Leukocyte Mobilization Research Articles

Kinetics of Immune Cell Mobilization during Acute Aerobic Exercise in Healthy Adults.

While pre-post differences in immune cell mobilization after acute aerobic exercise are well investigated, less is known about when and to what extent immune cells are mobilized during acute aerobic exercise. This experimental trial aimed to investigate the detailed kinetics of circulating immune cells in twelve healthy adults (n=6 females) who completed a 40-min aerobic exercise bout at 60% of the participants' V̇O2peak on a bicycle ergometer. Cellular inflammation markers and sex-dependent differences in circulating immune cells were analyzed. Blood samples were taken immediately before, after warm-up, during exercise after 5 min, 10 min, 15 min, 30 min, 40 min (cessation), and 60 min post exercise. Significant increases in leukocytes (p<0.001), lymphocytes (p<0.001), neutrophils (p=0.003) and platelets (p=0.047) can be observed after 5 min of exercise. The cellular inflammation markers show significant alterations only post exercise. Significant sex differences were observed for neutrophils (p=0.049) and neutrophil-to-lymphocyte ratio (p=0.007) one hour post exercise. These results indicate that i) leukocytes are already mobilized after 5 min of moderate-to-vigorous aerobic exercise, ii) the magnitude of exercise induced leukocyte mobilization is dependent on exercise duration, iii) integrative cellular inflammation markers are only altered after exercise cessation, and iv) the observed effects might be sex-dependent.

Endobiogenic Biology of Function Indices in a Cohort of Kidney Transplant Recipients.

Background and Objectives: Endobiogeny is a global systems approach to human biology based on the concept that the endocrine system manages the metabolism. Biology of function (BoF) indices are diagnostic tools in endobiogenic medicine that reflect the action of the endocrine system on the cells and the metabolic activity of an organism. Kidney transplant recipients are a very specific patient population due to their constant use of immunosuppressive agents such as steroids and anamnesis of chronic kidney disease. The aim of this study was to assess the tendencies of endobiogenic BoF indices in a kidney transplant recipient population and to determine the relationship between BoF index values and histology-proven kidney transplant rejection. Materials and Methods: A total of 117 kidney transplant recipients undergoing surveillance or indication allograft biopsy were included in this study. Endobiogenic BoF indices were calculated from complete blood count tests taken before the kidney biopsy. Histology samples were evaluated by an experienced pathologist according to the Banff classification system. Clinical and follow-up data were collected from an electronic patient medical record system. Results: Overall, <35% of the patients had BoF index values assumed to be normal, according to the general population data. Additionally, >50% of the patients had lower-than-normal adaptation, leucocyte mobilization, genital, and adjusted genital ratio indices, while the Cata-Ana, genito-thyroid ratio, adrenal gland, and cortisol indices were increased in >50% of the transplant recipients. The adaptation index was significantly higher in patients with biopsy-proven transplant rejection and demonstrated an AUC value of 0.649 (95%CI 0.540-0.759) for discriminating rejectors from patients without transplant rejection. Conclusions: Most of the kidney transplant recipients had abnormal BoF index values, reflecting increased corticotropic effects on their cells. The adaptation index distinguished patients with biopsy-proven transplant rejection from those without it.

Splenic Modulation of Early Post-Resuscitation Inflammation in a Porcine Model of Sudden Cardiac Arrest

