Macrophage Chemotactic Protein-1 Research Articles

Elevated cardiac hemoglobin expression is associated with a pro-oxidative and inflammatory environment in primary mitral regurgitation

BackgroundPrimary mitral regurgitation (PMR) is associated with oxidative and inflammatory myocardial damage. We reported greater exosome hemoglobin (Hb) in pericardial fluid (PCF) versus plasma, suggesting a cardiac source of Hb. ObjectiveTest the hypothesis that Hb is produced in the PMR heart and is associated with increased inflammation. Methods and resultsHb gene expression for subunits alpha (HBA) and beta (HBB) was assessed in right atria (RA), left atria (LA) and left ventricular (LV) tissue from donor hearts (n = 10) and PMR patient biopsies at surgery (n = 11). PMR patients (n = 22) had PCF and blood collected for macrophage markers, pro-inflammatory cytokines, and matrix metalloproteinases (MMPs). In-situ hybridization for HBA mRNA and immunohistochemistry for Hb-alpha (Hbα) and Hb-beta (Hbβ) protein was performed on PMR tissue. ResultsHBA and HBB genes are significantly increased (>4-fold) in RA, LA, and LV in PMR vs. normal hearts. In PMR tissue, HBA mRNA is expressed in both LV cardiomyocytes and interstitial cells by in-situ hybridization; however, Hbα and Hbβ protein is only expressed in interstitial cells by immunohistochemistry. PCF oxyHb is significantly increased over plasma along with low ratios (<1.0) of haptoglobin:oxyHb and hemopexin:heme supporting a highly oxidative environment. Macrophage chemotactic protein-1, tumor necrosis factor-α, interleukin-6, and MMPs are significantly higher in PCF vs. plasma. ConclusionThere is increased Hb production in the PMR heart coupled with the inflammatory state of the heart, suggests a myocardial vulnerability of further Hb delivery and/or production during cardiac surgery that could adversely affect LV functional recovery.

The influence of Salvia cadmica Boiss. extracts on the M1/M2 polarization of macrophages primed with Helicobacter pylori lipopolysaccharide in conjunction with NF-kappa B activation, production of cytokines, phagocytic activity and total DNA methylation.

The large number of secondary derivatives have been isolated from the genus Salvia with about 700 species, and used in the pharmacopoeia throughout the world. Various biological properties of Salvia formulations have been reported including as antioxidant, antimicrobial, hypotensive, anti-hyperglycemia, anti-hyperlipidemia, anti-cancer, and skin curative. Salvia cadmica Boiss. root and aerial part extracts enriched with polyphenols are bactericidal towards gastric pathogen Helicobacter pylori (Hp) and diminish deleterious effects induced by Hp lipopolysaccharide (LPS) towards gastric epithelial cells. To examine the influence of S. cadmica extracts on the M1/M2 polarization of macrophages primed with Hp LPS vs standard LPS Escherichia coli (Ec), and the macrophage cytokine as well as phagocytic activity, which are affected during Hp infection. Macrophages derived from THP-1 human monocytes primed with LPS Hp/Ec and/or S. cadmica extracts, were examined for the biomarkers of activation (surface, cytoplasmic or soluble), and phagocytic capacity. The bone marrow macrophages of Caviaporcellus were used to determine the engulfment of Hp. Priming of THP-1cells (24h) with LPS Hp/Ec resulted in polarization of M1 macrophages, activation of nuclear factor kappa B, secretion of tumor necrosis factor (TNF)-α, interleukin (IL)-1 beta, macrophage chemotactic protein (MCP)-1, immunoregulatory IL-10, and production of reactive oxygen species. These effects were diminished after restimulation of cells with S. cadmica extracts. THP-1 macrophages exposed to studied extracts showed an increased phagocytic capacity, in conjunction with elevated CD11b/CD11d expression and enhanced production of inducible nitric oxide synthase. They also increased Hp engulfment by bone marrow macrophages. These effects were not related to a global DNA methylation. S. cadmica extracts possess an immunomodulating activity, which might be useful in control of H. pylori LPS driven activity of macrophages.

