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1.
J Transl Med ; 20(1): 97, 2022 02 21.
Article in English | MEDLINE | ID: mdl-35193610

ABSTRACT

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a disorder characterized by bladder pain upon filling which severely affects quality of life. Clinical presentation can vary. Local inflammatory events typify the clinical presentation of IC/BPS patients with Hunner lesions (IC/BPS-HL). It has previously been proposed that B cells are more prevalent in HL, but understanding their exact role in this environment requires a more complete immunological profile of HL. We characterized immunological dysfunction specifically in HL using immunohistochemistry. We detected significantly more plasma cells (50× increase, p < 0.0001), B cells (28× increase, p < 0.0001), T cells (3× increase, p < 0.0001), monocytes/macrophages (6× increase, p < 0.0001), granulocytes (4× increase, p < 0.0001), and natural killer cells (2× increase, p = 0.0249) in IC/BPS patients with HL than in unaffected controls (UC). Patients with IC/BPS-HL also had significantly elevated urinary levels of IL-6 (p = 0.0054), TNF-α (p = 0.0064) and IL-13 (p = 0.0304) compared to patients with IC/BPS without HL (IC/BPS-NHL). In contrast, IL-12p70 levels were significantly lower in the patients with HL than in those without these lesions (p = 0.0422). Different cytokines were elevated in the urine of IC/BPS patients with and without HL, indicating that different disease processes are active in IC/BPS patients with and without HL. Elevated levels of CD138+, CD20+, and CD3+ cells in HL are consistent B and T-cell involvement in disease processes within HL.


Subject(s)
Cystitis, Interstitial , Cystitis, Interstitial/pathology , Cystitis, Interstitial/urine , Cytokines , Humans , Quality of Life
2.
Am J Physiol Heart Circ Physiol ; 321(5): H933-H939, 2021 11 01.
Article in English | MEDLINE | ID: mdl-34597185

ABSTRACT

CD4+ T cells expressing choline acetyltransferase (ChAT) have recently been shown to cause a drop in systemic blood pressure when infused into mice. The aim of this study was to determine if ChAT-expressing T cells could regulate coronary vascular reactivity. Preconstricted segments of epicardial and intramyocardial porcine coronary arteries relaxed in response to Jurkat T cells (JT) that overexpressed ChAT (JTChAT cells). The efficacy of the JTChAT cells was similar in epicardial and intramyocardial vessels with a maximum dilator response to 3 × 105 cells/mL of 38.0 ± 6.7% and 38.7 ± 7.25%, respectively. In contrast, nontransfected JT cells elicited a weak dilator response, followed by a weak contraction. The response of JTChAT cells was dependent on the presence of the endothelial cells. In addition, the response could be significantly reduced by Nω-nitro-l-arginine methyl ester (l-NAME) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) in the presence of indomethacin. JTChAT cells, but not JT cells, increased the expression of phosphorylated endothelial nitric oxide synthase (eNOS). JTChAT cells contained significantly greater levels of acetylcholine compared with JT cells; however, the nonselective muscarinic antagonist atropine and the M1 receptor antagonist pirenzepine both failed to block the dilator effect of JTChAT cells. Exogenously added acetylcholine induced only a weak relaxation (∼10%) at low concentrations, which became a contractile response at higher concentrations. These data illustrate the capacity for cells that express ChAT to regulate coronary vascular reactivity, via mechanisms that are dependent on interaction with the endothelium and in part mediated by the release of nitric oxide.NEW & NOTEWORTHY This study shows ChAT-expressing T cells can induce vasodilation of the blood vessel in the coronary circulation and that this effect relies on a direct interaction between T cells and the coronary vascular endothelium. The study establishes a potential immunomodulatory role for T cells in the coronary circulation. The present findings offer an additional possibility that a deficiency of ChAT-expressing T cells could contribute to reduced coronary blood flow and ischemic events in the myocardium.


Subject(s)
Cell Communication , Choline O-Acetyltransferase/metabolism , Coronary Vessels/enzymology , T-Lymphocytes/enzymology , Vasodilation , Acetylcholine/metabolism , Animals , Choline O-Acetyltransferase/genetics , Coronary Vessels/immunology , Endothelial Cells/enzymology , Endothelial Cells/immunology , Humans , Jurkat Cells , Nitric Oxide/metabolism , Nitric Oxide Synthase Type III/metabolism , Phosphorylation , Sus scrofa , T-Lymphocytes/immunology
3.
Crit Care Explor ; 3(5): e0392, 2021 May.
Article in English | MEDLINE | ID: mdl-34079941

