent decline of proteostasis (35,36). ...
The heart is a highly metabolic organ with extensive energy demands and hence relies on numerous fuel substrates including fatty acids and glucose. However, oxidative stress is a natural by-product of metabolism that, in excess, can contribute towards DNA damage and poly-ADP-ribose polymerase activation. This activation inhibits key glycolytic enzymes, subsequently shunting glycolytic intermediates into non-oxidative glucose pathways such as the hexosamine biosynthetic pathway (HBP). In this review we provide evidence supporting the dual role of the HBP, i.e. playing a unique role in cardiac physiology and pathophysiology where acute upregulation confers cardioprotection while chronic activation contributes to the onset and progression of cardio-metabolic diseases such as diabetes, hypertrophy, ischemic heart disease, and heart failure. Thus although the HBP has emerged as a novel therapeutic target for such conditions, proposed interventions need to be applied in a context- and pathology-specific manner to avoid any potential drawbacks of relatively low cardiac HBP activity.
... The total score was calculated by adding 4 individual scores, where 0 equals to no deficit and 48 equals to maximal deficit. Moreover, rotarod and open field tests were also performed to evaluate stroke outcomes, as we described previously [19,20]. In brief, mice were placed on an accelerating rotating rod (Med Associates Inc., St Albans, VT, USA) to perform the rotarod test, and the data were recorded. ...
The cerebral ischemic microvascular response and collateral circulation compensatory capacity are important for the outcome of ischemic stroke. Here, we sought to evaluate the effect of a linarin derivate 4 ′ -benzylapigenin-7-β-rutinoside (BLR) on neurological function and cerebral blood flow restoration in ischemic stroke. A mouse model of middle cerebral artery occlusion (30 min) with reperfusion (24 h) was used to mimic ischemic stroke in vivo, and 2,3,5-triphenyltetrazolium chloride (TTC) staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays, and immunofluorescence microscopy were used to assess the protective effects of BLR on infarct volume, neurological function, neuronal apoptosis, and inflammatory damage. Cerebral blood flow was assayed by laser speckle contrast imaging. Double immunostaining of GFAP-collagen IV and brain lucidification were performed to determine the protective effects of BLR on the disruption of brain vasculature. Differential gene expression was assessed by RNA sequencing. Coimmunoprecipitation and western blotting were used to explore the mechanism of BLR-induced neuroprotection. The results of in vivo experiments showed that BLR administration after reperfusion onset reduced infarct volume, improved neurological function, and decreased the neural cell apoptosis and inflammatory response in the ischemic brain, which was accompanied by increased cerebral blood flow and reduced detachment of astrocyte endfeet from the capillary basement membrane. The RNA sequencing data showed that BLR promoted the upregulation of extracellular matrix and angiogenesis pathway-related genes; in particular, BLR significantly increased the expression of the chondroitin sulfate proteoglycan 4 (CSPG4) gene, enhanced the membrane location of CSPG4, and promoted its downstream signaling protein expression, which is associated with KDEL receptor (KDELR) activation. In addition, activated KDELR further increased the phosphorylation of mitogen-activated protein kinases after BLR treatment. Taken together, our data showed that BLR could protect against ischemic brain injury and may serve as a new promising therapeutic candidate drug for ischemic stroke, and that KDELR might act as both a sensor and effector to activate CSPG4 to increase cerebral blood flow.
... Then, a PE-10 tube for mice or silicone tube for rats was placed. After 15 min of physiological stabilization, cardiac arrest (CA) was induced by solution of potassium chloride (KCl) as described previously [39,40]. In brief, 300 µL or 5 mL venous blood was withdrawn from the jugular vein in mice or rats into the heparin syringe. ...