Mycobacterium bovis BCG increase the selected determinants of monocyte/macrophage activity, which were diminished in response to gastric pathogen Helicobacter pylori

High antibiotic resistance of gastric pathogen Helicobacter pylori (Hp) and the ability to escape the host immune response prompt searching for therapeutic immunomodulators. Bacillus Calmette–Guerin (BCG) vaccine with Mycobacterium bovis (Mb) is a candidate for modulation the activity of immunocompetent cells, and onco-BCG formulation was successfully used in immunotherapy of bladder cancer. We determined the influence of onco-BCG on the phagocytic capacity of human THP-1 monocyte/macrophage cells, using the model of Escherichia coli bioparticles and Hp fluorescently labeled. Deposition of cell integrins CD11b, CD11d, CD18, membrane/soluble lipopolysaccharide (LPS) receptors, CD14 and sCD14, respectively, and the production of macrophage chemotactic protein (MCP)-1 were determined. Furthermore, a global DNA methylation, was also assessed. Human THP-1 monocytes/macrophages (TIB 202) primed or primed and restimulated with onco-BCG or Hp, were used for assessment of phagocytosis towards E. coli or Hp, surface (immunostaining) or soluble activity determinants, and global DNA methylation (ELISA). THP-1 monocytes/macrophages primed/restimulated with BCG showed increased phagocytosis capacity towards E. coli fluorescent particles, elevated expression of CD11b, CD11d, CD18, CD14, sCD14, increased MCP-1 secretion and DNA methylation. Preliminary results indicate that BCG mycobacteria may also induce the phagocytosis of H. pylori by THP-1 monocytes. Priming or priming and restimulation of monocytes/macrophages with BCG resulted in an increased activity of these cells, which was negatively modulated by Hp.

The Emerging Roles of IL-36, IL-37, and IL-38 in Diabetes Mellitus and its Complications.

Diabetes mellitus is a metabolic disease caused by a combination of genetic and environmental factors. The importance of the inflammatory response occurring in the pancreas and adipose tissue in the occurrence and progression of diabetes has been gradually accepted. Excess blood glucose and free fatty acids produce large amounts of inflammatory cytokines and chemokines through oxidative stress and endoplasmic reticulum stress. There is sufficient evidence that proinflammatory mediators, such as interleukin (IL)-1β, IL-6, macrophage chemotactic protein-1, and tumor necrosis factor-α, are engaged in insulin resistance in peripheral adipose tissue and the apoptosis of pancreatic β-cells. IL-36, IL-37, and IL-38, as new members of the IL-1 family, play an indispensable role in the regulation of immune system homeostasis and are involved in the pathogenesis of inflammatory and autoimmune diseases. Recently, the abnormal expression of IL-36, IL-37, and IL-38 in diabetes has been reported. In this review, we discuss the emerging functions, potential mechanisms, and future research directions on the role of IL-36, IL-37, and IL-38 in diabetes mellitus and its complications.

Aberrant pulmonary immune response of obese mice to periodontal infection.

Obesity and periodontitis constitute mutual risk factors in respiratory disorders; this study aimed to explore the pulmonary immune response to periodontal infection using combined animal models with diet-induced obesity (DIO). Thirty-two C57 BL/6J mice were randomly divided into low-fat (LF) or high-fat (HF) diet groups and fed an LF diet as a control or an HF diet to induce obesity. The 30-week mice in the diet group were divided into periodontal ligation group (10 days using Porphyromonas gingivalis ATCC 33277) or sham-ligation group. The expressions of the macrophage-specific maker (F4/80), macrophage chemotactic protein1 (MCP1), and inflammatory cytokines in lung tissues were analyzed. The mRNA and protein levels of F4/80, MCP1, interleukin (IL)-1β, and IL-6 expressions were significantly upregulated by obesity in lung tissues. However, the mRNA and protein levels of F4/80, MCP1, and IL-6 were downregulated by periodontitis in DIO mice relative to that of the HF control group. Periodontitis increased tumor necrosis factor-α level of lung tissues under LF, while IL-10 was not affected by obesity regardless of periodontitis. Periodontitis may aggravate pulmonary immune response in obese rodents. This may relate to the imbalance of the pro- and anti-inflammatory cytokine status of lung lesions, which tends to attenuate the infiltration of alveolar macrophages.