ABSTRACT

OBJECTIVES: The plasma level of N-terminal pro-brain natriuretic peptide is regulated by sex hormones. It has been controversial whether N-terminal pro-brain natriuretic peptide is a prognosis marker for sepsis. The aim of this study is to examine the sex-dependent association of plasma N-terminal pro-brain natriuretic peptide with organ dysfunction and mortality of sepsis patients. DESIGN: In this retrospective study, the association between plasma N-terminal pro-brain natriuretic peptide concentration on the day of sepsis diagnosis and the degree of organ dysfunction, occurrence of septic shock, or 30-day mortality in both male and female patients was analyzed. SETTING: This study was conducted in the Sepsis Laboratory at the Huaihe Hospital of Henan University in China. PATIENTS: Diagnoses of sepsis, and septic shock, were based on the recently revised criteria (Sepsis 3.0). All sepsis patients (517) hospitalized in the respiratory ICU of the Huaihe Hospital from June 2016 to December 2019 were enrolled in this study. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: No significant difference was found in the age, occurrence rate of septic shock, 30-day mortality, or degree of organ dysfunction between male and female patients. Median concentration of plasma N-terminal pro-brain Natriuretic peptide was higher by 93.48% in female than male patients. A significant association was found between N-terminal pro-brain natriuretic peptide and septic shock or 30-day mortality in female, but not in male patients of community- or hospital-acquired sepsis. N-terminal pro-brain natriuretic peptide levels correlated to functional deficiencies of the cardiac and nervous systems, only in female patients. CONCLUSIONS: The plasma N-terminal pro-brain natriuretic peptide level is a female-specific prognosis indicator of septic shock and mortality.

4.
Front Cardiovasc Med ; 8: 669975, 2021.
Article in English | MEDLINE | ID: mdl-34136546

ABSTRACT

Chronic hypoxic stress induces epigenetic modifications mainly DNA methylation in cardiac fibroblasts, inactivating tumor suppressor genes (RASSF1A) and activating kinases (ERK1/2) leading to fibroblast proliferation and cardiac fibrosis. The Ras/ERK signaling pathway is an intracellular signal transduction critically involved in fibroblast proliferation. RASSF1A functions through its effect on downstream ERK1/2. The antioxidant enzyme, extracellular superoxide dismutase (EC-SOD), decreases oxidative stress from chronic hypoxia, but its effects on these epigenetic changes have not been fully explored. To test our hypothesis, we used an in-vitro model: wild-type C57B6 male mice (WT) and transgenic males with an extra copy of human hEC-SOD (TG). The studied animals were housed in hypoxia (10% O2) for 21 days. The right ventricular tissue was studied for cardiac fibrosis markers using RT-PCR and Western blot analyses. Primary C57BL6 mouse cardiac fibroblast tissue culture was used to study the in-vitro model, the downstream effects of RASSF-1 expression and methylation, and its relation to ERK1/2. Our findings showed a significant increase in cardiac fibrosis markers: Collagen 1, alpha smooth muscle actin (ASMA), and SNAIL, in the WT hypoxic animals as compared to the TG hypoxic group (p < 0.05). The expression of DNA methylation enzymes (DNMT 1&3b) was significantly increased in the WT hypoxic mice as compared to the hypoxic TG mice (p < 0.001). RASSF1A expression was significantly lower and ERK1/2 was significantly higher in hypoxia WT compared to the hypoxic TG group (p < 0.05). Use of SiRNA to block RASSF1A gene expression in murine cardiac fibroblast tissue culture led to increased fibroblast proliferation (p < 0.05). Methylation of the RASSF1A promoter region was significantly reduced in the TG hypoxic group compared to the WT hypoxic group (0.59 vs. 0.75, respectively). Based on our findings, we can speculate that EC-SOD significantly attenuates RASSF1A gene methylation and can alleviate cardiac fibrosis induced by hypoxia.

5.
Mediators Inflamm ; 2020: 8094347, 2020.
Article in English | MEDLINE | ID: mdl-33293898

ABSTRACT

Connexin (Cx) family members form hemichannels (HCs) and gap junctions (GJs). Biological functions of Cx HCs have not been adequately characterized due to the inability to selectively target HCs or GJs. Recently, we developed a 6-mer peptide mimetic (P5) of the first extracellular loop of Cx43 and showed that it can block the permeability of HCs but not GJs formed by Cx43. In this study, we further characterized the HC blocking property of P5 and investigated the role of Cx HCs in acute lung injury (ALI). We found that P5 administration decreased HC permeability, in pulmonary microvascular endothelial cells, HepG2 cells, and even Cx43-deficient astrocytes, which express different sets of Cxs, suggesting that P5 is a broad spectrum Cx HC blocker. In addition, P5 reduced HC permeability of alveolar cells in vivo. Moreover, P5 decreased endotoxin-induced release, by vascular endothelial cells in vitro, of high mobility group box protein 1 (HMGB1), a critical mediator of acute lung injury (ALI), and reduced HMGB1 accumulation in bronchoalveolar lavage fluid (BALF) of mice subjected to intratracheal endotoxin instillation. Furthermore, P5 administration resulted in a significant decrease in the concentrations of ALT, AST, and LDH in the BALF, the accumulation of leukocytes in alveoli, and the mortality rate of mice subjected to ALI. Wright-Giemsa staining showed that P5 caused similar reductions of both neutrophils and monocytes in BALF of ALI mice. Together, these results suggest that Cx HCs mediate HMGB1 release, augment leukocyte recruitment, and contribute to ALI pathology.