Introduction Cardiac arrest (CA) and resuscitation induces global cerebral ischemia and reperfusion, causing neurologic deficits or death. Manganese porphyrins, superoxide dismutase mimics, are reportedly able to effectively reduce ischemic injury in brain, kidney, and other tissues. This study evaluates the efficacy of a third generation lipophilic Mn porphyrin, MnTnBuOE-2-PyP5+, Mn(III) ortho meso-tetrakis (N-n-butoxyethylpyridinium-2-yl)porphyrin (MnBuOE, BMX-001), in both mouse and rat models of CA. Methods Forty-eight animals were subjected to 8 min of CA and resuscitated subsequently by chest compression and epinephrine infusion. Vehicle or MnBuOE was given immediately after resuscitation followed by daily subcutaneous injections. Body weight, spontaneous activity, neurologic deficits, rotarod performance, and neuronal death were assessed. Kidney tubular injury was assessed in CA mice. Data were collected by the investigators who were blinded to the treatment groups. Results Vehicle mice had a mortality of 20%, which was reduced by 50% by MnBuOE. All CA mice had body weight loss, spontaneous activity decline, neurologic deficits, and decreased rotarod performance that were significantly improved at three days post MnBuOE daily treatment. MnBuOE treatment reduced cortical neuronal death and kidney tubular injury in mice (p < 0.05) but not hippocampus neuronal death (23% MnBuOE vs. 34% vehicle group, p = 0.49). In rats, they had a better body-weight recovery and increased rotarod latency after MnBuOE treatment when compared to vehicle group (p < 0.01 vs. vehicle). MnBuOE-treated rats had a low percentage of hippocampus neuronal death (39% MnBuOE vs. 49% vehicle group, p = 0.21) and less tubular injury (p < 0.05) relative to vehicle group. Conclusions We demonstrated the ability of MnBuOE to improve post-CA survival, as well as functional outcomes in both mice and rats, which jointly account for the improvement not only of brain function but also of the overall wellbeing of the animals. While MnBuOE bears therapeutic potential for treating CA patients, the females and the animals with comorbidities must be further evaluated before advancing toward clinical trials.
... All experimental animals were randomly divided into groups using Quickcalcs. CA/CPR operation was performed as previously described (28)(29)(30)(31). In brief, after tracheal intubation, 1.5% isoflurane was given to maintain anesthesia before cardiac arrest. ...
Background
Cardiac arrest/cardiopulmonary resuscitation (CA/CPR) represents one of the devastating medical emergencies and is associated with high mortality and neuro-disability. Post-cardiac arrest syndrome (PCAS) is mechanistically ascribed to acute systemic ischemia/reperfusion(I/R) injury. The lncRNA/microRNA/mRNA networks have been found to play crucial roles in the pathogenesis of the hypoxia-responsive diseases. Nonetheless, the precise molecular mechanisms by which lncRNA/miRNA/mRNA axes are involved in the astrocyte–microglia crosstalk in CA/CPR have not been fully elucidated.
Methods
We collected and purified the exosomes from the blood of CA/CPR patients and supernatant of OGD/R-stimulated astrocytes. On the basis of microarray analysis, bioinformatic study, and luciferase activity determination, we speculated that lncRNA GAS5/miR-137 is implicated in the astrocyte–microglia crosstalk under the insult of systemic I/R injury. The regulation of lncRNA GAS5/miR-137 on INPP4B was examined by cellular transfection in OGD/R cell culture and by lateral ventricle injection with miR-137 agomir in CA/CPR mice model. Flow cytometry and immunofluorescence staining were performed to detect the microglial apoptosis, M1/M2 phenotype transformation, and neuroinflammation. Neurological scoring and behavior tests were conducted in CA/CPR group, with miR-137 agomir lateral-ventricle infusion and in their controls.