Features of immunopathogenesis of a new coronavirus infection

The main biological characteristics of viruses of the Coronaviridae family are presented. The features of the immunopathogenesis of these infections are analyzed. It was found that the structural proteins of the spine, membrane, envelope and nucleocapsid play an important role in the immunopathogenesis of COVID-19 infection. They are associated with hyperactivation of neutrophils and monocytes-macrophages, secreting large amounts of pro-inflammatory cytokines and chemokines. This contributes to the development of a cytokine storm and an unfavorable prognosis of the disease. A particularly high risk of developing pneumonia exists against the background of an increase in the production of: macrophage inflammatory protein-1 alpha, macrophage chemotactic protein, interleukin 8. At the height of infection in some patients, macrophages and dendritic cells infected with SARS-CoV-2 lose their ability to produce type I interferons and pro-inflammatory cytokines. On the part of cellular immunity, a significant decrease in the number of CD4+ and CD8+-lymphocytes was noted. Among IgG sub-isotypes, IgG3 antibodies had the highest reactivity, and IgG1 antibodies were less reactive. Antibodies to spike protein with low specificity or low titer do not neutralize the virus and contribute to the contamination of immunocompetent cells via Fc receptors. Low-affinity antibodies or their low levels can contribute to increased cell sensitivity to SARS-CoV-2 and the development of severe forms of COVID-19 disease.

Effects of Thrombomodulin in Reducing Lethality and Suppressing Neutrophil Extracellular Trap Formation in the Lungs and Liver in a Lipopolysaccharide-Induced Murine Septic Shock Model.

Neutrophil extracellular trap (NET) formation, an innate immune system response, is associated with thrombogenesis and vascular endothelial injury. Circulatory disorders due to microvascular thrombogenesis are one of the principal causes of organ damage. NET formation in organs contributes to the exacerbation of sepsis, which is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. We have previously reported that recombinant human soluble thrombomodulin (rTM) reduces lipopolysaccharide (LPS)-induced NET formation in vitro. Here, we aimed to show that thrombomodulin (TM)-mediated suppression of NET formation protects against organ damage in sepsis. Mice were injected intraperitoneally (i.p.) with 10 mg/kg LPS. rTM (6 mg/kg/day) or saline was administered i.p. 1 h after LPS injection. In the LPS-induced murine septic shock model, extracellular histones, which are components of NETs, were observed in the liver and lungs. In addition, the serum cytokine (interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), macrophage chemotactic protein-1 (MCP-1), and interleukin-10 (IL-10)) levels were increased. The administration of rTM in this model prevented NET formation in the organs and suppressed the increase in the levels of all cytokines except IL-1β. Furthermore, the survival rate improved. We provide a novel role of TM in treating inflammation and NETs in organs during sepsis.

Gingival crevicular fluid levels of cytokine, chemokine, and growth factors in patients with periodontitis or gingivitis and periodontally healthy subjects: a cross-sectional multiplex study.

IntroductionGingival crevicular fluid (GCF) is an important resource for detecting inflammatory biomarkers related to periodontal disease. The purpose of this research was to identify the possible relation between cytokine levels and periodontal status.Material and methodsGCF samples collected from 25 periodontally healthy individuals, 24 with gingivitis, and 24 with periodontitis were analyzed using the MAGPIX system with a Bio-Plex Pro Human Cytokine 27-plex kit. Gingival index (GI), periodontal pocket depth (PPD), plaque index (PI), and clinical attachment level (CAL) were measured from each tooth to determine each patient’s periodontal status.ResultsAll clinical parameters showed statistically significant differences between groups. While interleukin (IL)-1β, IL-6, macrophage chemotactic protein 1 (MCP-1), interferon γ-induced protein 10 (IP-10) and vascular endothelial growth factor (VEGF) levels were statistically significantly higher in patients with periodontitis compared to periodontally healthy subjects, IL-15 levels were found to be statistically significantly higher in periodontally healthy individuals compared to periodontitis (p < 0.05). Also, IL-1β and IP-10 showed positive correlations with PPD, CAL, GI and bleeding on probing (BOP).ConclusionsIt is considered that IL-1β, IL-6, IL-15, MCP-1, VEGF and IP-10 could be related to periodontal disease and health and can be used as an adjunct to clinical examination in future research design. Scanning cytokines in GCF with a multiplex immunoassay technique is consequential, especially because many cytokine types are found in one sample.