Subject(s)
Acute Lung Injury/metabolism , Connexin 43/metabolism , Connexins/metabolism , Alveolar Epithelial Cells/metabolism , Animals , Astrocytes/cytology , Bronchoalveolar Lavage Fluid , Cells, Cultured , Endothelial Cells/metabolism , Gap Junctions/metabolism , HMGB1 Protein/metabolism , Hep G2 Cells , Humans , Leukocytes/cytology , Mice , NIH 3T3 Cells , Permeability , RAW 264.7 Cells
6.
Crit Care ; 23(1): 410, 2019 12 16.
Article in English | MEDLINE | ID: mdl-31842964

ABSTRACT

BACKGROUND: There is a compelling unmet medical need for biomarker-based models to risk-stratify patients with acute respiratory distress syndrome. Effective stratification would optimize participant selection for clinical trial enrollment by focusing on those most likely to benefit from new interventions. Our objective was to develop a prognostic, biomarker-based model for predicting mortality in adult patients with acute respiratory distress syndrome. METHODS: This is a secondary analysis using a cohort of 252 mechanically ventilated subjects with the diagnosis of acute respiratory distress syndrome. Survival to day 7 with both day 0 (first day of presentation) and day 7 sample availability was required. Blood was collected for biomarker measurements at first presentation to the intensive care unit and on the seventh day. Biomarkers included cytokine-chemokines, dual-functioning cytozymes, and vascular injury markers. Logistic regression, latent class analysis, and classification and regression tree analysis were used to identify the plasma biomarkers most predictive of 28-day ARDS mortality. RESULTS: From eight biologically relevant biomarker candidates, six demonstrated an enhanced capacity to predict mortality at day 0. Latent-class analysis identified two biomarker-based phenotypes. Phenotype A exhibited significantly higher plasma levels of angiopoietin-2, macrophage migration inhibitory factor, interleukin-8, interleukin-1 receptor antagonist, interleukin-6, and extracellular nicotinamide phosphoribosyltransferase (eNAMPT) compared to phenotype B. Mortality at 28 days was significantly higher for phenotype A compared to phenotype B (32% vs 19%, p = 0.04). CONCLUSIONS: An adult biomarker-based risk model reliably identifies ARDS subjects at risk of death within 28 days of hospitalization.


Subject(s)
Biomarkers/analysis , Respiratory Distress Syndrome/mortality , Risk Assessment/methods , APACHE , Adult , Biomarkers/blood , Cytokines/analysis , Cytokines/blood , Female , Humans , Interleukin 1 Receptor Antagonist Protein/analysis , Interleukin 1 Receptor Antagonist Protein/blood , Interleukin-1beta/analysis , Interleukin-1beta/blood , Interleukin-6/analysis , Interleukin-6/blood , Interleukin-8/analysis , Interleukin-8/blood , Intramolecular Oxidoreductases/analysis , Intramolecular Oxidoreductases/blood , Latent Class Analysis , Logistic Models , Macrophage Migration-Inhibitory Factors/analysis , Macrophage Migration-Inhibitory Factors/blood , Male , Middle Aged , Nicotinamide Phosphoribosyltransferase/analysis , Nicotinamide Phosphoribosyltransferase/blood , Peptide Fragments/analysis , Peptide Fragments/blood , Respiratory Distress Syndrome/blood , Respiratory Distress Syndrome/epidemiology , Risk Assessment/standards , Sphingosine-1-Phosphate Receptors/analysis , Sphingosine-1-Phosphate Receptors/blood , Vesicular Transport Proteins/analysis , Vesicular Transport Proteins/blood
7.
J Neurosurg ; : 1-6, 2019 Oct 04.
Article in English | MEDLINE | ID: mdl-31585427