Objective: The spleen has been implicated as a potential therapeutic target for acute anti-inflammatory intervention via modulation of splenic nerve activity, but the translational viability of this approach is unclear due to limited mechanistic understanding of splenic leukocyte mobilization in clinically relevant models. In contrast to prior rodent studies, we recently demonstrated that the spleen is not required for leukocyte mobilization after focal myocardial ischemia/reperfusion in swine. However, the spleen's role in the early inflammatory response to whole-body ischemia/reperfusion following resuscitation from sudden cardiac arrest (SCA) remains unexplored. Therefore, we used a surgical approach to investigate the spleen's contribution to early post-resuscitation inflammation in a porcine model of SCA. Methods: Eighteen swine were randomized to splenectomy (SPLX; n=9) or sham surgery (SHAM; n=9), and subsequently underwent 8 minutes of electrically-induced ventricular fibrillation SCA one week later. Mechanical CPR with defibrillation and intravenous epinephrine (EPI; 0.015 mg/kg) was performed to achieve return of spontaneous circulation (ROSC; defined as sustained MAP&gt;60mmHg). Hemodynamic parameters, cardiac function, circulating biomarkers of injury (cTnI) and inflammation (IL-6, TNF-⍺), and blood leukocyte levels were assessed for 4 hours post-ROSC, at which time the heart and brain were collected for post-mortem analysis of leukocyte infiltration via flow cytometry. Results: SPLX and SHAM animals were resuscitated at a similar rate (SHAM vs SPLX: 56% vs. 44%) and required a similar number of defibrillation attempts (4.3±0.8 vs. 5.2±1.3), but SPLX required more EPI boluses during CPR (3.3±1.3 vs. 1.4±0.2; p&lt;0.05) and took longer to achieve ROSC (779±196 vs. 455±37 sec; p&lt;0.05). After ROSC, SPLX animals required more EPI (43±10 vs. 13±10 μg/kg; p&lt;0.05) to maintain MAP &gt;60mmHg and tended to have higher circulating cTnI levels compared to SHAM (19.5±4.4 vs. 5.8±4.4 ng/mL; p=0.07). A significant elevation in circulating leukocytes was observed from pre-SCA to 4-hours post-ROSC in both SPLX (19.5±1.3 to 32.0±2.6 103/μl; p&lt;0.05) and SHAM (from 15.1±1.3 to 23.7±2.9 103/μl; p&lt;0.05), along with an increase in circulating IL-6 and TNF-α vs. pre-SCA values that tended to be higher in SPLX. Flow cytometry revealed post-ROSC leukocyte infiltration that was particularly evident in the brain, with an increased number of inflammatory granulocytes (CD172+CD163-) and dendritic cells (CD172+CD16+) in multiple brain regions of SPLX and SHAM animals compared with healthy controls. Conclusion: These results demonstrate that, in swine, the spleen is not required for the robust early inflammatory response to resuscitation from SCA. This observation provides further evidence that, in contrast to rodents, the spleen is not a primary contributor to sterile inflammation following ischemia/reperfusion injury in large animals. This translational study suggests that neuromodulation of splenic leukocyte mobilization may not be a viable therapeutic strategy for mitigating acute inflammation in clinical post-cardiac arrest syndrome. Supported by funding from the NIH and US Department of Veteran's Affairs. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Dose-Dependent Tranexamic Acid Blunting of Penumbral Leukocyte Mobilization and Blood-Brain Barrier Permeability Following Traumatic Brain Injury: An In Vivo Murine Study.

Early posttraumatic brain injury (TBI) tranexamic acid (TXA) may reduce blood-brain barrier (BBB) permeability, but it is unclear if this effect is fixed regardless of dose. We hypothesized that post-TBI TXA demonstrates a dose-dependent reduction of in vivo penumbral leukocyte mobilization, BBB microvascular permeability, and enhancement of neuroclinical recovery. CD1 male mice (n = 40) were randomly assigned to TBI by controlled cortical impact (injury [I]) or sham TBI (S), followed by intravenous bolus of either saline (placebo [P]) or TXA (15, 30, or 60mg/kg). At 48h, in vivo pial intravital microscopy visualized live penumbral BBB microvascular leukocytes and albumin leakage. Neuroclinical recovery was assessed by Garcia NeurologicalTest scores and animal weight changes at 24h and 48h after injury. I + TXA60 reduced live penumbral leukocyte rolling compared with I + P (p < 0.001) and both lower TXA doses (p = 0.017 vs. I + TXA15, p = 0.012 vs. I + TXA30). Leukocyte adhesion was infrequent and similar across groups. Only I + TXA60 significantly reduced BBB permeability compared with that in the I + P (p = 0.004) group. All TXA doses improved Garcia Test scores relative to I + P at both 24h and 48h (p < 0.001 vs. I + P for all at both time points). Mean 24-h body weight loss was greatest in the I + P (- 8.7 ± 1.3%) group and lowest in the I +TXA15 (- 4.4 ± 1.0%, p = 0.051 vs. I + P) group. Only higher TXA dosing definitively abrogates penumbral leukocyte mobilization, preserving BBB integrity post TBI. Some neuroclinical recovery is observed, even with lower TXA dosing. Better outcomes with higher dose TXA after TBI may occur secondary to blunting of leukocyte-mediated penumbral cerebrovascular inflammation.

Hepcidin and dicentracin peptides show preventive antiviral applications against NNV infection in European sea bass through immunomodulatory roles

Aquaculture is an extremely prosperous market threatened by pathogen outbreaks, including viruses as nodavirus (NNV), which infect fish species with special interest in trading such as European sea bass. Antimicrobial peptides (AMPs) might constitute potential antiviral agents, which had been previously evaluated in fish with positive prospects, based on their properties as immunomodulators or directly killing pathogens. In this line, we aimed to evaluate this dual role by administering two European sea bass synthetic AMPs (Hamp or Dic) prior to NNV infection. Both treatments conferred partial protection against NNV though viral replication and load were not affected. Both AMPs elicited, prior to infection, AMP response and leukocyte mobilization whilst down-regulated pro-inflammatory markers. Upon infection, Hamp and Dic peptides abrogated the inflammatory response provoked by NNV as well as avoid NNV-induced disturbance of the leucocyte distribution in the brain, mainly neutrophils, macrophages and CD8+ T cells. This study points that preventive applications of synthetic Hamp and Dic peptides exert their antiviral actions through the immunomodulatory role and not by a direct action of the antimicrobial on NNV. This work opens the door to the use of AMPs as potential prophylactic tools against NNV as well as immunostimulant in fish farms.

