Cerebrospinal fluid biomarkers of neuroinflammation in children with hydrocephalus and shunt malfunction

Abstract Background Approximately 30% of cerebrospinal fluid (CSF) shunt systems for hydrocephalus fail within the first year and 98% of all patients will have shunt failure in their lifetime. Obstruction remains the most common reason for shunt failure. Previous evidence suggests elevated pro-inflammatory cytokines in CSF are associated with worsening clinical outcomes in neuroinflammatory diseases. The aim of this study was to determine whether cytokines and matrix metalloproteinases (MMPs) contribute towards shunt failure in hydrocephalus. Methods Using multiplex ELISA, this study examined shunt failure through the CSF protein concentration profiles of select pro-inflammatory and anti-inflammatory cytokines, as well as select MMPs. Interdependencies such as the past number of previous revisions, length of time implanted, patient age, and obstruction or non-obstruction revision were examined. The pro-inflammatory cytokines were IL-1β, IL-2, IL-5, IL-6, IL-8, IL-12, IL-17, TNF-α, GM-CSF, IFN-γ. The anti-inflammatory cytokines were IL-4 and IL-10, and the MMPs were MMP-2, MMP-3, MMP-7, MMP-9. Protein concentration is reported as pg/mL for each analyte. Results Patient CSF was obtained at the time of shunt revision operation; all pediatric (< 18), totaling n = 38. IL-10, IL-6, IL-8 and MMP-7 demonstrated significantly increased concentrations in patient CSF for the non-obstructed subgroup. Etiological examination revealed IL-6 was increased in both obstructed and non-obstructed cases for PHH and congenital hydrocephalic patients, while IL-8 was higher only in PHH patients. In terms of number of past revisions, IL-10, IL-6, IL-8, MMP-7 and MMP-9 progressively increased from zero to two past revisions and then remained low for subsequent revisions. This presentation was notably absent in the obstruction subgroup. Shunts implanted for three months or less showed significantly increased concentrations of IL-6, IL-8, and MMP-7 in the obstruction subgroup. Lastly, only patients aged six months or less presented with significantly increased concentration of IL-8 and MMP-7. Conclusion Non-obstructive cases are reported here to accompany significantly higher CSF cytokine and MMP protein levels compared to obstructive cases for IL-10, IL-6, IL-8, MMP-7 and MMP-9. A closer examination of the definition of obstruction and the role neuroinflammation plays in creating shunt obstruction in hydrocephalic patients is suggested.

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Cerebrospinal Fluid Biomarkers of Neuroinflammation in Children with Hydrocephalus and Shunt Malfunction

10.21203/rs.3.rs-78728/v1 ◽

2020 ◽

Author(s):

Carolyn A Harris ◽

Diego M. Morales ◽

Rooshan Arshad ◽

James P. McAllister ◽

David D. Limbrick

Keyword(s):