ABSTRACT

OBJECTIVE: In patients with aneurysmal subarachnoid hemorrhage (aSAH), poor outcomes have been shown to be correlated with subsequent cerebral vasospasm (CV) and delayed cerebral ischemia (DCI). The identification of novel biomarkers may aid in the prediction of which patients are vulnerable to developing vasospasm, cerebral ischemia, and neurological deterioration. METHODS: In this prospective clinical study at North Shore University Hospital, patients with aSAH or normal pressure hydrocephalus (NPH) with external ventricular drains were enrolled. The concentration of macrophage migration inhibitory factor (MIF) in CSF was assessed for correlation with CV or DCI, the primary outcome measures. RESULTS: Twenty-five patients were enrolled in the aSAH group and 9 were enrolled in the NPH group. There was a significant increase in aggregate CSF MIF concentration in patients with aSAH versus those with NPH (24.4 ± 19.2 vs 2.3 ± 1.1 ng/ml, p < 0.0002). Incidence of the day of peak MIF concentration significantly correlated with the onset of clinical vasospasm (rho = 0.778, p < 0.0010). MIF concentrations were significantly elevated in patients with versus those without evidence of DCI (18.7 ± 4.93 vs 8.86 ± 1.28 ng/ml, respectively, p < 0.0025). There was a significant difference in MIF concentrations between patients with infection versus those without infection (16.43 ± 4.21 vs 8.5 ± 1.22 ng/ml, respectively, p < 0.0119). CONCLUSIONS: Preliminary evidence from this study suggests that CSF concentrations of MIF are correlated with CV and DCI. These results, however, could be confounded in the presence of clinical infection. A study with a larger patient sample size is necessary to corroborate these findings.

8.
Pediatr Res ; 85(5): 735, 2019 Apr.
Article in English | MEDLINE | ID: mdl-30842552

ABSTRACT

In the original version of this article, the name of the author "Kamesh Ayasolla" was incorrectly given as "Kamesh Ayyasola". This has now been corrected to "Kamesh Ayasolla" in both the PDF and HTML versions of the article.

9.
Pediatr Res ; 85(5): 711-718, 2019 04.
Article in English | MEDLINE | ID: mdl-30759452

ABSTRACT

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a complex birth anomaly with significant mortality and morbidity. Lung hypoplasia and persistent pulmonary hypertension (PPHN) limit survival in CDH. Macrophage migration inhibitory factor (MIF), a key regulator of innate immunity, is involved in hypoxia-induced vascular remodeling and PPHN. We hypothesized that antenatal inhibition of MIF in CDH fetuses, would reduce vascular remodeling, and improve angiogenesis and lung development. METHODS: Pregnant rats were randomized into three groups: Control, nitrofen, and nitrofen + ISO-92. Lung volumes of pups were measured by CT scanning. Right ventricular systolic pressure (RVSP) and vascular wall thickness (VWT) were measured together with MIF concentration, angiogenesis markers, lung morphometry, and histology. RESULTS: Prenatal treatment with ISO-92, an MIF inhibitor, improved normalization of static lung volume, lung volume-to-body weight ratio, decreased alveolar septal thickness, RVSP and VWT and improved radial alveolar count as compared to the non-treated group. Expression of MIF was unaffected by ISO-92; however, ISO-92 increased p-eNOS and VEGF activities and reduced arginase 1, 2 and Sflt-1. CONCLUSION: Prenatal inhibition of MIF activity in CDH rat model improves angiogenesis and lung development. This selective intervention may be a future therapeutic strategy to reduce the morbidity and mortality of this devastating condition.


Subject(s)
Hernias, Diaphragmatic, Congenital/therapy , Intramolecular Oxidoreductases/antagonists & inhibitors , Lung/drug effects , Macrophage Migration-Inhibitory Factors/antagonists & inhibitors , Neovascularization, Physiologic/drug effects , Animals , Animals, Newborn , Body Weight , Disease Models, Animal , Female , Hemodynamics , Hernias, Diaphragmatic, Congenital/chemically induced , Hernias, Diaphragmatic, Congenital/pathology , Hypertension, Pulmonary/etiology , Immunity, Innate , Inflammation , Lung/growth & development , Maternal Exposure , Phenyl Ethers , Pregnancy , Pregnancy, Animal , Rats , Systole , Tomography, X-Ray Computed , Vascular Remodeling , Ventricular Function, Right
10.
HPB (Oxford) ; 21(4): 465-472, 2019 04.
Article in English | MEDLINE | ID: mdl-30253909

ABSTRACT

BACKGROUND: Elevated concentrations of D-dopachrome tautomerase (D-DT) were associated with adverse outcome in various clinical settings. However, no study assessed D-DT concentrations in patients requiring orthotopic liver transplantation (OLT). The aim of this observational study was to measure serum D-DT concentrations in patients undergoing OLT and associate D-DT with survival and acute kidney injury (AKI). METHODS: Forty-seven adults with end-stage liver disease undergoing OLT were included. Areas under the receiver operating curves (AUC) were calculated to assess predictive values of D-DT for outcome and AKI after OLT. Survival was analyzed by Kaplan-Meier curves. RESULTS: Serum D-DT concentrations were greater in non-survivors than in survivors prior to OLT (86 [50-117] vs. 53 [31-71] ng/ml, P = 0.008), and on day 1 (357 [238-724] vs. 189 [135-309] ng/ml, P = 0.001) and day 2 (210 [142-471] vs. 159 [120-204] ng/ml, P = 0.004) following OLT. Serum D-DT concentrations predicted lethal outcome when measured preoperatively (AUC = 0.75, P = 0.017) and on postoperative day 1 (AUC = 0.75, P = 0.015). One-year survival of patients with preoperative D-DT concentrations >85 ng/ml was 50%, whereas that of patients with preoperative D-DT concentrations <85 ng/ml was 83% (Chi2 = 5.83, P = 0.016). In contrast, D-DT was not associated with AKI after OLT. CONCLUSION: In patients undergoing OLT, serum D-DT might predict outcome after OLT.