Immunomodulatory effects of epiphytic Loranthus micranthus leaf extracts collected from two host plants: Psidium guajava and Parkia biglobosa

BackgroundImmunological abnormalities are implicated in the pathogenesis of many chronic diseases. Due to the drug-related adverse effects of currently available orthodox immunomodulators, natural immunomodulators are being looked upon as potential agents to replace them in therapeutic regimens. This research aimed to investigate the immunomodulatory potential of L. micranthus extracts epiphytic on Psidium guajava (LMPGE) and Parkia biglobosa (LMPBE).MethodsPhytochemical screening and acute toxicity testing were carried out to identify the phytoconstituents and safety profiles of the extracts. The extracts’ innate and adaptive immunomodulatory potentials were determined in experimental animals using in vivo leucocyte mobilization, delayed-type hypersensitivity (DTH) response, hemagglutination antibody titre, and cyclophosphamide-induced myelosuppression models. Levamisole was used as the standard drug throughout the study.ResultsCompared to LMPBE, LMPGE contained significantly (p < 0.05) more tannins, cyanogenic glycosides, saponins, reducing sugars, glycosides, flavonoids, and alkaloids. Furthermore, the groups treated with the extracts had a significant (p < 0.05) increase in the total number of leucocytes, neutrophils, basophils, and antibody titers relative to the untreated control. In the same way, the treatment raised TLC in cyclophosphamide-intoxicated rats, with 250 mg/kg b. w. of LMPGE and LMPBE recording 9712.50 ± 178.00 and 8000.00 ± 105.00 × 109 /L, respectively, compared to 3425.00 ± 2 5.00 × 109 /L in the untreated group. Overall, LMPGE was more effective.ConclusionsThe findings from this study suggest that L. micranthus epiphytic in Psidium guajava and Parkia biglobosa has possible immune stimulating potential.

Bacteria- and fungus-derived PAMPs induce innate immune memory via similar functional, metabolic, and transcriptional adaptations.

Exposure to pathogen-associated molecular patterns (PAMPs) induces an augmented, broad-spectrum antimicrobial response to subsequent infection, a phenomenon termed innate immune memory. This study examined the effects of treatment with β-glucan, a fungus-derived dectin-1 ligand, or monophosphoryl lipid A (MPLA), a bacteria-derived Toll-like receptor 4 ligand, on innate immune memory with a focus on identifying common cellular and molecular pathways activated by these diverse PAMPs. Treatment with either PAMP prepared the innate immune system to respond more robustly to Pseudomonas aeruginosa infection in vivo by facilitating mobilization of innate leukocytes into blood, recruitment of leukocytes to the site of infection, augmentation of microbial clearance, and attenuation of cytokine production. Examination of macrophages ex vivo showed amplification of metabolism, phagocytosis, and respiratory burst after treatment with either agent, although MPLA more robustly augmented these activities and more effectively facilitated killing of bacteria. Both agents activated gene expression pathways in macrophages that control inflammation, antimicrobial functions, and protein synthesis and suppressed pathways regulating cell division. β-glucan treatment minimally altered macrophage differential gene expression in response to lipopolysaccharide (LPS) challenge, whereas MPLA attenuated the magnitude of the LPS-induced transcriptional response, especially cytokine gene expression. These results show that β-glucan and MPLA similarly augment the innate response to infection in vivo. Yet, MPLA more potently induces alterations in macrophage metabolism, antimicrobial functions, gene transcription and the response to LPS.

Human-specific CHRFAM7A primes macrophages for a heightened pro-inflammatory response at the earlier stage of inflammation.