Commentary: Myths and facts on vitamin D amidst the COVID-19 pandemic

Commentary: Myths and facts on vitamin D amidst the COVID-19 pandemic

Study of urinary monocytic chemotactic factor

The review presents the data on clinical diagnostic value of studying one of the components of urinary proteome - macrophage chemotactic protein -1 (MCP-1). Along with the general characteristics of MCP-1, there are given the data on changes in its concentration regarding various diseases of the urinary system. It was shown that for various diseases and research conditions, the concentration of MCP-1 can be an important diagnostic criterion in assessing inflammatory, metabolic, fibrotic and other renal lesions.

Predicting Complete Response to Itacitinib and Corticosteroids in Acute Graft Versus Host Disease

<h3>Background</h3> Acute graft versus host disease (aGVHD) represents a serious and potentially life threatening condition in patients receiving hematopoietic stem cell transplantation (HSCT). aGVHD is characterized by increased levels of inflammatory mediators and activated T cells in circulation leading to tissue and organ damage. In a parallel-cohort phase 1 trial (NCT02614612) that evaluated the combination of corticosteroids and itacitinib, a potent and highly selective JAK1 inhibitor, we utilized broad proteomic analysis to identify potentially predictive biomarkers of therapeutic response to the combination treatment. <h3>Methods</h3> Plasma was collected from 25 patients enrolled in the clinical trial prior to and at designated times following treatment. Proteomic analysis on plasma was conducted by OLINK Proteomics using a proximity extension assay. Statistical differences were identified using unpaired T tests and one-way ANOVA. Significance was conferred when p<0.05. All participants provided written consent. <h3>Results</h3> Patients were stratified based on their overall response to treatment with itacitinib and corticosteroid at day 28 (based on CIBMTR). Patients included 10 complete responders (CR), 1 very good partial responder (VGPR), 8 partial responders (PR) and 6 patients with progressive disease and/or death (PD/death) prior to day 28. Biomarkers were identified and associated with therapeutic response by comparing the levels of approximately 1000 proteins in the CR (N=10) and PD/Death (N=6) cohorts specifically. Initial analysis identified 55 proteins significantly upregulated (P<0.05) and 75 proteins significantly downregulated (P<0.05) at baseline in the CR cohort and the PD/Death cohort. Potential biomarkers were further screened based on correlation to known aGVHD biomarkers, degree of separation between the populations, as well as reliable and consistent testing (ie, coefficient of variation <20%). Novel biomarkers identified include macrophage chemotactic protein 3 (MCP3/CCL7), stem cell factor (SCF/KIT-L), interleukin 8 (IL8), paraoxonase 3 (PON3), calcitonin (CALCA), and tumor necrosis factor receptor super family 6B (TNFRSF6B). (Table 1). Each of these biomarkers demonstrated a significant (P<.05) difference between CR and PD/death cohorts, with intermediate levels detected in patients with an intermediate (VGPR/PR) response to treatment. <h3>Conclusion</h3> Biomarkers identified in this study may be useful in predicting complete responses to treatment with a combination of corticosteroids and itacitinib in patients with aGVHD post HSCT.

Apoptosis Inhibitor of Macrophage, Monocyte Chemotactic Protein-1, and C-Reactive Protein Levels Are Increased in Patients with Metabolic Syndrome: A Pilot Study.

