scholarly journals Sustained peripheral immune hyper-reactivity (SPIHR): an enduring biomarker of altered inflammatory responses in adult rats after perinatal brain injury

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Yuma Kitase ◽  
Eric M. Chin ◽  
Sindhu Ramachandra ◽  
Christopher Burkhardt ◽  
Nethra K. Madurai ◽  
...  
Keyword(s):  
Cerebral Palsy ◽  
Brain Injury ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Serum Levels ◽  
In Utero ◽  
Cell Populations ◽  
Perinatal Brain Injury ◽  
Chemokine Ligand ◽  
Immune Changes

Abstract Background Chorioamnionitis (CHORIO) is a principal risk factor for preterm birth and is the most common pathological abnormality found in the placentae of preterm infants. CHORIO has a multitude of effects on the maternal–placental–fetal axis including profound inflammation. Cumulatively, these changes trigger injury in the developing immune and central nervous systems, thereby increasing susceptibility to chronic sequelae later in life. Despite this and reports of neural–immune changes in children with cerebral palsy, the extent and chronicity of the peripheral immune and neuroinflammatory changes secondary to CHORIO has not been fully characterized. Methods We examined the persistence and time course of peripheral immune hyper-reactivity in an established and translational model of perinatal brain injury (PBI) secondary to CHORIO. Pregnant Sprague–Dawley rats underwent laparotomy on embryonic day 18 (E18, preterm equivalent). Uterine arteries were occluded for 60 min, followed by intra-amniotic injection of lipopolysaccharide (LPS). Serum and peripheral blood mononuclear cells (PBMCs) were collected at young adult (postnatal day P60) and middle-aged equivalents (P120). Serum and PBMCs secretome chemokines and cytokines were assayed using multiplex electrochemiluminescent immunoassay. Multiparameter flow cytometry was performed to interrogate immune cell populations. Results Serum levels of interleukin-1β (IL-1β), IL-5, IL-6, C–X–C Motif Chemokine Ligand 1 (CXCL1), tumor necrosis factor-α (TNF-α), and C–C motif chemokine ligand 2/monocyte chemoattractant protein-1 (CCL2/MCP-1) were significantly higher in CHORIO animals compared to sham controls at P60. Notably, CHORIO PBMCs were primed. Specifically, they were hyper-reactive and secreted more inflammatory mediators both at baseline and when stimulated in vitro. While serum levels of cytokines normalized by P120, PBMCs remained primed, and hyper-reactive with a robust pro-inflammatory secretome concomitant with a persistent change in multiple T cell populations in CHORIO animals. Conclusions The data indicate that an in utero inflammatory insult leads to neural–immune changes that persist through adulthood, thereby conferring vulnerability to brain and immune system injury throughout the lifespan. This unique molecular and cellular immune signature including sustained peripheral immune hyper-reactivity (SPIHR) and immune cell priming may be a viable biomarker of altered inflammatory responses following in utero insults and advances our understanding of the neuroinflammatory cascade that leads to perinatal brain injury and later neurodevelopmental disorders, including cerebral palsy.

scholarly journals The Role of Extracellular Vesicles in the Developing Brain: Current Perspective and Promising Source of Biomarkers and Therapy for Perinatal Brain Injury

2021 ◽  
Vol 15 ◽  
Author(s):  
Teena K. J. B. Gamage ◽  
Mhoyra Fraser
Keyword(s):  
Stem Cell ◽  
Brain Injury ◽  
Extracellular Vesicles ◽  
Inflammatory Responses ◽  
Brain Structures ◽  
Developing Brain ◽  
Long Term Effects ◽  
Perinatal Brain Injury ◽  
Current Perspective ◽  
Promising Source

This comprehensive review focuses on our current understanding of the proposed physiological and pathological functions of extracellular vesicles (EVs) in the developing brain. Furthermore, since EVs have attracted great interest as potential novel cell-free therapeutics, we discuss advances in the knowledge of stem cell- and astrocyte-derived EVs in relation to their potential for protection and repair following perinatal brain injury. This review identified 13 peer-reviewed studies evaluating the efficacy of EVs in animal models of perinatal brain injury; 12/13 utilized mesenchymal stem cell-derived EVs (MSC-EVs) and 1/13 utilized astrocyte-derived EVs. Animal model, method of EV isolation and size, route, timing, and dose administered varied between studies. Notwithstanding, EV treatment either improved and/or preserved perinatal brain structures both macroscopically and microscopically. Additionally, EV treatment modulated inflammatory responses and improved brain function. Collectively this suggests EVs can ameliorate, or repair damage associated with perinatal brain injury. These findings warrant further investigation to identify the optimal cell numbers, source, and dosage regimens of EVs, including long-term effects on functional outcomes.

scholarly journals Neonatal Functional and Structural Connectivity Are Associated with Cerebral Palsy at Two Years of Age