α7-Nicotinic acetylcholine receptor (α7-nAChR) is the key effector molecule of the cholinergic anti-inflammatory pathway. Evolution has evolved a uniquely human α7-nAChR encoded by CHRFAM7A. It has been demonstrated that CHRFAM7A dominant negatively regulates the functions of α7-nAChR. However, its role in inflammation remains to be fully characterized. CHRFAM7A transgenic (Tg) mice were phenotypically normal and their peritoneal macrophages exhibited decreased ligand-binding capability and, importantly, an activated gene expression profile of pro-inflammatory cytokines. Surprisingly, when challenged with sepsis, the Tg mice showed no survival disadvantage relative to their wild-type (Wt) counterparts. Further analysis showed that the complete blood count and serum levels of pro-inflammatory cytokines were comparable at resting state, but the degrees of leukocyte mobilization and the increase of pro-inflammatory cytokines were significantly higher in Tg than Wt mice at the early stage of sepsis. In vitro, peritoneal macrophages of the Tg mice exhibited an exaggerated response to lipopolysaccharides (LPSs), especially at the earlier time points and at lower dosages of LPS. Remarkably, monocytes from CHRFAM7A-carrier showed similar dynamic changes of the pro-inflammatory cytokines to that observed in the Tg mice upon LPS challenge. Our results suggest that CHRFAM7A increases the mobilization of leukocytes and primes macrophages that confer an enhanced immune response at the early stage of inflammation, which may lead to prompt pathogen clearance, an evolutionary advantage in less severe inflammatory conditions.

Anti-inflammatory Assessment of Methanol Extract of Acalypha ciliata Leaves and It’s Leucocyte Mobilization in Adult Wistar Rats

Aim: The study's objective was to examine the anti-inflammatory activity and leucocyte mobilization of a methanol extract of leaves from Acalypha ciliata in adult Wistar rats.&#x0D; Study Design: Egg albumin-induced edema was used for anti-inflammatory test and leucocyte mobilization test was carried out to check for total leucocyte cout and differentials. &#x0D; Place and Duration of the Study: This original study was conducted between January and June 2013 at the Department of Biochemistry, Faculty of Biological Sciences, University of Nigeria Nsukka.&#x0D; Methology: The pulverized leaf of Acalypha ciliata was extracted using cold maceration, and the Treas and Evans technique of phytochemical screening was used. The anti-inflammatory study was conducted using the method of Winter et al., and the acute toxicity study was assessed using Lorke's method. ANOVA was used to statistically examine the collected data.&#x0D; Results: Preliminary phytochemical screening revealed the presence of flavonoids, alkaloids, soluble carbohydrates, phenols, glycosides, saponins, terpenoids and steroids. Flavonoids, Alkaloids, and Soluble carbohydrates appeared in abundant concentration (2199.76±10.81, 2141.6±7.583, 913±21.06). Acute toxicity tests showed no toxicity and mortality at doses up to 5000 mgkg-1. Anti-inflammatory study revealed that group treated with 100, 200 and 400 mg/kg b.w of extract significantly (P =0.05) and in a dose dependant manner decreased in TLC when compared with normal control. Moreover, the group treated with 100,200,400 mg/kg b.w of extract and reference drug(Indometacin) mobilized the leucocyte at the rate of 36, 22, 12 and 62 % respectively. A significant (P = 0.05) reduction in the mean paw oedema was observed for all the treatment groups from 1 hour to 5 hours when compared to the toxic group.&#x0D; Conclusion: As a result of this study's findings, it can be concluded that methanol extract of the Acalypha ciliata leaf has anti-inflammatory characteristics. High dosages of the extract resulted in a better decrease of oedema and an increase in leukocyte mobilization in response to agar suspension than low doses. Many anti-inflammatory herbs and substances alter inflammatory reactions by hastening the breakdown of or reversing the effect of the inflammatory mediators. The plant's anti-inflammatory properties could potentially result from the interaction of different photochemical substances present. The findings suggest that, if used, the plant may serve as a source of anti-inflammatory compounds.

Differential Anti-Tumor Effects of IFN-Inducible Chemokines CXCL9, CXCL10, and CXCL11 on a Mouse Squamous Cell Carcinoma Cell Line.

Chemokines are a group of cytokines involved in the mobilization of leukocytes, which play a role in host defense and a variety of pathological conditions, including cancer. Interferon (IFN)-inducible chemokines C-X-C motif ligand 9 (CXCL), CXCL10, and CXCL11 are anti-tumor chemokines; however, the differential anti-tumor effects of IFN-inducible chemokines are not completely understood. In this study, we investigated the anti-tumor effects of IFN-inducible chemokines by transferring chemokine expression vectors into a mouse squamous cell carcinoma cell line, SCCVII, to generate a cell line stably expressing chemokines and transplanted it into nude mice. The results showed that CXCL9- and CXCL11-expressing cells markedly inhibited tumor growth, whereas CXCL10-expressing cells did not inhibit growth. The NH2-terminal amino acid sequence of mouse CXCL10 contains a cleavage sequence by dipeptidyl peptidase 4 (DPP4), an enzyme that cleaves the peptide chain of chemokines. IHC staining indicated DPP4 expression in the stromal tissue, suggesting CXCL10 inactivation. These results suggest that the anti-tumor effects of IFN-inducible chemokines are affected by the expression of chemokine-cleaving enzymes in tumor tissues.