Background: Apoptosis inhibitor of macrophage (AIM) and monocyte chemotactic protein-1 (MCP-1) are molecules that cause migration of M1 macrophages to visceral adipocytes, which is the first step in development of metabolic syndrome. The aim of this study is to evaluate the status of AIM and MCP-1 in metabolic syndrome and to investigate their use as biomarkers. Methods: Forty metabolic syndrome patients and 40 healthy individuals were enrolled in the study. Serum AIM, MCP-1, and C-reactive protein (CRP) levels were measured by enzyme-linked immunosorbent assay. Results: AIM, MCP-1, and CRP levels were significantly higher in the metabolic syndrome group (P < 0.01, P < 0.01, and P < 0.05, respectively). There was a positive correlation of serum AIM, MCP-1, and CRP levels with waist circumference (r = 0.480, r = 0.663, and r = 0.418, respectively; P < 0.01). Receiver operating characteristic (ROC) curve analyses revealed AIM, MCP-1, and CRP cutoff points as 2383.7 ng/mL, 172.8 pg/mL, and 0.366 mg/dL, which could be used in the diagnosis of metabolic syndrome with highest sensitivity and specificity. In the logistic regression model, including age, AIM, CRP, and MCP-1 as covariates, having serum AIM and CRP levels above cutoffs were significant independent predictors for metabolic syndrome (odds ratios 13.8 and 21.3), whereas the serum MCP-1 level was not a significant independent predictor, although the odds ratio was 2.6 (P = 0.193). Conclusions: These results suggest that AIM and MCP-1 may play a role in the pathogenesis of metabolic syndrome. AIM and CRP levels may be used as biomarkers in the diagnosis of metabolic syndrome. Although MCP-1 is not an independent predictor, its elevation in metabolic syndrome is noteworthy, which warrants further analyses in larger groups.

Differential Expression of Circulating Inflammatory Proteins Following Sport-Related Traumatic Brain Injury.

Sport-related traumatic brain injury (TBI) elicits a multifaceted inflammatory response leading to brain injury and morbidity. This response could be a predictive tool for the progression of TBI and to stratify the injury of which mild TBI is most prevalent. Therefore, we examined the differential expression of serum inflammatory markers overtime and identified novel markers in repetitively concussed athletes. Neuropsychological assessment by Wechsler Adult Intelligence Scale (WAIS) and Immediate Post Concussion Assessment and Cognitive Test (ImPACT) was performed on rugby players and serum was taken from healthy, concussed and repetitively concussed athletes. Serum was also obtained <1 week and >1 week after trauma and analyzed for 92 inflammatory protein markers. Fibroblast growth factor 21 (FGF21) and interleukin-7 (IL-7) differentiated repetitively concussed athletes. Macrophage chemotactic protein-1 (MCP-1), tumor necrosis factor superfamily member 14 (TNFSF14) were significantly reduced >1 week and chemokine (C-X3-C motif) ligand 1 (CX3CL1) upregulated <1 week after injury. FGF21 and MCP-1 negatively correlated with symptoms and their severity. We have identified dynamic changes in the inflammatory response overtime and in different classes of concussion correlating with disease progression. This data supports the use of inflammatory biomarkers as predictors of symptom development due to secondary complications of sport-related mTBI.

A Biomarker Signature to Predict Complete Response to Itacitinib and Corticosteroids in Acute Graft Versus Host Disease

