Decrease In Blood Lymphocytes Research Articles

Portulaca oleracea L. extracts alleviate 2,4-dinitrochlorobenzene-induced atopic dermatitis in mice.

Atopic dermatitis (AD) is a common chronic allergic skin disease characterized clinically by severe skin lesions and pruritus. Portulaca oleracea L. (PO) is a resourceful plant with homologous properties in medicine and food. In this study, we used two different methods to extract PO, and compared the therapeutic effects of PO aqueous extract (POAE) and PO ultrasound-assisted ethanol extract (POEE) on 2,4-dinitrochlorobenzene (DNCB)-induced AD mice. The results showed that in POAE and POEE, the extraction rates of polysaccharides were 16.95% and 9.85%, while the extraction rates of total flavonoids were 3.15% and 3.25%, respectively. Compared with AD mice, clinical symptoms such as erythema, edema, dryness and ulceration in the back and left ear were alleviated, and pruritus behavior was reduced after POAE and POEE treatments. The thickness of the skin epidermis was thinned, the density of skin nerve fibers labeled with protein gene product 9.5 (PGP9.5) was decreased, and mast cell infiltration was reduced. There was a decrease in blood lymphocytes, eosinophils and basophils, a significant decrease in spleen index and a noticeable decrease in serum immunoglobulin E (Ig E). POEE significantly reduced the concentration of the skin pruritic factor interleukin (Il)-31. POAE and POEE reduced the concentration of skin histamine (His), down-regulated mRNA expression levels of interferon-γ (Ifnγ), tumor necrosis factor-α (Tnf-α), thymic stromal lymphopoietin (Tslp) and Il-4, with an increase of Filaggrin (Flg) and Loricrin (Lor) in skin lesions. These results suggested that POAE and POEE may inhibit atopic response and alleviate the clinical symptoms of AD by inhibiting the expression of immune cells, inflammatory mediators and cytokines. PO may be a potential effective drug for AD-like diseases.

Growth inhibitory effects of the Diruthenium-Ibuprofen compound, [Ru2Cl(Ibp) 4], in human glioma cells in vitro and in the rat C6 orthotopic glioma in vivo.

The Diruthenium-Ibuprofen compound [Ru2Cl(Ibp)4] (or RuIbp) is known to cause significant inhibition of C6 rat glioma cell proliferation in vitro. RuIbp increased the expression of cell cycle-related proteins such as p21 and p27 and the pro-apoptotic protein Bax, as well as causing a reduction in mitochondrial membrane potential and a modest increase in apoptosis in vitro. The present study extended these findings by (i) investigating the effects of RuIbp on human glioma cell line proliferation in vitro and (ii) investigating the acute and chronic toxicology of the compound in normal Wistar rats. The compound was then tested for its anti-tumour properties by either chronic 14 days intra-peritoneal (IP) administration or chronic Alzet osmotic pump infusion, in the rat C6 orthotopic glioma model in vivo. The IP injection of RuIbp caused a 41 % inhibition of tumour area without significant toxic effects but with an increase in blood neutrophils and monocytes and a decrease in blood lymphocytes. In an attempt to reduce this effect RuIbp was administered by Alzet osmotic pump infusion directly into the tumour at a dose of 15 mg/kg with an infusion rate of 0.5 µL/h for 14 days. The direct infusion of RuIbp caused a 45 % inhibition of tumour area without alterations in differential blood leukocyte counts. These results prove the efficacy of RuIbp in human glioma cell lines in vitro and in an in vivo glioma model and point to its potential as an inhibitor of tumour growth in vivo.

Brain Penetration of the Oral Immunomodulatory Drug FTY720 and Its Phosphorylation in the Central Nervous System during Experimental Autoimmune Encephalomyelitis: Consequences for Mode of Action in Multiple Sclerosis

FTY720 [2-amino-2-[2-(4-octylphenyl) ethyl]propane-1,3-diol hydrochloride] is an oral sphingosine-1-phosphate receptor modulator under development for the treatment of multiple sclerosis (MS). The drug is phosphorylated in vivo by sphingosine kinase 2 to its bioactive form, FTY720-P. Although treatment with FTY720 is accompanied by a reduction of the peripheral lymphocyte count, its efficacy in MS and experimental autoimmune encephalomyelitis (EAE) may be due to additional, direct effects in the central nervous system (CNS). We now show that FTY720 localizes to the CNS white matter, preferentially along myelin sheaths. Brain trough levels of FTY720 and FTY720-P in rat EAE are of the same magnitude and dose dependently increase; they are in the range of 40 to 540 ng/g in the brain tissue at efficacious doses and exceed blood concentrations severalfold. In a rat model of chronic EAE, prolonged treatment with 0.03 mg/kg was efficacious, but limiting the dosing period failed to prevent EAE despite a significant decrease in blood lymphocytes. FTY720 effectiveness is likely due to a culmination of mechanisms involving reduction of autoreactive T cells, neuroprotective influence of FTY720-P in the CNS, and inhibition of inflammatory mediators in the brain.