The effect of acute exercise on circulating immune cells in newly diagnosed breast cancer patients

The role of exercise in cancer prevention and control is increasingly recognized, and based on preclinical studies, it is hypothesized that mobilization of leukocytes plays an important role in the anti-tumor effect. Thus, we examined how 10-min acute exercise modulates immune cells in newly diagnosed breast cancer patients. Blood samples were taken at rest, immediately after exercise and 30 min after exercise and phenotypic characterization of major leukocyte subsets was done using 9-color flow cytometry. Total leukocyte count increased by 29%, CD8+ T cell count by 34%, CD19+ B cell count by 18%, CD56+CD16+ NK cell count by 130%, and CD14+CD16+ monocyte count by 51% immediately after acute exercise. Mobilization of CD45+, CD8+, CD19+, and CD56+CD16+ cells correlated positively with exercising systolic blood pressure, heart rate percentage of age predicted maximal heart rate, rate pressure product, and mean arterial pressure. Our findings indicate that a single bout of acute exercise of only 10 min can cause leukocytosis in breast cancer patients. Mobilization of leukocytes appear to be directly related to the intensity of exercise. It is possible that the positive effect of exercise on oncologic outcome might be partly due to immune cell mobilization as documented in the present study.

TREM2 acts as a receptor for IL-34 to suppress acute myeloid leukemia in mice

AbstractThe bone marrow microenvironment supports leukocyte mobilization and differentiation and controls the development of leukemias, including acute myeloid leukemia (AML). Here, we found that the development of AML xenotransplants was suppressed in mice with osteoclasts tuberous sclerosis 1 (Tsc1) deletion. Tsc1-deficient osteoclasts released a high level of interleukin-34 (IL-34), which efficiently induced AML cell differentiation and prevented AML progression in various preclinical models. Conversely, AML development was accelerated in mice deficient in IL-34. Interestingly, IL-34 inhibited AML independent of its known receptors but bound directly to triggering receptor expressed on myeloid cells 2 (TREM2), a key hub of immune signals. TREM2-deficient AML cells and normal myeloid cells were resistant to IL-34 treatment. Mechanistically, IL-34–TREM2 binding rapidly phosphorylated Ras protein activator like 3 and inactivated extracellular signal-regulated protein kinase 1/2 signaling to prevent AML cell proliferation and stimulate differentiation. Furthermore, TREM2 was downregulated in patients with AML and associated with a poor prognosis. This study identified TREM2 as a novel receptor for IL-34, indicating a promising strategy for overcoming AML differentiation blockade in patients with AML.

Immunostimulatory and Antimicrobial Claims of Super-7 Herbal Mixture (SHM) and Odogwu Cleanser Herbal Mixture (OCHM) Commercially Available in Enugu State, Nigeria

The continuous increase in resistance associated with conventional drugs is gradually shifting focus to herbal remedies as an alternative globally. This study was designed to investigate the immunostimulatory and antimicrobial claims of Super-7 herbal mixture (SHM) and Odogwu cleanser herbal mixture (OCHM) commercially available in Enugu State, Nigeria. Immunomodulatory properties of the products on the Delayed Type Hypersensitivity reaction (DTHr), the Primary and Secondary humoral response and the <i>in vivo</i> leucocyte mobilization were evaluated using a total of one hundred and forty-six (146) Swiss albino rats. The spectrum of antimicrobial activity was evaluated by agar well diffusion method using eight (8) selected microorganisms. The LD₅₀ of both products was greater than 100% ml/kg body weight. OCHM elicited significant (p<0.05) dose dependent increase in total leucocyte and neutrophil counts compared to Levamisole (2.5mg/kg) and the untreated group. A 100% ml/kg SHM (78.07%) also exhibited significantly (p<0.05) higher oedema inhibitory potentials compared to the standard drug (levamisole = 65.78%). Samples of SHM demonstrated dose dependent antibacterial activities against <i>B. subtilis </i>and <i>S. typhi</i>, while only exhibiting antifungal activity against<i> C. albicans </i>(IZD = 9.0±0.0 mm). OCHM was observed to inhibit <i>E. coli, S. typhi, S. aureus, B. subtilis, S. typhi </i>and the fungus<i> C. albicans</i>. An average bioload of 2.8 x 10⁴±1.0 CFU/ml which was higher than the average count (2.8 x 10⁴±1.0 CFU/ml) obtained for OCHM. Conclusively, this study showed that samples of SHM and OCHM exhibited significant immunostimulatory and antimicrobial properties, but also recorded the presence of microbial contaminants.