Subject(s)
Acute Kidney Injury/enzymology , Intramolecular Oxidoreductases/blood , Liver Transplantation , Postoperative Complications/enzymology , Biomarkers/blood , End Stage Liver Disease/surgery , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Risk Factors , Survival Analysis
11.
Sci Rep ; 8(1): 11336, 2018 07 27.
Article in English | MEDLINE | ID: mdl-30054559

ABSTRACT

Nontuberculous mycobacterial lung disease (NTM), including Mycobacterium avium complex (MAC), is a growing health problem in North America and worldwide. Little is known about the molecular alterations occurring in the tissue microenvironment during NTM pathogenesis. Utilizing next generation sequencing, we sequenced sputum and matched lymphocyte DNA in 15 MAC patients for a panel of 19 genes known to harbor cancer susceptibility associated mutations. Thirteen of 15 NTM subjects had a diagnosis of breast cancer (BCa) before or after NTM infection. Thirty three percent (4/12) of these NTM-BCa cases exhibited at least 3 somatic mutations in sputa compared to matched lymphocytes. Twenty four somatic mutations were detected with at least one mutation in ATM, ERBB2, BARD1, BRCA1, BRCA2, AR, TP53, PALB2, CASP8, BRIP1, NBN and TGFB1 genes. All four NTM-BCa patients harboring somatic mutations also exhibited 15 germ line BRCA1 and BRCA2 mutations. The two NTM subjects without BCa exhibited twenty somatic mutations spanning BRCA1, BRCA1, BARD1, BRIP1, CHEK2, ERBB2, TP53, ATM, PALB2, TGFB1 and 3 germ line mutations in BRCA1 and BRCA2 genes. A single copy loss of STK11 and AR gene was noted in NTM-BCa subjects. Periodic screening of sputa may aid to develop risk assessment biomarkers for neoplastic diseases in NTM patients.


Subject(s)
Genetic Predisposition to Disease , Mutation/genetics , Mycobacterium Infections, Nontuberculous/diagnosis , Mycobacterium Infections, Nontuberculous/genetics , Sputum/microbiology , Aged , BRCA1 Protein/genetics , BRCA2 Protein/genetics , Breast Neoplasms/complications , Breast Neoplasms/genetics , Chromosomes, Human/genetics , DNA Copy Number Variations/genetics , Female , Genome, Human , Humans , Middle Aged , Mycobacterium Infections, Nontuberculous/complications
13.
Atherosclerosis ; 270: 68-75, 2018 03.
Article in English | MEDLINE | ID: mdl-29407890

ABSTRACT

BACKGROUND AND AIMS: Chronic intermittent hypoxia (CIH) exposure causes atherosclerosis, although the underlying mechanisms are poorly understood. This study defines the role of endothelial intrinsic NF-κB signaling in the atherogenic response to CIH. METHODS: We created ApoE-ECI-κBmt mice that are deficient in the apolipoprotein E gene (ApoE-/-) and overexpress an I-κBα mutant (I-κBmt) selectively in endothelial cells. ApoE-/- and ApoE-ECI-κBmt mice were fed a normal chow diet (NCD) or high cholesterol diet (HCD) and exposed to sham or CIH, and atherosclerotic lesions were quantified. RESULTS: CIH exposure activated NF-κB in aortas, and induced the expression of endothelial-specific and NF-κB-dependent genes, E-selectin and vascular cell adhesion molecule (VCAM)-1, in the aortas and hearts. Endothelial I-κBmt overexpression in ApoE-ECI-κBmt mice significantly inhibited CIH-induced NF-κB activity, and suppressed E-selectin and VCAM-1 expressions, confirming endothelial NF-κB inhibition in ApoE-ECI-κBmt mice. ApoE-/- mice, on NCD, developed mild atherosclerotic lesions spontaneously, and developed advanced and larger areas of atherosclerotic plaques when exposed to CIH. ApoE-/- mice also developed advanced atherosclerotic lesions when fed an HCD alone. The HCD-induced atherosclerotic plaques became more advanced, and plaque area was doubled in mice exposed to HCD + CIH. Endothelial I-κBmt overexpression in ApoE-ECI-κBmt mice attenuated spontaneously developed atherosclerotic lesions, abrogated CIH-induced atherosclerosis and mitigated CIH-mediated facilitation of HCD-induced atherosclerosis. CONCLUSIONS: These results suggest that endothelial intrinsic NF-kB signaling may play a pivotal role in CIH-induced atherosclerosis.