Cerebrospinal Fluid ◽

Inflammatory Cytokines ◽

Protein Concentration ◽

Shunt Revision ◽

Csf Shunt ◽

Shunt Failure ◽

Revision Operation ◽

Gm Csf ◽

Cerebrospinal Fluid Biomarkers ◽

Anti Inflammatory

Abstract Background: Cerebrospinal fluid (CSF) shunt systems fail approximately 30% of the time within the first year of shunt implantation, while 98% of all patients with hydrocephalus (HCP) will suffer shunt failure in their lifetime. Perhaps due to the heterogeneity in etiology or the unique environment housing CSF shunt systems, the underlying reasons for shunt failure continue to elude researchers and clinicians. Still, obstruction remains the most common reason for shunt failure and it is vital to understand what factors may be contributing or driving shunt failure for improving patient outcomes and ultimately quality of life.Methods: Using multiplex ELISA, this study first examined the protein concentration profiles of select pro-inflammatory and anti-inflammatory cytokines, as well as select matrix metalloproteinases (MMPs) in 38 pediatric patients and their CSF obtained at shunt revision operation; all patients pediatric (<18). Shunt failure was further examined for interdependencies between the past number of previous revisions, length of time implanted, patient age, and the surgeon-described reason for revision noted as obstruction or non-obstruction. The pro-inflammatory cytokines were IL-1β, IL-2, IL-5, IL-6, IL-8, IL-12, IL-17, TNF-α, GM-CSF, IFN-γ. The anti-inflammatory cytokines were IL-4 and IL-10, and the MMPs are MMP-2, MMP-3, MMP-7, MMP-9. protein concentration is reported as pg/mL for each analyte. Results: IL-10, IL-6, IL-8 and MMP-7 demonstrated significantly increased concentrations in patient CSF for the non-obstructed subgroup compared to the obstructed subgroup (p=<0.05). Under generalized etiology, these analytes present within communicating HCP cases (15 of which were diagnosed with PHH) compared to non-communicating HCP or traumatic brain injury (TBI) cases. Further examination revealed that CSF IL-6 was significantly increased in both obstructed and non-obstructed cases, predominately for PHH and congenital HCP patients while IL-8 was significantly higher only in PHH patients. In terms of number of past revisions, IL-10, IL-6, IL-8, MMP-7 and MMP-9 significantly and progressively increased from zero to two past revisions and then significantly declined and remained low for subsequent revisions (p=<0.05). In terms of implantation time, CSF from shunts implanted for three months or less show significantly increased concentration for IL-6, IL-8, and MMP-7 (p=<0.05). Lastly, Six months or less was the age identified to coincide with significantly increased concentration of IL-6, IL-8, and MMP-7 (p=<0.05). Conclusion: Of all the cytokines and MMPs tested, IL-10, IL-6, IL-8, MMP-7 and MMP-9 were significantly elevated compared to other cytokines and MMPs in the various dependencies evaluated. IL-6 and IL-8 stand out in our study with significantly increased concentration in select etiologies, age, length of time implanted. The aforementioned cytokines and MMPs all showed an interesting relation with number of past revisions which warrants further examination. Non-obstruction cases were determined to be accompany significantly higher CSF cytokine MMP presence compared to obstructive cases. This suggests closer examination to the extent of the role neuroinflammation plays for causing obstruction in HCP patients. Additionally, IL-10 was associated with the length of time implanted as well as number of past revisions, and higher in non-obstructed cases compared to obstructed cases. A severity-dependent interplay between IL-10, IL-6 and IL-8 is an area for expansion and may provide foundation for therapeutic control of neuroinflammation.Trial registration: Not applicable.

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Pro-inflammatory cytokines reduce human TAFI expression via tristetraprolin-mediated mRNA destabilisation and decreased binding of HuR

Thrombosis and Haemostasis ◽

10.1160/th14-08-0653 ◽

2015 ◽

Vol 114 (08) ◽

pp. 337-349 ◽

Cited By ~ 7

Author(s):

Dragana Komnenov ◽

Corey Scipione ◽

Zainab Bazzi ◽

Justin Garabon ◽

Marlys Koschinsky ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Inflammatory Mediators ◽

Hepg2 Cells ◽

Inflammatory Cells ◽

Gene Encoding ◽

Protein Levels ◽

Anti Inflammatory ◽

Mechanistic Basis ◽

Pro Inflammatory Cytokines

SummaryThrombin activatable fibrinolysis inhibitor (TAFI) is the zymogen form of a basic carboxypeptidase (TAFIa) with both anti-fibrinolytic and anti-inflammatory properties. The role of TAFI in inflammatory disease is multifaceted and involves modulation both of specific inflammatory mediators as well as of the behaviour of inflammatory cells. Moreover, as suggested by in vitro studies, inflammatory mediators are capable of regulating the expression of CPB2, the gene encoding TAFI. In this study we addressed the hypothesis that decreased TAFI levels observed in inflammation are due to post-transcriptional mechanisms. Treatment of human HepG2 cells with pro-inflammatory cytokines TNFα, IL-6 in combination with IL-1β, or with bacterial lipopolysaccharide (LPS) decreased TAFI protein levels by approximately two-fold over 24 to 48 hours of treatment. Conversely, treatment of HepG2 cells with the anti-inflammatory cytokine IL-10 increased TAFI protein levels by two-fold at both time points. We found that the mechanistic basis for this modulation of TAFI levels involves binding of tristetraprolin (TTP) to the CPB2 3′-UTR, which mediates CPB2 mRNA destabilisation. In this report we also identified that HuR, another ARE-binding protein but one that stabilises transcripts, is capable of binding the CBP2 3’UTR. We found that pro-inflammatory mediators reduce the occupancy of HuR on the CPB2 3’-UTR and that the mutation of the TTP binding site in this context abolishes this effect, although TTP and HuR appear to contact discrete binding sites. Interestingly, all of the mediators tested appear to increase TAFI protein expression in THP-1 macrophages, likewise through effects on CPB2 mRNA stability.