BACKGROUND: Acute graft versus host disease (aGVHD) represents a serious and potentially life-threatening condition in patients receiving hematopoietic stem cell transplantation (HSCT). Development of aGVHD is characterized by increased levels of inflammatory mediators and activated T cells in circulation, leading to tissue and organ damage. Previously, we demonstrated that a panel measuring ST2, REG3A, and TNFR1 poorly predicted response to the combination of corticosteroids and itacitinib, a potent and highly selective JAK1 inhibitor, in a parallel-cohort phase 1 trial (NCT02614612). In this study, we utilized broad proteomic analysis to identify potentially predictive biomarkers of therapeutic response to the combination treatment. METHODS: Plasma samples were collected from 25 patients enrolled in the Phase 1 clinical trial prior to and at designated times following treatment. Broad proteomic analysis was conducted by OLINK Proteomics using a proximity extension assay. Selected biomarkers were quantitated by the same method based on standard curves generated using recombinant proteins. Statistical differences were identified using unpaired T tests and significance conferred when p&lt;0.05. All participants provided written consent before enrollment. RESULTS: The 25 patients in this study were stratified based on overall response to treatment with itacitinib and corticosteroid at day 28 (based on CIBMTR). Patients included 10 complete responders (CR), 1 very good partial responder (VGPR), 8 partial responders (PR) and 6 patients with progressive disease and/or death (PD/death) prior to day 28. Novel biomarkers were identified and associated with therapeutic response by comparing the levels of approximately 1000 proteins in the CR (N=10) and PD/Death (N=6) cohorts specifically. The initial analysis identified 50 proteins significantly upregulated (P&lt;.05) and 52 proteins significantly down-regulated (P&lt;.05) in the CR cohort at baseline compared with the PD/Death cohort. The list of candidates were further screened based on correlation to known aGVHD biomarkers, degree of separation between the populations, as well as reliable and consistent testing (ie, coefficient of variation &lt;20%). From these analyses, candidate biomarkers were identified and representative examples are shown in table 1. Novel biomarkers include macrophage chemotactic protein 3 (MCP3/CCL7), stem cell factor (SCF/KIT-L), interleukin 8 (IL8), and tumor necrosis factor receptor super family 6B (TNFRSF6B). Each of these candidate biomarkers demonstrated a significant (P&lt;.05) difference between CR and PD/death cohorts, with intermediate levels detected in patients with an intermediate (VGPR/PR) response to treatment. Because MCP3, IL8, and TNFRSF6B presumably associate with inflammation, elevation of these biomarkers in the PD/Death cohort that poorly respond to a JAK inhibitor (JAKi) is not surprising. In addition, elevation of SCF in responders to JAKi is consistent with supporting hematopoiesis. CONCLUSION: Potentially novel biomarkers may be useful in predicting complete responses to treatment with a combination of corticosteroids and itacitinib in patients with aGVHD post HSCT. Disclosures Pratta: Incyte Research Institute: Employment. Liu:Incyte: Employment, Equity Ownership. Owens:Incyte Corporation: Employment, Equity Ownership. Yan:Incyte Corporation: Employment. Arbushites:Incyte: Employment. Howell:Incyte: Employment.

Superiority of the Non-Glycosylated Form Over the Glycosylated Form of Irisin in the Attenuation of Adipocytic Meta-Inflammation: A Potential Factor in the Fight Against Insulin Resistance.

Irisin is an adipomyokine that promotes the browning of white adipose tissue and exhibits protective potential against the development of insulin resistance and type 2 diabetes. In our bodies, it occurs in its glycosylated form (G-IR): its activity is still poorly understood, because the majority of studies have used its non-glycosylated counterpart (nG-IR). Glycosylation can affect protein function: therefore, the present study attempted to compare the actions of both forms of irisin toward inflammatory activation of the main component of adipose tissue. The study was carried out in a coculture of 3T3 adipocytes and RAW 264.7 macrophages maintained in the presence of nG-IR or G-IR. The impact on vitality and the expression and release of key inflammatory mediators important for insulin resistance and diabetes development were assessed. The studies showed that both forms effectively inhibited the expression and release of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, macrophage chemotactic protein (MCP)-1, high-mobility group box (HMGB1), leptin, and adiponectin. However, in the case of TNF-α, IL-1β, MCP-1, and HMGB1, the inhibition exerted by nG-IR was more prominent than that by G-IR. In addition, only nG-IR significantly inhibited macrophage migration. Here, nG-IR seemed to be the stronger inhibitor of the development of obesity-related inflammation; however, G-IR also had anti-inflammatory potential.