2019 ◽  
Vol 37 (02) ◽  
pp. 137-145
Author(s):  
Stephanie L. Merhar ◽  
Elveda Gozdas ◽  
Jean A. Tkach ◽  
Nehal A. Parikh ◽  
Beth M. Kline-Fath ◽  
...  
Keyword(s):  
Cerebral Palsy ◽  
Brain Injury ◽  
Functional Connectivity ◽  
Diffusion Tensor ◽  
Structural Connectivity ◽  
Motor Task ◽  
Structural Mri ◽  
Perinatal Brain Injury ◽  
The Right ◽  
Almost All

Objective The accuracy of structural magnetic resonance imaging (MRI) to predict later cerebral palsy (CP) in newborns with perinatal brain injury is variable. Diffusion tensor imaging (DTI) and task-based functional MRI (fMRI) show promise as predictive tools. We hypothesized that infants who later developed CP would have reduced structural and functional connectivity as compared with those without CP. Study Design We performed DTI and fMRI using a passive motor task at 40 to 48 weeks' postmenstrual age in 12 infants with perinatal brain injury. CP was diagnosed at age 2 using a standardized examination. Results Five infants had CP at 2 years of age, and seven did not have CP. Tract-based spatial statistics showed a widespread reduction of fractional anisotropy (FA) in almost all white matter tracts in the CP group. Using the median FA value in the corticospinal tracts as a cutoff, FA was 100% sensitive and 86% specific to predict CP compared with a sensitivity of 60 to 80% and a specificity of 71% for structural MRI. During fMRI, the CP group had reduced functional connectivity from the right supplemental motor area as compared with the non-CP group. Conclusion DTI and fMRI obtained soon after birth are potential biomarkers to predict CP in newborns with perinatal brain injury.

Connecting chloride transporter impairment following perinatal brain injury to cerebral palsy

2020 ◽  
pp. 405-430
Author(s):  
Jessie C. Newville ◽  
Akosua Y. Oppong ◽  
Shenandoah Robinson ◽  
Lauren L. Jantzie
Keyword(s):  
Cerebral Palsy ◽  
Brain Injury ◽  
Perinatal Brain Injury

scholarly journals In utero and early-life exposure to thirdhand smoke causes profound changes to the immune system

2021 ◽  
Author(s):  
Antoine M Snijders ◽  
Mi Zhou ◽  
Todd P Whitehead ◽  
Briana Fitch ◽  
Priyatama Pandey ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Immune System ◽  
B Cell ◽  
Early Life ◽  
Immune Cell ◽  
Lymphoblastic Leukemia ◽  
In Utero ◽  
Cell Populations ◽  
Thirdhand Smoke ◽  
Knockout Mouse Model

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Thirdhand smoke (THS) is the residual tobacco contamination that remains after the smoke clears. We investigated the effects of THS exposure in utero and during early life in a transgenic Cdkn2a knockout mouse model that is vulnerable to the development of leukemia/lymphoma. Female mice, and their offspring, were exposed from the first day of pregnancy to weaning. Plasma cytokines, body weight and hematologic parameters were measured in the offspring. To investigate THS exposure effects on the development of leukemia/lymphoma, bone marrow was collected from control and THS-exposed mice and transplanted into bone-marrow-ablated recipient mice, which were followed for tumor development for one year. We found that in utero and early life THS exposure caused significant changes in plasma cytokine concentrations and in immune cell populations; changes appeared more pronounced in male mice. Spleen and bone marrow B-cell populations were significantly lower in THS-exposed mice. We furthermore observed that THS exposure increased the leukemia/lymphoma-free survival in bone marrow transplantation recipient mice, potentially caused by THS-induced B cell toxicity. A trend towards increased solid tumors in irradiated mice reconstituted with THS exposed bone marrow stimulates the hypothesis that the immunosuppressive effects of in utero and early-life THS exposure might contribute to carcinogenesis by lowering the host defense to other toxic exposures. Our study adds to expanding evidence that THS exposure alters the immune system and that in utero and early life developmental periods represent vulnerable windows of susceptibility for these effects.

scholarly journals Punicalagin alleviates brain injury and inflammatory responses, and regulates HO-1/Nrf-2/ARE signaling in rats after experimental intracerebral haemorrhage

2020 ◽  
Vol 19 (4) ◽  
pp. 727-737
Author(s):  
Fuchi Zhang ◽  
Kang Wu ◽  
Xiaolin Wu ◽  
Can Xin ◽  
Minghui Zhou ◽  
...  
Keyword(s):  
Brain Injury ◽  
Signaling Pathway ◽  
Intracerebral Haemorrhage ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Cell Damage ◽  
Neuroprotective Effect ◽  
Serum Levels ◽  
Underlying Mechanism ◽  
Sprague Dawley