Subject(s)
Aortic Diseases/prevention & control , Atherosclerosis/prevention & control , Endothelial Cells/metabolism , Hypoxia/complications , NF-KappaB Inhibitor alpha/metabolism , NF-kappa B/metabolism , Signal Transduction , Animals , Aortic Diseases/genetics , Aortic Diseases/metabolism , Aortic Diseases/pathology , Atherosclerosis/genetics , Atherosclerosis/metabolism , Atherosclerosis/pathology , Chronic Disease , Diet, High-Fat , Disease Models, Animal , E-Selectin/genetics , E-Selectin/metabolism , Endothelial Cells/pathology , Lipids/blood , Mice, Inbred C57BL , Mice, Knockout, ApoE , NF-KappaB Inhibitor alpha/genetics , Plaque, Atherosclerotic , Vascular Cell Adhesion Molecule-1/genetics , Vascular Cell Adhesion Molecule-1/metabolism
14.
Article in English | MEDLINE | ID: mdl-29104965

ABSTRACT

Mesenchymal stromal cells (MSCs) are multipotent progenitor cells that can be isolated and expanded from various sources. MSCs modulate the function of immune cells, including T and B lymphocytes, dendritic cells, and natural killer cells. An understanding of the interaction between MSCs and the inflammatory microenvironment will provide critical information in revealing the precise in vivo mechanisms involved in MSCs-mediated therapeutic effects, and for designing more practical protocols for the clinical use of these cells. In this review we describe the current knowledge of the unique biological properties of MSCs, the immunosuppressive effects on immune-competent cells and the paracrine role of soluble factors. A summary of the participation of MSCs in preclinical and clinical studies in treating autoimmune diseases and other diseases is described. We also discuss the current challenges of their use and their potential roles in cell therapies.

15.
Int J Biochem Cell Biol ; 92: 141-147, 2017 11.
Article in English | MEDLINE | ID: mdl-28987523

ABSTRACT

BACKGROUND AND OBJECTIVE: Pulmonary Hypertension (pH) is a chronic progressive disease. Endothelial cells (EC) play a central and critical role in the initiation and progression of pH. The NF-κB family (NF-κB1 (p50/p105), NF-κB2 (p52/p100), RelA (p65), RelB, and C-Rel) regulates a wide array of genes involved in inflammatory responses, cell proliferation, and survival. The involvement of specific NF-κB family members in the pathogenesis of hypoxia-induced pH remains to be determined. The objective of this study was to assess the specific role of individual NF-κB family members in mediating endothelial cell responses to hypoxia and its downstream effect on smooth muscle cell proliferation. METHODS AND RESULTS: NF-κB family members' expression were selectively reduced by siRNA in human pulmonary microvascular endothelial cells. Cells were then exposed to hypoxia (1%) for 24h. Endothelin1, ICAM1 gene expression and Stat1 and Stat3 phosphorylation were assessed. Smooth muscle cells (SMC) proliferation was assessed by culturing them with EC conditioned media. Reduction of either NF-κB2 or RelA in EC, led to a significant decrease in Endothelin1 and ICAM1 gene expression. C-Rel knockdown resulted in a significant increase in phosphorylated STAT1; both C-Rel and RelA knockdown significantly decreased phosphorylated STAT3 in EC. There was a significant reduction in SMC proliferation, and AKT/ERK phosphorylation in SMC, when cultured in RelA knockdown, EC conditioned media. CONCLUSION: RelA in EC plays crucial role in hypoxia induced vascular remodeling and development of pH. Targeting RelA in EC alleviates SMC proliferation as well as inflammation related processes.


Subject(s)
Lung/blood supply , NF-kappa B/metabolism , Vascular Remodeling , Animals , Cell Hypoxia , Cell Proliferation , Endothelial Cells/cytology , Endothelin-1/metabolism , Gene Expression Regulation , Gene Knockdown Techniques , Hydrogen-Ion Concentration , Intercellular Adhesion Molecule-1/metabolism , Lung/cytology , Male , Mice , Mice, Inbred C57BL , Myocytes, Smooth Muscle/cytology , NF-kappa B/deficiency , NF-kappa B/genetics
16.
PLoS One ; 12(8): e0183162, 2017.
Article in English | MEDLINE | ID: mdl-28813470