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Estrogen receptor α phosphorylated at Ser216 confers inflammatory function to mouse microglia

10.21203/rs.2.18935/v1 ◽

2019 ◽

Author(s):

Sawako Shindo ◽

Shih-Heng Chen ◽

Saki Gotoh ◽

Kosuke Yokobori ◽

Hao Hu ◽

...

Keyword(s):

Estrogen Receptor ◽

Inflammatory Cytokines ◽

Estrogen Receptor Α ◽

Microglia Activation ◽

Immune Functions ◽

Protein Levels ◽

Brain Extracts ◽

Anti Inflammatory ◽

The Brain ◽

Pro Inflammatory Cytokines

Abstract Background Estrogen has been suggested to regulate anti-inflammatory signaling in brain microglia through estrogen receptor α (ERα), the only resident immune cells of the brain. The mechanism of how ERα regulates is not well understood. Previously, ERα is phosphorylated at Ser216 in mouse neutrophils, regulating their infiltration into the uterus. Therefore, ERα has now been examined as to its phosphorylation in microglia to regulate their inflammatory functions.MethodsAn antibody against an anti-phospho-S216 peptide of ERα (αP-S216) was used for double immunofluorescence staining to detect to ERα in cultured microglia. A knock-in (KI) mouse line bearing the phosphorylation-blocked ERα mutation S216A (ERα KI) was generated to examine whether this phosphorylation regulate immune functions of microglia.ResultsPhosphorylated ERα at Ser216 was present in microglia but not astrocytes. Staining with an anti-Iba-1 antibody showed that microglia activation was augmented in substantial nigra of ERα KI brains. Lipopolysaccharide (LPS) treatments aggravated microglia activation in ERα KI brains, pro-inflammatory cytokines were increased while anti-inflammatory cytokines were decreased at mRNA and protein levels in whole brain extracts. These increases and decreases of cytokine proteins were also observed in LPS-treated microglia cultured from brains of ERα KI neonates. FACS analysis revealed that ERα KI mutation increased number of IL-6 producing microglia and apoptosis. ERα KI mice decreased motor connection ability in Rotarod tests.ConclusionsBlocking of Ser216 phosphorylation aggravated microglia activation and inflammation of mouse brain, thus confirming that phosphorylated ERα exerts anti-inflammatory functions. ERα KI mice enable us to further investigate the mechanism by which phosphorylated ERα regulates brain immunity and inflammation.

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Immunosuppressant Cyclosporin A-Based Regulation of Lipopolysaccharide-Triggered Pro- and Anti-Inflammatory Cytokines in the Genital Tract of Female Rabbits

10.20944/preprints201811.0289.v1 ◽

2018 ◽

Author(s):

Li-Qin Yang ◽

Qiu-Ying Wu ◽

Xuan-Yu Chen ◽

Chun Wang ◽

Zhang Yan ◽

...