TEMPORAL ASSOCIATION BETWEEN PULMONARY AND SYSTEMIC EFFECTS OF PARTICULATE MATTER IN HEALTHY AND CARDIOVASCULAR COMPROMISED RATS

Exposure to particulate matter (PM) has been associated with increased morbidity and mortality among individuals with cardiovascular disease. It is hypothesized that systemic alterations occur concurrent to pulmonary injury/inflammation, and contribute to cardiac events in compromised hosts. We explored this hypothesis using a rat model for human hypertension and cardiovascular disease (spontaneously hypertensive, SH), and normotensive Wistar Kyoto (WKY) rats. SH and WKY rats (12-13 wk old) were exposed either intratracheally (IT; 0.0, 1.0, or 5.0 mg/kg in saline) or nose-only (15 mg/m 3 2 6 h/d 2 3 d/wk 2 1, 2 or 4 wk) to combustion source residual oil fly ash (ROFA) with low metal content, and examined 1, 2 or 4 d later. Bronchoalveolar lavage fluid (BALF) albumin and neutrophils increased (SH WKY) at d 1 following ROFA IT. With inhalation exposure, both strains experienced progressive histological lung damage and increases in BALF albumin and neutrophils during 1 to 4 wk (SH > WKY). Acute lung injury from ROFA IT was temporally associated with increases in plasma fibrinogen in both strains, but only the SH rats responded to the acute 1-wk ROFA inhalation. Longer term (2 or 4 wk) ROFA caused progressive lung injury (SH > WKY), but did not sustain the increase in fibrinogen. BALF glutathione increased in a temporal fashion similar to fibrinogen; however, only WKY rats demonstrated this response. There was a small but consistent decrease in blood lymphocytes and an increase in blood neutrophils in SH rats exposed to ROFA acutely. In conclusion, acute PM exposure can provoke an acute systemic thrombogenic response associated with pulmonary injury/inflammation and oxidative stress in cardiovascular compromised rats. This evidence is consistent with greater cardiovascular events during acute PM episodes in compromised humans.

Prolonged alpha-adrenergic stimulation causes changes in leukocyte distribution and lymphocyte apoptosis in the rat

We have previously shown in the rat model that acutely or chronically increased peripheral catecholamines lead to suppression of lymphocyte responsiveness via alpha 2-adrenoceptor activation. Here we investigated the effects of alpha-adrenergic treatment on total leukocyte numbers and proportions of leukocyte subsets in peripheral blood and lymphoid tissues. It was found that a 12-h treatment with subcutaneously implanted tablets, one containing norepinephrine (NE) and one propranolol, leads to an increase in total blood leukocyte counts, due to a pronounced increase in granulocytes. In contrast, the numbers of all classes of lymphocytes other than NK cells were decreased. This decrease in blood lymphocytes is apparently not due to redistribution, since in the thymus, spleen, mesenteric and peripheral lymph nodes, the total numbers of lymphocytes were decreased as well, without any changes in subpopulations. Analogous results were obtained with rats adrenalectomized before the catecholamine treatment. Animals that received the alpha-adrenergic treatment displayed significantly more apoptotic cells in the lymphoid organs, as determined by the TUNEL technique. In the spleen, the enhanced rate of apoptosis was confined to the white pulp; red pulp areas exhibited significantly fewer apoptotic cells. Thus, an increased alpha-adrenergic tone in rats led to a general loss of lymphocytes due to lymphocyte directed apoptosis that was independent of glucocorticoids.

Evidence that FTY720 induces T cell apoptosis in vivo

The immunosuppressant FTY720 induces a drastic decrease in blood lymphocytes, especially T cells; a decrease which is assumed to be the immunosuppressive mechanism of this drug. FTY720 causes cell death in vitro in lymphocytes and leukemia cells. However, the deletion mechanism of blood lymphocytes in vivo remains unclear. We investigated whether administration of FTY720 induced lymphocyte apoptosis in blood circulation. A marked decrease in the number of blood lymphocytes was observed within an hour after a single oral administration of FTY720 at doses of 5–10 mg/kg in rats and mice. Experiments using fluorescein isothiocyanate (FITC)-Annexin V and APO-BRDU™ methods revealed that FTY720 induced blood lymphocyte apoptosis in a dose-dependent manner. On the other hand, lymphocyte homing to Peyer's patches was proposed as the mechanism underlying the blood lymphocyte decrease at these doses. However, similar results were obtained when using aly/aly mice, which lack Peyer's patches and lymph nodes. Thus, we concluded that apoptosis of blood lymphocytes was induced immediately after administration of FTY720, and the cells could be immediately scavenged by phagocytes or the reticuloendothelial system in addition to Peyer's patches homing. We also concluded that T cells were highly sensitive to FTY720, which induced apoptosis in vivo.