Role of Rap1 GTPases in Growth, Differentiation, and Migration of Myeloid Cells

Background:Rap1 is a Ras-like small-molecular-weight GTP-binding protein involved in signal transduction cascades. It cycles between a GDP-bound inactive and a GTP-bound active form. This switching is regulated by specific GEFs and GAPs. Rap1 exists in two isoforms - Rap1a and Rap1b. While Rap1 has been implicated in regulating several hematologic disorders, including chronic lymphocytic leukemia, its role in the development and function of hematopoietic stem cells and progenitors (HSC/Ps) has not been investigated. Macrophages play an essential role in the retention of hematopoietic cells in the mesenchymal niche. Resident macrophages in the spleen retain HSCs through VCAM1 adhesion. Previous studies have shown that loss of both isoforms of Rap1 in mice results in enhanced peripheral blood leukocyte counts and mobilization of primitive hematopoietic stem cells (Lin-KIT+Sca1+) into peripheral blood circulation. Given this loss of retention of primitive hematopoietic cells in the bone marrow, we hypothesized that perhaps Rap1 plays an essential role in adhesive interactions of HSC/Ps in the bone marrow.&#x0D; Methods:To test this hypothesis, we derived macrophages from the bone marrow of wild-type (WT) and Rap1a/b double knockout (DKO) mice and compared their growth, survival and differentiation using proliferation and adhesion assays, as well as flow cytometry to assess apoptosis, macrophage differentiation, MCSF receptor expression, and expression of integrins.&#x0D; Results:Our studies show that macrophages derived from Rap1 DKO mouse bone marrow show impaired growth, survival and differentiation along with impaired adhesion in response to extracellular matrix components including fibronectin.&#x0D; Future Directions:In the future, we hope to study macrophage adhesive interactions in response to SDF1, collagen, and other extracellular matrix proteins in myeloid-specific deletion of Rap1 in mice, and to study the role of Rap1 in different lineages of hematopoietic cells using different CRE drivers.

Persistent Blunting of Penumbral Leukocyte Mobilization by Beta Blockade Administered for Two Weeks After Traumatic Brain Injury

IntroductionBeta-blockers (BB) after traumatic brain injury (TBI) accelerate cognitive recovery weeks after injury. BBs also inhibit leukocyte (LEU) mobilization to the penumbral blood brain barrier (BBB) 48-h after TBI. It is unclear whether the latter effects persist longer and accompany the persistent cognitive improvement. We hypothesized that 2 wk of BB after TBI reduce penumbral BBB leukocyte-endothelial interactions. MethodsThirty CD1 mice underwent TBI (controlled cortical impact, CCI: 6 m/s velocity, 1 mm depth, 3 mm diameter) or sham craniotomy followed by i.p. saline (NS) or propranolol (1, 2, 4 mg/kg) every 12 h for 14 d. On day 14, in vivo pial intravital microscopy visualized endothelial-LEU interactions and BBB microvascular leakage. Day 14 Garcia neurological test scores and animal weights were compared to preinjury levels reflecting concurrent clinical recovery. ResultsLEU rolling was greatest in CCI + NS when compared to sham (P = 0.03). 4 mg/kg propranolol significantly reduced postCCI LEU rolling down to uninjured sham levels (P = 0.03). LEU adhesion and microvascular permeability were not impacted at this time interval. Untreated injured animals (CCI + NS) scored lower Garcia neurological test and greater weight loss recovery at day 14 when compared to preinjury (P < 0.05). Treatment with higher doses of propranolol (2, 4 mg/kg), improved weight loss recovery (P < 0.001). ConclusionsLEU rolling alone, was influenced by BB therapy 14 d after TBI suggesting that certain penumbral neuroinflammatory cellular effects of BB therapy after TBI persist up to 2 wk after injury potentially explaining the pervasive beneficial effects of BBs on learning and memory.

Long-lasting leukocytosis in patients with schizophrenia treated with clozapine after electroconvulsive therapy : ECT stabilizes white blood cell count.