Keyword(s):

Mrna Expression ◽

Inflammatory Cytokines ◽

Genital Tract ◽

Protein Production ◽

Control Group ◽

Protein Levels ◽

Lps Challenge ◽

Anti Inflammatory ◽

Uterine Body ◽

Pro Inflammatory Cytokines

In this study, we evaluated the effects of Cyclosporine A (CsA) on Lipopolysaccharide (LPS)-induced cytokine production in the genital tract of female rabbits. Twelve sexually mature and healthy female rabbits were randomly divided into four groups (n = 3 each). The rabbits in the LPS group were given an intrauterine infusion of Escherichia coli LPS (4 mg/kg body weight (BW)). Rabbits in the CsA group were given CsA (20 mg/kg BW). Rabbits in the LPS + CsA group were given LPS (4 mg/kg BW) and CsA (20 mg/kg BW). The control group received only LPS and CsA carrier. The gene expression and protein levels of pro- and anti-inflammatory cytokines were observed using qRT-PCR and immuno-histochemical (IHC) assay, respectively. Our study showed that IL-1β, IL-6, IL-8, TNF-α, IFN-γ, IL-4, IL-10, IL-13, and TGF-β were expressed in female genital organs. The LPS challenge increased the mRNA expression of IL-6 and TNF-α in the uterine body and IL-1β in the uterotubal junction compared to the control group. CsA increased the basal mRNA expression of anti-inflammatory cytokines (i.e., IL-4 in the uterine body, uterotubal junction, and oviductal ampulla; IL-10 in the cervix, oviductal isthmus, and ampulla; and TGF-β in the uterotubal junction and oviductal ampulla) and pro-inflammatory cytokines (i.e., IL-6 and IL-8 in the cervix; IL-1β in the oviductal isthmus; TNF-α in the oviductal ampulla; and IFN-γ in the uterine body compared to the control group). In addition, CsA inhibited the mRNA expression of pro-inflammatory cytokines, such as IL-6 in the uterine body, uterotubal junction, and oviductal isthmus; TNF-α in the uterine body; and IFN-γ in the uterotubal junction and oviductal isthmus induced by the LPS challenge. The IHC assay showed the LPS-induced increase in protein production of IL-6 in the uterine body and oviductal isthmus. CsA increased the protein production of IL-10 in the cervix, uterine body, oviductal ampulla, and isthmus. Moreover, CsA decreased the protein production of IL-6 in the uterine body and oviductal isthmus induced by LPS.

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Effect of Protein Concentration on the Flow of Cerebrospinal Fluid Through Shunt Tubing

Neurosurgery ◽

10.1227/neu.0000000000000956 ◽

2015 ◽

Vol 77 (6) ◽

pp. 972-978 ◽

Cited By ~ 3

Author(s):

Joseph T. Cheatle ◽

Alexis N. Bowder ◽

Jonathan L. Tefft ◽

Sandeep K. Agrawal ◽

Leslie C. Hellbusch

Keyword(s):

Cerebrospinal Fluid ◽

Protein Concentration ◽

Control Valve ◽

Csf Shunt ◽

Laboratory Setting ◽

Shunt Valve ◽

Protein Levels ◽

Flow Through ◽

The Relationship ◽

Shunt Tubing

BACKGROUND: Protein levels in cerebrospinal fluid (CSF) are commonly thought to be related to sterile shunt malfunction. OBJECTIVE: To investigate the relationship between protein concentration and flow through CSF shunt tubing and a shunt valve. METHODS: New and explanted shunt catheters were tested with and without a shunt valve attached at various protein concentrations. The protein concentrations used were 0.5, 2, 5, and 10 g/L. A flask with artificial CSF attached to the proximal end provided flow. The flow was allowed to stabilize over 1 hour, and then the change in pressure between the proximal and distal end of the catheter was measured and recorded. The resistance to flow was calculated for new and explanted catheters for adult shunt systems, as well as with the addition of a programmable siphon control valve. The resistance was examined after the addition of various protein concentrations to a normal CSF solution. RESULTS: Both new and explanted catheters exhibited a decrease in the resistance to flow with higher concentrations of protein. CONCLUSION: In our laboratory setting, there was decreased resistance of adult CSF shunt catheters with and without a valve as the concentration of protein in the CSF increased. The decrease in the resistance of CSF shunt catheters with the addition of protein to the CSF may be related to the lowering of surface tension. This is the first study to examine the effects of varying protein concentrations across different lengths of shunt tubing for both new and explanted catheters.