Results
In all the micRNAs, miR-137 was among the top 10 micRNAs that experienced greatest changes, in both the blood of CA/CPR patients and supernatant of OGD/R-stimulated astrocytes. Bioinformatic analysis revealed that miR-137 was sponged by lncRNA GAS5, targeting INPP4B, and the result was confirmed by Luciferase activity assay. qRT-PCR and Western blotting showed that lncRNA GAS5 and INPP4B were over-expressed whereas miR-137 was downregulated in the blood of CA/CPR patients, OGD/R-stimulated astrocytes, and brain tissue of CA/CPR mice. Silencing lncRNA GAS5 suppressed INPP4B expression, but over-expression of miR-137 negatively modulated its expression. Western blotting exhibited that PI3K and Akt phosphorylation was increased when lncRNA GAS5 was silenced or miR-137 was over-expressed. However, PI3K and Akt phosphorylation was notably suppressed in the absence of miR-137, almost reversing their phosphorylation in the silencing lncRNA GAS5 group. Then we found that GAS5 siRNA or miR-137 mimic significantly increased cell viability and alleviated apoptosis after OGD/R injury. Furthermore, over-expression of miR-137 attenuated microglial apoptosis and neuroinflammation in CA/CPR mice model, exhibiting significantly better behavioral tests after CA/CPR.
Conclusion
LncRNA GAS5/miR-137 may be involved in the astrocyte–microglia communication that inhibits PI3K/Akt signaling activation via regulation of INPP4B during CA/CPR.
... In mouse models of forebrain ischemia/reperfusion or cardiac arrest/resuscitation, a transient elevation in O-GlcNAc modification can be seen in the cortex or hippocampus, suggesting the activation of an endogenous stress response pathway [8,37]. By comparison, the O-GlcNAc modification level of cortical neurons induced by OGD/R increases only slightly, indicating an impaired ability of neurons to activate this pro-survival pathway ( Figure 6A,B). ...
O-GlcNAcylation is a nutrient-driven post-translational modification known as a metabolic sensor that links metabolism to cellular function. Recent evidences indicate that the activation of O-GlcNAc pathway is a potential pro-survival pathway and that acute enhancement of this response is conducive to the survival of cells and tissues. 2-(4-methoxyphenyl)ethyl-2-acetamido-2-deoxy-β-d-pyranoside (SalA-4g), is a salidroside analogue synthesized in our laboratory by chemical structure-modification, with a phenyl ring containing a para-methoxy group and a sugar ring consisting of N-acetylglucosamine. We have previously shown that SalA-4g elevates levels of protein O-GlcNAc and improves neuronal tolerance to ischemia. However, the specific target of SalA-4g regulating O-GlcNAcylation remains unknown. To address these questions, in this study, we have focused on mitochondrial network homeostasis mediated by O-GlcNAcylation in SalA-4g’s neuroprotection in primary cortical neurons under ischemic-like conditions. O-GlcNAc-modified mitochondria induced by SalA-4g demonstrated stronger neuroprotection under oxygen glucose deprivation and reoxygenation stress, including the improvement of mitochondrial homeostasis and bioenergy, and inhibition of mitochondrial apoptosis pathway. Blocking mitochondrial protein O-GlcNAcylation with OSMI-1 disrupted mitochondrial network homeostasis and antagonized the protective effects of SalA-4g. Collectively, these data demonstrate that mitochondrial homeostasis mediated by mitochondrial protein O-GlcNAcylation is critically involved in SalA-4g neuroprotection.
... It has been well established that CA causes ER stress, and activates the UPR in various organs including the brain. 5,13,14 However, unlike the PERK and IRE1 UPR branches, the ATF6 branch appears to not be activated in the postischemic brain, [13][14][15] which may confer brain cells less resistant to proteotoxic stress caused by ischemic insult. Notably, the ATF6 branch has been extensively studied in the heart. ...
... It has been well established that CA causes ER stress, and activates the UPR in various organs including the brain. 5,13,14 However, unlike the PERK and IRE1 UPR branches, the ATF6 branch appears to not be activated in the postischemic brain, [13][14][15] which may confer brain cells less resistant to proteotoxic stress caused by ischemic insult. Notably, the ATF6 branch has been extensively studied in the heart. ...