ABSTRACT

INTRODUCTION: Several biomarkers have been suggested as early predictors of acute kidney injury (AKI) after orthotopic liver transplantation (OLT). Neutrophil gelatinase-associated lipocalin-2 (NGAL) appears to be a promising predictor of AKI after OLT, but the clinical benefit remains to be proven. Recently, systemic macrophage migration inhibitory factor (MIF) has been proposed as early indicator for requirement of renal replacement therapy after OLT. The aim of this prospective, observational pilot study was to compare the predictive values of serum and urinary MIF for severe AKI after OLT to those of serum and urinary NGAL. METHODS: Concentrations of MIF and NGAL were measured in serum and urine samples collected from patients undergoing OLT. Acute kidney injury was classified according to the KDIGO criteria, with stages 2 and 3 summarized as severe AKI. Areas under the receiver operating curves (AUC) were calculated to assess predictive values of MIF and NGAL for the development of severe AKI. RESULTS: Forty-five patients (mean age 55±8 years) were included. Nineteen patients (38%) developed severe AKI within 48 hours after reperfusion. At the end of OLT, serum MIF was predictive of severe AKI (AUC 0.73; 95% confidence intervals, CI 0.55-0.90; P = 0.03), whereas urinary MIF, serum NGAL, and urinary NGAL were not. On the first postoperative day, serum MIF (AUC 0.78; CI 0.62-0.93; P = 0.006), urinary MIF (AUC 0.71; CI 0.53-0.88; P = 0.03), and urinary NGAL (AUC 0.79; CI 0.64-0.93; P = 0.02) were predictive for severe AKI, while serum NGAL was not. CONCLUSION: In the setting of OLT, MIF and NGAL had similar predictive values for the development of severe AKI.


Subject(s)
Acute Kidney Injury/blood , Acute Kidney Injury/surgery , Lipocalin-2/blood , Liver Transplantation , Macrophage Migration-Inhibitory Factors/blood , Acute Kidney Injury/urine , Female , Humans , Lipocalin-2/urine , Macrophage Migration-Inhibitory Factors/urine , Male , Middle Aged , Predictive Value of Tests , Prospective Studies , ROC Curve
17.
Int J Mol Sci ; 18(6)2017 Jun 17.
Article in English | MEDLINE | ID: mdl-28629122

ABSTRACT

This review examines the current status of knowledge of sepsis and pneumonia in the elderly population and how the dynamics of the pulmonary challenge affects outcome and consequences. Led by an unprecedented shift in demographics, where a larger proportion of the population will reach an older age, clinical and experimental research shows that aging is associated with certain pulmonary changes, but it is during infectious insult of the lungs, as in the case of pneumonia, that the age-related differences in responsiveness and endurance become obvious and lead to a worse outcome than in the younger population. This review points to the neutrophil, and the endothelium as important players in understanding age-associated changes in responsiveness to infectious challenge of the lung. It also addresses how the immunological set-point influences injury-repair phases, remote organ damage and how intake of drugs may alter the state of responsiveness in the users. Further, it points out the importance of considering age as a factor in inclusion criteria in clinical trials, in vitro/ex vivo experimental designs and overall interpretation of results.


Subject(s)
Aging/immunology , Aging/physiology , Lung/immunology , Lung/physiology , Acute Lung Injury/immunology , Age Factors , Animals , Biomarkers , Gram-Positive Bacteria/pathogenicity , Humans , Lung/microbiology , Neutrophils/immunology , Pneumonia/immunology , Pneumonia/microbiology , Risk Factors , Sepsis/diagnosis , Sepsis/immunology , Treatment Outcome
18.
Clin Transplant ; 31(6)2017 06.
Article in English | MEDLINE | ID: mdl-28370484

ABSTRACT

Experimental studies suggest that macrophage migration inhibitory factor (MIF) mediates ischemia/reperfusion injury during liver transplantation. This study assessed whether human liver grafts release MIF during preservation, and whether the release of MIF is proportional to the extent of hepatocellular injury. Additionally, the association between MIF and early allograft dysfunction (EAD) after liver transplantation was evaluated. Concentrations of MIF, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and creatine kinase (CK) were measured in effluents of 38 liver grafts, and in serum of recipients. Concentrations of MIF in the effluent were greater than those in the recipients' serum before and after reperfusion (58 [interquartile range, IQR:23-79] µg/mL vs 0.06 [IQR:0.03-0.07] µg/mL and 1.3 [IQR:0.7-1.8] µg/mL, respectively; both P<.001). Effluent MIF concentrations correlated with effluent concentrations of the cell injury markers ALT (R=.51, P<.01), AST (R=.51, P<.01), CK (R=.45, P=.01), and LDH (R=.56, P<.01). Patients who developed EAD had greater MIF concentrations in effluent and serum 10 minutes after reperfusion than patients without EAD (Effluent: 80 [IQR:63-118] µg/mL vs 36 [IQR:20-70] µg/mL, P=.02; Serum: 1.7 [IQR:1.2-2.5] µg/mL vs 1.1 [IQR:0.6-1.7] µg/mL, P<.001). CONCLUSION: Human liver grafts release MIF in proportion to hepatocellular injury. Greater MIF concentrations in effluent and recipient's serum are associated with EAD after liver transplantation.