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AAnti-Inflammatory Effects of Plasma Circulating Exosomes Obtained from Normal-Weight and Obese Subjects on Hepatocytes

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530320666200505121426 ◽

2020 ◽

Vol 20 ◽

Author(s):

Reza Afrisham ◽

Sahar Sadegh-Nejadi ◽

Reza Meshkani ◽

Solaleh Emamgholipour ◽

Molood Bagherieh ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Hepg2 Cells ◽

Human Liver ◽

Liver Cells ◽

Normal Weight ◽

Protein Levels ◽

Human Liver Cells ◽

Tnf Α ◽

Anti Inflammatory

Introduction: Obesity is a disorder with low-grade chronic inflammation that plays a key role in the hepatic inflammation and steatosis. Moreover, there are studies to support the role of exosomes in the cellular communications, the regulation of metabolic homeostasis and immunomodulatory activity. Accordingly, we aimed to evaluate the influence of plasma circulating exosomes derived from females with normal-weight and obesity on the secretion of inflammatory cytokines in human liver cells. Methods: Plasma circulating exosomes were isolated from four normal (N-Exo) and four obese (O-Exo) women. The exosomes were characterized and approved for CD63 expression (common exosomal protein marker) and morphology/size using the western blot and TEM methods, respectively. The exosomes were used for stimulation of HepG2 cells in vitro. After 24 h incubation, the protein levels of TNF-α,IL-6, and IL-1β were measured in the culture supernatant of HepG2 cells using the ELISA kit. Results: The protein levels of IL-6 and TNF-α in the cells treated with O-Exo and N-Exo reduced significantly in comparison with control group (P=0.039 and P<0.001 respectively), while significance differences were not found between normal and obese groups (P=0.808, and P=0.978 respectively). However, no significant differences were found between three groups in term of IL-1β levels (P=0.069). Based on the correlation analysis, the protein levels of IL-6 were positively correlated with TNF-α (r 0.978, P<0.001). Conclusion: These findings suggest that plasma circulating exosomes have probably anti-inflammatory properties independently from body mass index and may decrease the secretion of inflammatory cytokines in liver. However, further investigations in vitro and in vivo are needed to address the anti-inflammatory function of N-Exo and O-Exo in human liver cells and/or other cells.

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Computational Identification of Potential Anti-Inflammatory Natural Compounds Targeting the p38 Mitogen-Activated Protein Kinase (MAPK): Implications for COVID-19-Induced Cytokine Storm

Biomolecules ◽

10.3390/biom11050653 ◽

2021 ◽

Vol 11 (5) ◽

pp. 653

Author(s):

Seth O. Asiedu ◽

Samuel K. Kwofie ◽

Emmanuel Broni ◽

Michael D. Wilson

Keyword(s):

Molecular Docking ◽

P38 Mapk ◽

Inflammatory Cytokines ◽

Binding Energies ◽

Mitogen Activated Protein Kinase ◽

Inflammatory Activity ◽

Computational Techniques ◽

Cytokine Storm ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

Severely ill coronavirus disease 2019 (COVID-19) patients show elevated concentrations of pro-inflammatory cytokines, a situation commonly known as a cytokine storm. The p38 MAPK receptor is considered a plausible therapeutic target because of its involvement in the platelet activation processes leading to inflammation. This study aimed to identify potential natural product-derived inhibitory molecules against the p38α MAPK receptor to mitigate the eliciting of pro-inflammatory cytokines using computational techniques. The 3D X-ray structure of the receptor with PDB ID 3ZS5 was energy minimized using GROMACS and used for molecular docking via AutoDock Vina. The molecular docking was validated with an acceptable area under the curve (AUC) of 0.704, which was computed from the receiver operating characteristic (ROC) curve. A compendium of 38,271 natural products originating from Africa and China together with eleven known p38 MAPK inhibitors were screened against the receptor. Four potential lead compounds ZINC1691180, ZINC5519433, ZINC4520996 and ZINC5733756 were identified. The compounds formed strong intermolecular bonds with critical residues Val38, Ala51, Lys53, Thr106, Leu108, Met109 and Phe169. Additionally, they exhibited appreciably low binding energies which were corroborated via molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) calculations. The compounds were also predicted to have plausible pharmacological profiles with insignificant toxicity. The molecules were also predicted to be anti-inflammatory, kinase inhibitors, antiviral, platelet aggregation inhibitors, and immunosuppressive, with probable activity (Pa) greater than probable inactivity (Pi). ZINC5733756 is structurally similar to estradiol with a Tanimoto coefficient value of 0.73, which exhibits anti-inflammatory activity by targeting the activation of Nrf2. Similarly, ZINC1691180 has been reported to elicit anti-inflammatory activity in vitro. The compounds may serve as scaffolds for the design of potential biotherapeutic molecules against the cytokine storm associated with COVID-19.