The present study was conducted to investigate the possible hematologic impact of long-term electroconvulsive therapy (ECT) in patients with drug-resistant schizophrenia and receiving clozapine therapy. In this retrospective study, clinical charts of 57 hospitalized patients with schizophrenia who required clozapine therapy because of active psychotic symptoms resistant to other antipsychotics were examined. For 18 who underwent ECT, the first assessment was conducted at the end of that therapy (average two months after start, 7.68 sessions) and the second two months later. As for the 39 patients who did not undergo ECT, the first and second assessment points were at two and four months, respectively, after a randomly chosen time point. Multiple regression analysis revealed that modified ECT (m-ECT) (ß = 0.346, p = 0.005), gender (males showed greater increase) (ß = 0.273, p = 0.023), and disease duration (longer associated with greater increase) (ß = 0.258, p = 0.033) were correlated with a change in white blood cell (WBC) count (ΔR2 = 0.277, p < 0.001) at the first assessment point. At the second assessment point, multiple regression analysis showed that m-ECT (ß = 0.262, p = 0.039), gender (males showed greater increase) (ß = 0.264, p = 0.036), and disease duration (longer associated with greater increase) (ß = 0.234, p = 0.068) were again correlated with changed WBC count (ΔR2 = 0.203, p < 0.007). An increase in leukocytes may have a protective influence against the adverse myelosuppressive effects of clozapine. However, a simple mobilization of leukocytes from bone marrow to peripheral circulation may not enhance the immune system, leading to only a masking of the effects of a potential immuno-insufficient state in the treated patient. In either case, should leukocytosis be induced and then remain for an extended period, hematologists, as well as psychiatrists involved in electroconvulsive intervention for clozapine-treated patients, must keep this factor in mind.

A Limited Role for AMD3100 Induced Stem Cell Mobilization for Modulation of Thoracic Trauma Outcome.

Thoracic trauma is a major cause of mortality due to the associated inflammatory acute respiratory distress syndrome and morbidity due to impaired tissue regeneration. Trauma-induced lung inflammation is characterized by the early recruitment of cells with pro- or anti-inflammatory activity to the lung. Therapeutic interventions reducing the level of tissue inflammation may result in decreased tissue damage and improved healing and recovery. Stem cells might be able to improve trauma outcome via immunomodulation or by enhancing tissue regeneration.Here, we describe the migratory dynamics of murine mesenchymal, hematopoietic and endothelial stem and progenitor cells (SPCs) as well as mature inflammatory cells (monocytes, neutrophils, lymphocytes) to peripheral blood (PB) and lung tissue between 0.2 and 48 h post-blunt chest trauma (TXT). We demonstrate that the kinetics of immune cell and SPC distribution upon trauma are both cell-type and tissue-dependent. We identified a transient, early increase in the number of inflammatory cells in PB and lung at 2 h post-TXT and a second wave of infiltrating SPCs in lungs by 48 h after TXT induction, suggesting a role for SPCs in tissue remodeling after the initial inflammatory phase. Cxcl12/Cxcr4 blockade by AMD3100 within the first 6 h after TXT, while inducing a strong and coordinated mobilization of SPCs and leukocytes to PB and lung tissue, did not significantly affect TXT associated inflammation or tissue damage as determined by inflammatory cytokine levels, plasma markers for organ function, lung cell proliferation and survival, and myofibroblast/fibroblast ratio in the lung. Further understanding the dynamics of the distribution of endogenous SPCs and inflammatory cells will therefore be indispensable for stem cell-based or immunomodulation therapies in trauma.

Stretch‐induced Myocardial Injury and Inflammation After Transient Vasopressin‐Mediated Left Ventricular Pressure Overload in Swine

ObjectiveUsing the α1‐adrenergic agonist phenylephrine (PE), we have previously demonstrated that an acute episode of transient pressure overload (TPO) elicits stretch‐induced myocardial injury and reversible left ventricular (LV) systolic dysfunction. Although this was accompanied by leukocyte mobilization, a rise in inflammatory cytokine levels, and increased pro‐inflammatory gene expression in the heart, the extent to which this resulted from direct activation of α1‐adrenergic receptors on immune cells vs. an inflammatory response to mechanical stretch‐induced myocardial injury is unclear. Accordingly, the present study was designed to determine if an inflammatory response to myocardial injury is evident when TPO is produced by vasopressin (VP), a vasoconstrictor without direct α1‐adrenergic agonist properties.MethodsHemodynamic and echocardiographic parameters were assessed in propofol‐anesthetized swine before, during, and after a 30‐minute infusion of VP (VP‐TPO; 0.04 U/kg/min, n=7) to increase LV end‐diastolic pressure (EDP) to ~30mmHg. Serial jugular venous blood sampling was performed to quantify circulating cardiac troponin I (cTnI), leukocytes, and inflammatory cytokines (TNF‐α and IL‐6) at baseline and 3‐hours after cessation of VP‐TPO. Leukocyte and cytokine levels were compared with those observed after PE‐mediated TPO in a separate group of animals (PE‐TPO; n=6).ResultsVP elicited a significant rise in mean arterial pressure (91±5 to 165±11 mmHg) and LV EDP (10±1 to 29±2 mmHg; both p&lt;0.05 vs. baseline). This was accompanied by a significant rise in LV end‐diastolic volume (73±5 to 110±7 mL) and end‐systolic volume (20±3 to 53±6 mL), as well as a reduction in LV ejection fraction (EF; 72±3 to 52±3 %; all p&lt;0.05 vs. baseline). One hour after cessation of VP‐TPO, LV EF remained depressed vs. baseline (60±3 %; p&lt;0.05) and circulating cTnI levels began to rise, reaching a concentration that was ~10‐fold higher than baseline concentrations at the 3‐hour post‐TPO timepoint (18±5 to 118±21 ng/L; p&lt;0.05). These changes were accompanied by a significant rise in circulating neutrophils, monocytes, TNF‐α, and IL‐6 that was similar to that observed after PE‐TPO (Figure).ConclusionsVP‐TPO elicits myocardial injury, leukocyte mobilization, and an acute rise in circulating pro‐inflammatory cytokines, thereby recapitulating several features of PE‐TPO in the absence of direct α1‐adrenergic stimulation. These findings suggest that stretch‐induced myocardial injury provokes an inflammatory response that may play an important role in promoting the development of cardiac fibrosis and diastolic dysfunction after exposure to repetitive episodes of TPO.