Purpose: To investigate the effect of punicalagin, an ellagitannin present in pomegranates, on intracerebral haemorrhage (ICH)-induced inflammatory responses and oxidative stress, and also unravel the underlying mechanism(s) of action. Methods: Collagenase type IV (0.2 U) was used to induce ICH in adult male Sprague-Dawley rats. Punicalagin was given to the rats at doses of 25, 50, and 75 mg/kg body weight via oral gavage for 15 days before ICH induction. The animals were sacrificed 24h following induction of ICH, and their brains were excised immediately and used for analysis. Histological changes were determined with Haematoxylin and Eosin (H&E) staining. Permeability to blood-brain barrier (BBB) was determined by quantifying the extent of extravasation of Evan Blue (EB). Protein expressions of HO-1/Nrf-2/ARE and NF-κB signaling were assayed using immunoblotting and RT-PCR. Levels of reactive oxygen species (ROS) and serum levels of cytokines were also determined. Results: Punicalagin treatment reduced inflammatory cell infiltration and cell damage, improved brain tissue architecture and BBB integrity. The punicalagin treatment increased the activities of antioxidant enzymes, and enhanced antioxidant status via activation of Nrf-2/ARE/HO-1 signaling pathway (p < 0.05). The treatment upregulated the expressions of HO-1 to 174 %, relative to 127 % in ICH control rats. Furthermore, it enhanced NF-κB levels and reversed the ICH injury-induced upregulations of IL-6, IL-18 and IL-1β. Conclusion: These findings indicate that punicalagin exerts neuroprotective effect in rats after experimental ICH through regulation of theHO-1/Nrf-2/ARE signaling pathway. Thus, punicalagin has therapeutic potential for ICH. Keywords: Brain injury, Haemoxygenase-1, Intracerebral haemorrhage, Inflammatory responses, Nrf2/ARE signalling, Punicalagin

scholarly journals Peripheral immune cells and perinatal brain injury: a double-edged sword?

2021 ◽  
Author(s):  
Josephine Herz ◽  
Ivo Bendix ◽  
Ursula Felderhoff-Müser
Keyword(s):  
Brain Injury ◽  
Immune Cells ◽  
Drug Exposure ◽  
Immune Cell ◽  
List Type ◽  
Perinatal Brain Injury ◽  
Immune Cell Subsets ◽  
Peripheral Immune Cells ◽  
Critical Aspects

Abstract Perinatal brain injury is the leading cause of neurological mortality and morbidity in childhood ranging from motor and cognitive impairment to behavioural and neuropsychiatric disorders. Various noxious stimuli, including perinatal inflammation, chronic and acute hypoxia, hyperoxia, stress and drug exposure contribute to the pathogenesis. Among a variety of pathological phenomena, the unique developing immune system plays an important role in the understanding of mechanisms of injury to the immature brain. Neuroinflammation following a perinatal insult largely contributes to evolution of damage to resident brain cells, but may also be beneficial for repair activities. The present review will focus on the role of peripheral immune cells and discuss processes involved in neuroinflammation under two frequent perinatal conditions, systemic infection/inflammation associated with encephalopathy of prematurity (EoP) and hypoxia/ischaemia in the context of neonatal encephalopathy (NE) and stroke at term. Different immune cell subsets in perinatal brain injury including their infiltration routes will be reviewed and critical aspects such as sex differences and maturational stage will be discussed. Interactions with existing regenerative therapies such as stem cells and also potentials to develop novel immunomodulatory targets are considered. Impact Comprehensive summary of current knowledge on the role of different immune cell subsets in perinatal brain injury including discussion of critical aspects to be considered for development of immunomodulatory therapies.

scholarly journals MCP-1/CCL2 in a Bulgarian Cohort of Children with Bronchial Asthma and Cystic Fibrosis

2018 ◽  
Author(s):  
Tsvetelina Velikova ◽  
Ekaterina Krasimirova ◽  
Snezhina Lazova ◽  
Penka Perenovska ◽  
Anna Valerieva ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Bronchial Asthma ◽  
Inflammatory Responses ◽  
Serum Levels ◽  
Cross Sectional Study ◽  
Healthy Children ◽  
Cross Sectional ◽  
Monocyte Chemoattractant Protein 1 ◽  
Chronic Pulmonary Diseases ◽  
Chemokine Ligand

C-C motif chemokine ligand 2 (CCL2), also called monocyte chemoattractant protein-1 (MCP-1) is a key &beta;-chemokine involved in the migration of monocytes and macrophages, playing a significant role in the inflammatory responses in the airways. We aimed to assess the serum levels of MCP-1/CCL2 in a pilot cross-sectional study of Bulgarian children with bronchial asthma (BA) and cystic fibrosis (CF). Forty-two children were recruited to the study as follows: twenty with BA, twelve with CF and ten healthy children. Serum MCP-1/CCL2 levels were measured using ELISA. We found higher serum level of MCP-1/CCL2 in children with BA (191.09&plusmn;64.96 pg/ml) and CF (258.51&plusmn;76.45 pg/ml) compared to healthy children (70.30&plusmn;64.30 pg/ml, p=0.022, and p=0.068, respectively). Younger patients with BA had higher levels of MCP-1/CCL2, as well as children with CF, with levels decreasing gradually with age. We observed also higher levels of MCP-1/CCL2 in children with moderate to severe BA compared to mild BA. We documented the significantly higher level of MCP-1/CCL2 in children with these chronic pulmonary diseases than in healthy controls, which suggesting that investigation of serum MCP-1/CCL2 levels could turn out to be beneficial for the severity of the disease.

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