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Role of Inflammatory Cytokines in COVID-19 Patients: A Review on Molecular Mechanisms, Immune Functions, Immunopathology and Immunomodulatory Drugs to Counter Cytokine Storm

Vaccines ◽

10.3390/vaccines9050436 ◽

2021 ◽

Vol 9 (5) ◽

pp. 436

Author(s):

Ali A. Rabaan ◽

Shamsah H. Al-Ahmed ◽

Javed Muhammad ◽

Amjad Khan ◽

Anupam A Sule ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Inflammatory Markers ◽

Therapeutic Drug ◽

Molecular Pathways ◽

Cytokine Storm ◽

Immunomodulatory Drugs ◽

Alveolar Cells ◽

Systemic Complications ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a severe pandemic of the current century. The vicious tentacles of the disease have been disseminated worldwide with unknown complications and repercussions. Advanced COVID-19 syndrome is characterized by the uncontrolled and elevated release of pro-inflammatory cytokines and suppressed immunity, leading to the cytokine storm. The uncontrolled and dysregulated secretion of inflammatory and pro-inflammatory cytokines is positively associated with the severity of the viral infection and mortality rate. The secretion of various pro-inflammatory cytokines such as TNF-α, IL-1, and IL-6 leads to a hyperinflammatory response by recruiting macrophages, T and B cells in the lung alveolar cells. Moreover, it has been hypothesized that immune cells such as macrophages recruit inflammatory monocytes in the alveolar cells and allow the production of large amounts of cytokines in the alveoli, leading to a hyperinflammatory response in severely ill patients with COVID-19. This cascade of events may lead to multiple organ failure, acute respiratory distress, or pneumonia. Although the disease has a higher survival rate than other chronic diseases, the incidence of complications in the geriatric population are considerably high, with more systemic complications. This review sheds light on the pivotal roles played by various inflammatory markers in COVID-19-related complications. Different molecular pathways, such as the activation of JAK and JAK/STAT signaling are crucial in the progression of cytokine storm; hence, various mechanisms, immunological pathways, and functions of cytokines and other inflammatory markers have been discussed. A thorough understanding of cytokines’ molecular pathways and their activation procedures will add more insight into understanding immunopathology and designing appropriate drugs, therapies, and control measures to counter COVID-19. Recently, anti-inflammatory drugs and several antiviral drugs have been reported as effective therapeutic drug candidates to control hypercytokinemia or cytokine storm. Hence, the present review also discussed prospective anti-inflammatory and relevant immunomodulatory drugs currently in various trial phases and their possible implications.

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Human umbilical cord mesenchymal stem cell-derived extracellular vesicles attenuate experimental autoimmune encephalomyelitis via regulating pro and anti-inflammatory cytokines

Scientific Reports ◽

10.1038/s41598-021-91291-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Samira Ahmadvand Koohsari ◽

Abdorrahim Absalan ◽

Davood Azadi

Keyword(s):