Assessment of the Aqueous Methanol Extract and Ethyl Acetate Fraction of Tapinanthus globiferus Leaves and their Effects on Ulceration and Leukocyte Mobilization in Wistar Albino Rats

This study aimed to ascertain the anti-ulcerative, leukocyte mobilizing, haematologic, and antioxidant effect of methanol extract of Tapinanthus globiferus leaves (METGL) and ethyl acetate fraction of Tapinanthus globiferus leaves (EAFTGL) in rat models. Phytochemical analysis of T. globiferus leaves recorded substantial levels of phenolics, flavonoids, alkaloids, saponins, steroids, terpenoids, and tannins. The experimental design was categorized into three phases. Ulcer and inflammation were inflicted on phases I and II rats using indomethacin and inflammatory stimulus (1 mL of 3 % agar suspension), respectively, treatments with reference drug and different concentrations (100 and 200 mg/kg body weight) METGL and EAFTGL ensued. In phase III, group 1 (normal control) received 3 ml/kg bw 3 % tween 80, while groups 2-5 were administered with varied dosages (100 and 200 mg/kg bw) of METGL and EAFTGL, respectively. The results revealed that both METGL and EAFTGL effectively instituted gastro-protection, exerted a significant (p &lt; 0.05) increase in hematological indices and antioxidant parameters, and caused a significant (p&lt;0.05) decrease in leukocyte infiltration. These suggest that T. globiferus leaves may be useful in managing ulcer and inflammatory conditions, validating its use in traditional medicine.

Beta blockade in TBI: Dose-dependent reductions in BBB leukocyte mobilization and permeability in vivo.

Traumatic brain injury (TBI) is accompanied by a hyperadrenergic catecholamine state that can cause penumbral neuroinflammation. Prospective human studies demonstrate improved TBI survival with beta blockade (bb), although mechanisms remain unclear. We hypothesized that deranged post-TBI penumbral blood brain barrier (BBB) leukocyte mobilization and permeability are improved by bb. CD1 male mice (n = 64) were randomly assigned to severe TBI-controlled cortical impact: 6 m/s velocity, 1 mm depth, 3 mm diameter-or sham craniotomy, and IP injection of either saline or propranolol (1, 2, or 4 mg/kg) every 12 hours for 2 days. At 48 hours, in vivo pial intravital microscopy visualized live endothelial-leukocyte (LEU) interactions and BBB microvascular leakage. Twice daily clinical recovery was assessed by regaining of lost body weight and the Garcia Neurological Test (motor, sensory, reflex, balance assessments). Brain edema was determined by hemispheric wet-to-dry ratios. Propranolol after TBI reduced both in vivo LEU rolling and BBB permeability in a dose-dependent fashion compared with no treatment (p < 0.001). Propranolol reduced cerebral edema (p < 0.001) and hastened recovery of lost body weight at 48 hours (p < 0.01). Compared with no treatment (14.9 ± 0.2), 24-hour Garcia Neurologic Test scores were improved with 2 (15.8 ± 0.2, p = 0.02) and 4 (16.1 ± 0.1, p = 0.001) but not with 1 mg/kg propranolol. Propranolol administration reduces post-TBI LEU mobilization and microvascular permeability in the murine penumbral neurovasculature and leads to reduced cerebral edema. This is associated with hastened recovery of post-TBI weight loss and neurologic function with bb treatment. Dose-dependent effects frame a mechanistic relationship between bb and improved human outcomes after TBI.