Subject(s)
Biomarkers/metabolism , Graft Rejection/metabolism , Intramolecular Oxidoreductases/metabolism , Liver Transplantation/adverse effects , Liver/metabolism , Macrophage Migration-Inhibitory Factors/metabolism , Postoperative Complications , Tissue Donors , Female , Follow-Up Studies , Graft Rejection/etiology , Graft Rejection/pathology , Graft Survival , Humans , Liver/injuries , Liver/pathology , Male , Middle Aged , Pilot Projects , Prognosis , Prospective Studies , Risk Factors
19.
Nat Biotechnol ; 34(10): 1066-1071, 2016 Oct.
Article in English | MEDLINE | ID: mdl-27617738

ABSTRACT

Blood pressure regulation is known to be maintained by a neuro-endocrine circuit, but whether immune cells contribute to blood pressure homeostasis has not been determined. We previously showed that CD4+ T lymphocytes that express choline acetyltransferase (ChAT), which catalyzes the synthesis of the vasorelaxant acetylcholine, relay neural signals. Here we show that these CD4+CD44hiCD62Llo T helper cells by gene expression are a distinct T-cell population defined by ChAT (CD4 TChAT). Mice lacking ChAT expression in CD4+ cells have elevated arterial blood pressure, compared to littermate controls. Jurkat T cells overexpressing ChAT (JTChAT) decreased blood pressure when infused into mice. Co-incubation of JTChAT and endothelial cells increased endothelial cell levels of phosphorylated endothelial nitric oxide synthase, and of nitrates and nitrites in conditioned media, indicating increased release of the potent vasorelaxant nitric oxide. The isolation and characterization of CD4 TChAT cells will enable analysis of the role of these cells in hypotension and hypertension, and may suggest novel therapeutic strategies by targeting cell-mediated vasorelaxation.


Subject(s)
Blood Pressure/physiology , CD4-Positive T-Lymphocytes/physiology , Choline O-Acetyltransferase/metabolism , Hemostasis/physiology , Animals , Cells, Cultured , Feedback, Physiological/physiology , Female , Male , Mice , Mice, Inbred C57BL
20.
Exp Lung Res ; 42(7): 335-345, 2016 09.
Article in English | MEDLINE | ID: mdl-27585839

ABSTRACT

INTRODUCTION: Sepsis is characterized by dysregulated systemic inflammation and cytokine storm. Angiopoietin-2 (Ang-2) is known to closely correlate with severity of sepsis-related acute lung injury and mortality. The aim of this study was to clarify the mechanisms involved in Ang-2 secretion to better understand the pathophysiology of sepsis. MATERIALS AND METHODS: The concentration of Ang-2 was assessed in culture medium of pulmonary microvascular endothelial cells in the presence or absence of Gram-positive bacteria cell wall components [lipoteichoic acid (LTA) and peptidoglycan (PGN)] stimulation at different time points ranging from 15 minutes to 24 hours. Constitutive and LTA-PGN-stimulated Ang-2 level changes were also assessed after cells were pretreated with different pathway inhibitors for 1 hour. RESULTS: Two distinctive mechanisms of Ang-2 secretion, constitutive and stimulated secretion, were identified. Constitutive secretion resulted in slow but continuous increase in Ang-2 in culture medium over time. It was regulated by 3'5'-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-Ca2+ and nitric oxide (NO)-3'5'-cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG)-Ca2+ pathways and partially regulated by N-ethyl-maleimide-sensitive factor-Ca2+ pathways. LTA-PGN stimulation caused rapid and potent increase followed by gradual decrease of Ang-2. It was partially regulated by both Ral A-phospholipase D and NSF-Ca2+ pathways. CONCLUSIONS: We demonstrated characteristics and involved pathways for two distinctive secretory mechanisms, constitutive and stimulated, of Ang-2 in pulmonary microvascular endothelial cells. Considering the close correlation of Ang-2 with sepsis outcomes, our findings provide a better understanding of an important mechanism associated with sepsis pathophysiology and identify possible therapeutic targets to improve outcomes in the potentially lethal disease.


Subject(s)
Angiopoietin-2/metabolism , Endothelial Cells/metabolism , Lung/blood supply , Cell Wall/chemistry , Cells, Cultured , Endothelial Cells/drug effects , Gram-Positive Bacteria/chemistry , Humans , Lipopolysaccharides/pharmacology , Lung/cytology , Peptidoglycan/pharmacology , Sepsis/physiopathology , Teichoic Acids/pharmacology
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