Compartmentalisation of the inflammatory response following aneurysmal subarachnoid haemorrhage

IntroductionThere is some evidence to suggest that a systemic and central nervous system (CNS) inflammatory response occurs following aneurysmal subarachnoid haemorrhage (aSAH) which may be related to the pathophysiology of early brain injury and delayed ischaemic neurological deficit (DIND). The aim of this study was to measure inflammatory mediator levels in plasma and cerebrospinal fluid (CSF) in the days following aSAH and to determine their association with aSAH, DIND and clinical outcome. Material and methodsPlasma and CSF samples were obtained prospectively from patients with aSAH on days 1–3, 5, 7 and 9 and profiled for interleukin (IL)-1α, IL-1β, IL-4, IL-6, IL-8, IL-10, IL-15, IL-17, IL-18, macrophage chemotactic protein (MCP)-1, vascular endothelial growth factor (VEGF) and tumour necrosis factor (TNF)-α. Plasma and CSF samples from non-aSAH patients undergoing spinal anaesthesia were used as controls. ResultsThe CSF levels of all cytokines investigated except for IL-1α were significantly higher in aSAH compared to controls in the first seven days of ictus. CSF levels of IL-1α (p = 0.014), IL-18 (p = 0.016), IL-6 (p = 0.0006) and IL-8 (p = 0.006) showed significant increases in the days following aSAH. Conversely IL-17 demonstrated a decrease. In particular, IL-4 was higher in the CSF of patients who had DIND at all time-points (p = 0.032). Plasma IL-6 and IL-8 levels were higher, and IL-1α levels lower, than controls at most time-points. All mediators demonstrated persistent elevation in the CSF compared to plasma apart from IL-1α and IL-18 which followed the opposite trend. Day 3 plasma IL-6 levels predicted poor outcome at six months (Exp(B) 1.12 1.03-1.22, P = 0.012), although this association was lost in the second analysis incorporating Fisher grade, WFNS grade and age. ConclusionThe post aSAH inflammatory response peaks on days 5–7 post ictus and remains largely compartmentalised within the CNS. IL-4 may have a particular association with DIND although its precise role in the pathophysiology of the disorder remains unclear. IL-6 predicted poor outcome but not independently of clinical grade, suggesting that it may be a surrogate marker of early brain injury.

Distinct release strategies are required to modulate macrophage phenotype in young versus aged animals

The role of innate immunity and macrophages in the host response to biomaterials has received renewed attention. A context-dependent spectrum of macrophage phenotypes are shown to affect tissue integration and performance of implanted biomaterials and medical devices. Recent studies by our group demonstrated that the host response in aged animals was characterized by delayed macrophage recruitment, differences in marker expression and a shifted pro-inflammatory (M1) response, associated with an unresolved host response in the long-term. The present work sought to study the effects of single and sequential cytokine delivery regimens in aged mice to restore delayed recruitment of macrophages and shift the inflammatory host response towards an M2-like phenotype, using MCP-1 (macrophage chemotactic protein-1) and IL-4 (interleukin-4), respectively. Implantation of cytokine-eluting implants showed a preserved response to MCP-1 in both young and aged animals, restoring delayed macrophage recruitment in aged mice. However, the response elicited by IL-4, sequential delivery of MCP-1/IL-4 and coating components was distinct in young versus aged mice. While single delivery of IL-4 did not counteract the high inflammatory response observed in aged mice, the sequential delivery of MCP-1/IL-4 was capable of restoring both recruitment and shifting the macrophage response towards an M2-like phenotype, associated with decreased implant scarring in the long-term. In young mice, sequential delivery was not as effective as IL-4 alone at promoting an M2-like response, but did result in a reduction of M1 macrophages and capsule deposition downstream. These results demonstrate that a proper understanding of patient/context-dependent biological responses are needed to design biomaterial-based therapies with improved outcomes in the setting of aging.