Spinal Cord ◽

Body Weight ◽

Extracellular Vesicles ◽

Inflammatory Cytokines ◽

Clinical Score ◽

Human Umbilical Cord ◽

Therapeutic Effects ◽

Leukocyte Infiltration ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

AbstractThe therapeutic effects of mesenchymal stem cells-extracellular vesicles have been proved in many inflammatory animal models. In the current study, we aimed to investigate the effect of extracellular vesicles (EVs) derived from human umbilical cord-MSC (hUCSC-EV) on the clinical score and inflammatory/anti-inflammatory cytokines on the EAE mouse model. After induction of EAE in C57Bl/6 mice, they were treated intravenously with hUCSC-EV or vehicle. The clinical score and body weight of all mice was registered every day. On day 30, mice were sacrificed and splenocytes were isolated for cytokine assay by ELISA. Cytokine expression of pro-/anti-inflammatory cytokine by real-time PCR, leukocyte infiltration by hematoxylin and eosin (H&E) staining, and the percent of glial fibrillary acidic protein (GFAP) and myelin basic protein (MBP) positive cells by immunohistochemistry were assessed in the spinal cord. Our results showed that hUCSC-EV-treated mice have lower maximum mean clinical score (MMCS), pro-inflammatory cytokines, and inflammatory score in comparison to the control mice. We also showed that hUCSC-EV administration significantly improved body weight and increased the anti-inflammatory cytokines and the frequency of Treg cells in the spleen. There was no significant difference in the percent of GFAP and MBP positive cells in the spinal cord of experimental groups. Finally, we suggest that intravenous administration of hUCSC-EV alleviate induce-EAE by reducing the pro-inflammatory cytokines, such as IL-17a, TNF-α, and IFN-γ, and increasing the anti-inflammatory cytokines, IL-4 and IL-10, and also decrease the leukocyte infiltration in a model of MS. It seems that EVs from hUC-MSCs have the same therapeutic effects similar to EVs from other sources of MSCs, such as adipose or bone marrow MSCs.

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Focal intra-colon cooling reduces organ injury and systemic inflammation after REBOA management of lethal hemorrhage in rats

Scientific Reports ◽

10.1038/s41598-021-93064-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Awadhesh K. Arya ◽

Kurt Hu ◽

Lalita Subedi ◽

Tieluo Li ◽

Bingren Hu

Keyword(s):

Inflammatory Response ◽

Inflammatory Cytokines ◽

Troponin I ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Balloon Catheter ◽

Organ Injury ◽

Upper Body ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

AbstractResuscitative endovascular balloon occlusion of the aorta (REBOA) is a lifesaving maneuver for the management of lethal torso hemorrhage. However, its prolonged use leads to distal organ ischemia–reperfusion injury (IRI) and systemic inflammatory response syndrome (SIRS). The objective of this study is to investigate the blood-based biomarkers of IRI and SIRS and the efficacy of direct intestinal cooling in the prevention of IRI and SIRS. A rat lethal hemorrhage model was produced by bleeding 50% of the total blood volume. A balloon catheter was inserted into the aorta for the implementation of REBOA. A novel TransRectal Intra-Colon (TRIC) device was placed in the descending colon and activated from 10 min after the bleeding to maintain the intra-colon temperature at 37 °C (TRIC37°C group) or 12 °C (TRIC12°C group) for 270 min. The upper body temperature was maintained at as close to 37 °C as possible in both groups. Blood samples were collected before hemorrhage and after REBOA. The organ injury biomarkers and inflammatory cytokines were evaluated by ELISA method. Blood based organ injury biomarkers (endotoxin, creatinine, AST, FABP1/L-FABP, cardiac troponin I, and FABP2/I-FABP) were all drastically increased in TRIC37°C group after REBOA. TRIC12°C significantly downregulated these increased organ injury biomarkers. Plasma levels of pro-inflammatory cytokines TNF-α, IL-1b, and IL-17F were also drastically increased in TRIC37°C group after REBOA. TRIC12°C significantly downregulated the pro-inflammatory cytokines. In contrast, TRIC12°C significantly upregulated the levels of anti-inflammatory cytokines IL-4 and IL-10 after REBOA. Amazingly, the mortality rate was 100% in TRIC37°C group whereas 0% in TRIC12°C group after REBOA. Directly cooling the intestine offered exceptional protection of the abdominal organs from IRI and SIRS, switched from a harmful pro-inflammatory to a reparative anti-inflammatory response, and mitigated mortality in the rat model of REBOA management of lethal hemorrhage.

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