... CA/cardiopulmonary resuscitation (CPR) surgery was performed as described previously. 13,19 Briefly, anesthesia was induced with 5% isoflurane. After endotracheal intubation, mice were maintained on 1.5% to 1.7% isoflurane before CA induction. ...
Background
Ischemia/reperfusion injury impairs proteostasis, and triggers adaptive cellular responses, such as the unfolded protein response (UPR), which functions to restore endoplasmic reticulum homeostasis. After cardiac arrest (CA) and resuscitation, the UPR is activated in various organs including the brain. However, the role of the UPR in CA has remained largely unknown. Here we aimed to investigate effects of activation of the ATF6 (activating transcription factor 6) UPR branch in CA.
Methods and Results
Conditional and inducible sATF6‐KI (short‐form ATF6 knock‐in) mice and a selective ATF6 pathway activator 147 were used. CA was induced in mice by KCl injection, followed by cardiopulmonary resuscitation. We first found that neurologic function was significantly improved, and neuronal damage was mitigated after the ATF6 pathway was activated in neurons of sATF6‐KI mice subjected to CA/cardiopulmonary resuscitation. Further RNA sequencing analysis indicated that such beneficial effects were likely attributable to increased expression of pro‐proteostatic genes regulated by ATF6. Especially, key components of the endoplasmic reticulum–associated degradation process, which clears potentially toxic unfolded/misfolded proteins in the endoplasmic reticulum, were upregulated in the sATF6‐KI brain. Accordingly, the CA‐induced increase in K48‐linked polyubiquitin in the brain was higher in sATF6‐KI mice relative to control mice. Finally, CA outcome, including the survival rate, was significantly improved in mice treated with compound 147.
Conclusions
This is the first experimental study to determine the role of the ATF6 UPR branch in CA outcome. Our data indicate that the ATF6 UPR branch is a prosurvival pathway and may be considered as a therapeutic target for CA.
... Three days after CA/CPR, behavioral tests were performed by experimenters who were blinded to group assignments, whenever possible. 16,17 Open Field Mice were gently placed into a square arena (50×50 cm; CleverSys, Reston, VA) and allowed to move freely. Spontaneous locomotor activity was Downloaded from http://ahajournals.org by on May 20, 2021 recorded for 10 minutes, with a 10-second delay. ...
Background
Animal disease models represent the cornerstone in basic cardiac arrest (CA) research. However, current experimental models of CA and resuscitation in mice are limited. In this study, we aimed to develop a mouse model of asphyxial CA followed by cardiopulmonary resuscitation (CPR), and to characterize the immune response after asphyxial CA/CPR.
Methods and Results
CA was induced in mice by switching from an O 2 /N 2 mixture to 100% N 2 gas for mechanical ventilation under anesthesia. Real‐time measurements of blood pressure, brain tissue oxygen, cerebral blood flow, and ECG confirmed asphyxia and ensuing CA. After a defined CA period, mice were resuscitated with intravenous epinephrine administration and chest compression. We subjected young adult and aged mice to this model, and found that after CA/CPR, mice from both groups exhibited significant neurologic deficits compared with sham mice. Analysis of post‐CA brain confirmed neuroinflammation. Detailed characterization of the post‐CA immune response in the peripheral organs of both young adult and aged mice revealed that at the subacute phase following asphyxial CA/CPR, the immune system was markedly suppressed as manifested by drastic atrophy of the spleen and thymus, and profound lymphopenia. Finally, our data showed that post‐CA systemic lymphopenia was accompanied with impaired T and B lymphopoiesis in the thymus and bone marrow, respectively.
Conclusions
In this study, we established a novel validated asphyxial CA model in mice. Using this new model, we further demonstrated that asphyxial CA/CPR markedly affects both the nervous and immune systems, and notably impairs lymphopoiesis of T and B cells.