Intravenous injection of l-aspartic acid β-hydroxamate attenuates choroidal neovascularization via anti-VEGF and anti-inflammation

Choroidal neovascularization (CNV) is a hallmark of exudative age-related macular degeneration (exAMD) and a major cause of visual loss in AMD. Despite the widespread use of anti-VEGF therapy, serious adverse effects arise from repeated intravitreal injection of anti-VEGF antibodies, which warrant alternative strategy. We report herein that in a CNV murine model created by krypton red laser, intravenous injection of a serine racemase inhibitor, l-Aspartic acid β-hydroxamate (L-ABH), significantly reduced CNV at the dose 6 mg/kg on the first day before and followed by 3 mg/kg on the third day after laser injury. The CNV volumes were analyzed with isolectin GS-IB4 staining on choroidal/RPE flat mounts on the seventh day after laser injury. Injection of L-ABH did not produce negative effects on retinal function and visual behavior. To dissect the mechanism in vitro, pretreatment with L-ABH in primary RPE cultures significantly reduced production of vascular endothelial growth factor (VEGF) and macrophage chemotactic protein 1 (MCP-1) by TNFα-primed RPEs. Consistent with these observations, L-ABH pretreatment significantly attenuated macrophage migration mediated by TNFα-primed RPE. Collectively, intravenous injection of L-ABH significantly reduced CNV volumes via reducing production of VEGF and MCP-1 by inflammation-primed RPEs.

Effect of Ocimum basilicum, Ocimum selloi, and Rosmarinic Acid on Cerebral Vascular Damage in a Chronic Hypertension Model.

The main objective of treatment against hypertension is not only to reduce blood pressure levels, but also to reduce vascular risk in general. In the present work, administering angiotensin II (AGII; 0.2 µg/kg intraperitoneally (i.p.) for 12 weeks) activates the hypothalamic-pituitary-adrenal (HPA) axis, which caused an increase in corticosterone levels, as well as in proinflammatory cytokines (interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-α)) and macrophage chemotactic protein 1 (MCP-1), and decreased anti-inflammatory cytokines (interleukin 10 (IL-10) and interleukin 4 (IL-4)). On observing the behavior in the different models, an anxiogenic effect (elevated plus maze (EPM)) and cognitive impairment (water Morris maze (WMM)) was observed in animals with AGII. By administering organic extracts from Ocimum basilicum (Oba-EtOAc) and Ocimum selloi (Ose-EtOAc), and some doses of rosmarinic acid (RA) (6 weeks per os (p.o.)), the damage caused by AGII was stopped by re-establishing corticosterone serum levels and by decreasing the proinflammatory cytokines and MCP-1.

Anti-Inflammatory Effect of Surfactant Lipid in the Vaginal Mucosa: A Pilot Study.

The aim of the study was to test the hypothesis that vaginal administration of surfactant lipids, which may counter-balance the proinflammatory effects of vaginal surfactant protein A, will decrease proinflammatory cytokines and increase anti-inflammatory cytokines in vaginal mucosal fluid in healthy women. Three groups of healthy cycling women were randomized to receive vaginally a single dose of the following: (1) low-dose calfactant, a type of surfactant lipids, 0.8 mg/ml; (2) high-dose calfactant 8.0 mg/ml; or (3) placebo, at the time of resolution of menses. Vaginal mucosal fluid was collected before administration and also 1 and 8 days after administration of each treatment. After 1 mo, each group was randomized to each alternative treatment; thus, for a 3-month treatment period, each group received each of the 3 treatments. Vaginal fluid was tested using a Multiplex Immunoassay System. Cytokine concentrations on day 1 and day 8 were compared with day zero and tested for significance with the Student's t test. Six healthy subjects completed each treatment. Subjects given high-dose calfactant had, by day 8, a significant reduction in macrophage chemotactic protein-1 and interleukin 15 (IL-15) compared with low-dose calfactant or placebo. High-dose calfactant resulted in an increase in anti-inflammatory cytokines that trended toward significance on day 1 (IL-1RA) or day 8 (IL-10). This pilot study in healthy women demonstrates that calfactant reduces proinflammatory cytokines and increases anti-inflammatory cytokines in the vagina. We propose that calfactant may be an effective vaginal anti-inflammatory therapy for inflammatory vaginitis and similar disorders for which current therapy is ineffective.