Modified total lymphoid irradiation and low dose corticosteroids in progressive multiple sclerosis

In a double-blind prospective randomized trial, we assessed the efficacy and safety of modified total lymphoid irradiation (TLI) plus low dose prednisone (TLI-LDP) as compared to sham TLI plus identical prednisone therapy (sham TLI-LDP) in 46 patients with progressive forms of multiple sclerosis (MS). No significant difference existed between groups at study entry in patient age, sex, duration of MS, or disability status. However, following treatment, significantly fewer TLI patients showed a sustained one point decline in the Expanded Disability Status Scale, the primary study endpoint, as compared to the sham TLI group using the Kaplan-Meier Product-limit survival analysis, ( P<0.005). Risk for relapse requiring treatment with intravenous methylprednisolone was reduced by 54% in the TLI-treated group ( P<0.05). Significantly fewer TLI-LDP patients had gadolinium enhancing plus new T2-weighted lesions ( P=0.018) when compared to the sham group post-treatment. There was also a substantial and significant decrease in blood lymphocytes in the TLI-LDP group when compared to either pretreatment values or to sham TLI-LDP through at least 12 months post-therapy. Side effects secondary to TLI were generally mild and well-tolerated. These results further support the hypothesis that TLI and systemic immunosuppression have a beneficial effect in progressive forms of MS.

Fever and leucocytosis accompanying asthmatic reactions due to occupational agents: frequency and associated factors.

Fever is sometimes associated with asthmatic reactions following specific inhalation challenges with occupational agents. Our aims were to estimate the prevalence of fever in subjects with occupational asthma confirmed by specific inhalation challenge and to examine the characteristics and clinical correlates of subjects who develop fever on specific inhalation challenge. We performed a retrospective analysis of 317 subjects who had positive specific inhalation challenge to occupational agents and a comparison of subjects who developed fever after specific inhalation challenge with a random sample of those who did not. Fifteen subjects (5%) developed fever associated with positive specific inhalation challenge. They were compared with a random sample of 60 subjects who did not develop fever. The fever group: 1) showed a larger increase in absolute number of blood neutrophils, and a larger decrease both of blood lymphocytes and forced vital capacity after specific inhalation challenge; 2) included fewer atopics; 3) had been exposed more frequently to low rather than high molecular compounds; and 4) always experienced a late reaction and had more atypical reactions. We conclude that after positive specific inhalation challenge; fever occurs infrequently, and is associated with an increase in blood neutrophils and a decrease in blood lymphocytes and forced vital capacity. Such reactions seem more likely to occur in nonatopic subjects exposed to low molecular weight agents.

Changes in the EEG of the hypothalamus and limbic system after administration of ACTH, SU-4885 and ACH in rabbits with special reference to neurohumoral feedback regulation of pituitary-adrenal system.

The neurohumoral interaction in the feedback control of ACTH secretion was studied by means of EEG observation before and after intravenous administration of adrenocorticotrophic hormone, SU-4885 which is an inhibitory substance for the adrenocortical hormone production by the adrenal cortex, and hydrocortisone acetate in rabbit. For further clarification of this problem, crystalline hydrocortisone acetate was implanted or a localized lesion was made in the brain and alterations in the stress response were observed.The results were as follows:A. The EEG activity showed the following alterations after injection of adrenocorticotrophic hormone.1. In jection of adrenocorticotrophic hormones brought about a decrease in slower components of 2-13 cps in the dorsal hippocampus (alveus) and the median eminence-periventricular arcuate nucleus, and an increase in the amygdala (lateral basal portion), anterior hypothalamic area, mammillary body and the midbrain reticular formation. In some cases 40 cps spindle-like burst increased after injection. The medial preoptic area revealed a diphasic alteration by injection, first an increase and then a decrease in the slower components. Little change occurred in the activity of the posterior hypothalamic area.2. With administration of SU-4885, there was an increase in the slower frequency components in the dorsal hippocampus, anterior hypothalamic area, median eminence-periventricular arcuate nucleus and the posterior hypothalamic area. In the amygdala these components first decreased but from 2-4 hours after injection then increased. In some cases the 40 cps waves showed a remarkable increase. In the midbrain reticular formation the slower components showed a diphasic change, first a decrease and then an increase.3. With hydrocortisone acetate injection, there was an increase in the slower components of the dorsal hippocampus and the median eminence-periventricular arcuate nucleus, but these components markedly decreased in the amygdala, anterior hypothalamic area and the midbrain reticular formation.B. After implantation of hydrocortisone acetate or localized electrolytic destruction in the median eminence-periventricular arcuate nucleus and the nucleus ventromedialis hypothalami, the stress response of the rabbit, as indicated by the decrease of blood lymphocytes or the increase of urinary Porter-Silber chromogen excretion, showed a depression. In cases of the septum pellucidum, posterior hypothalamic area, central grey and the midbrain reticular formation, no remarkable change occurred following these treatments in the stress response.On a basis of these results it was suggested that the basal hypothalamus might be a focus for the negative feedback control for the maintenance of homeostasis of adrenocorticotrophic hormone and adrenocortical hormone, and that the hippocampus and the amygdala might participate in this mechanism by acting on the basal hypothalamus when their activities were influenced by the changes in adrenocorticotrophic or adrenocortical hormone level.