Biomedical subjects

David A Lawrence

Publications and source records attributed to David A Lawrence.

At least 19 recordsLinked to original sources

PubMed2007

Polychlorinated biphenyls induce proinflammatory cytokine release and dopaminergic dysfunction: protection in interleukin-6 knockout mice.

Proinflammatory cytokines are not only important mediators of brain development, but also pose an increased risk for neurodegeneration following exposure to neurotoxicants or trauma. We have used the ubiquitous environmental and occupational neurotoxicant polychlorinated biphenyls (PCBs) to investigate the putative role of inflammatory agents in mediating processes involved in basal ganglia dysfunctions. PCBs induced inflammatory responses in C57BL/6 adult male mice, significantly elevating serum levels of IL-6 (31%), IL-1beta (71%) and TNF-alpha (22%) and significantly reducing striatal dopamine (DA, 21%), tyrosine hydroxylase (TH, 26%), dopamine transporter (DAT, 39%), and synaptophysin (29%) concentrations. We also exposed mice deficient in the proinflammatory cytokine interleukin-6 (IL-6-/-) to PCBs, to explore the role of this specific cytokine in mediating PCB-induced DA neurodegeneration. Not only did the PCB-treated IL-6-/- mice exhibit a decrease in serum levels of IL-1beta and TNF-alpha, but they were also protected from PCB-induced striatal dopaminergic dysfunction, displaying no signs of toxicant-induced reductions in DA levels, or TH, DAT or synaptophysin expression. Taken together, these results suggest that: (1) PCB exposure results in a peripheral inflammatory response associated with striatal terminal degeneration; and (2) the absence of IL-6 prevents PCB-induced dopaminergic losses in the striatum.

Analysis of Variance↗

PubMed2007

Analysis of the thiol status of peripheral blood leukocytes in rheumatoid arthritis patients.

Although the exact etiology of rheumatoid arthritis (RA) remains unknown, there is increasing evidence that reactive oxygen species and a pro-oxidant/antioxidant imbalance are an important part of the pathogenesis of joint tissue injury. Flow cytometry was used to evaluate the thiol status [surface-thiols and intracellular glutathione (iGSH)] of leukocytes from RA patients and controls. Levels of surface-thiols and iGSH of leukocytes from RA patients were significantly lower than of leukocytes from controls. CD53, a glycoprotein of the tetraspanin superfamily, which coprecipitates with the GSH recycling enzyme gamma-glutamyl transpeptidase, was elevated significantly on leukocytes from RA patients compared with leukocytes from controls. Surface-thiols and GSH play important roles in redox buffering of cells, providing protection from oxidative stress. The chronic inflammation of RA has been associated with oxidative stress, which is shown to cause a decline in the levels of cellular antioxidant sulfhydryls (R-SH). As antioxidant-protective levels also decline with age, the problem is compounded in older RA patients, who did have fewer R-SH. Chronic stress can also have an effect on telomere lengths, determining cell senescence and longevity. Although telomeres shorten with increasing age, our flow cytometry studies indicate that accelerated shortening in telomere lengths occurs with increasing age of RA patients, suggesting premature cellular aging. The paradox is that lymphocytes from RA patients are believed to resist apoptosis, and we suggest that the elevated expression of CD53, which results from the increased oxidative stress, may protect against apoptosis.

Adult↗

PubMed2006

Posttranscriptional inhibition of interferon-gamma production by lead.

Lead (Pb) is known to preferentially suppress the activation and development of type-1 CD4+ helper T cell (Th1) responses, whereas it enhances the development of type-2 CD4+ helper T cell (Th2) responses. The inhibition of interferon-gamma (IFNgamma) production has been demonstrated in vitro with a Th1 clone and DO11.10 ovalbumin-transgenic (OVA-tg) CD4+ T cells, and in vivo with wild-type and OVA-tg BALB/c mice; however, the mechanisms responsible for the Pb-induced downregulation of IFNgamma have not been reported. Here, we assessed the modulation of IFNgamma production at the mRNA and protein levels. Pb did not significantly affect IFNgamma mRNA expression by a Th1 clone or activated splenocytes, as measured by reverse transcriptase-polymerase chain reaction (RT-PCR), ribonuclease protection, and real-time RT-PCR. However, Pb did significantly lower the amount of IFNgamma protein in supernatants and cell lysates of antigen-activated T cells in comparison to stimulated controls, suggesting that the lower amounts of IFNgamma released into culture supernatants were not due to a blockage of secretion that gave rise to a cytoplasmic accumulation of IFNgamma. Pb inhibition also was not prevented by addition of zinc or iron. Pb did not enhance protein degradation of IFNgamma, in that lactacystin, an effective blocker of proteosomal proteolysis, did not prevent loss of IFNgamma; additionally, Pb did not accelerate loss of IFNgamma after cycloheximide treatment. Pb did, however, significantly suppress IFNgamma biosynthesis, as investigated using 35S-incorporation in pulse/chase experiments, although it did not suppress total protein synthesis, indicating that Pb selectively inhibits IFNgamma biosynthesis. Thus, Pb appears to selectively interfere with the translation of certain proteins, such as IFNgamma. IL-12 blocked Pb's preferential promotion of Th2 cells, but absence of STAT6 did not prevent the Pb skewing. Thus, Pb may modulate unique regulatory pathways.

Animals↗

PubMed2006

Antibody induction of lupus-like neuropsychiatric manifestations.

Although systemic lupus erythematosus (SLE) is usually evaluated with regard to autoimmune reactivity toward the kidney, there are multiple psychiatric abnormalities associated with this autoimmune disease. Lupus-prone male NZM88 mice, derived from NZB/NZW F1 mice, develop early neuropsychiatric manifestations without any signs of nephritis. In addition to the usual repertoire of antibody specificities, including autoantibodies to dsDNA and renal antigens, mice of this inbred strain express autoantibodies to numerous brain antigens. Here, we show that autoantibodies to brain antigens, assessed by Western analysis, are as individually varied as are the diverse neuropsychiatric manifestations observed in SLE patients. Additionally, a monoclonal antibody derived from the spleen of an untreated NZM88 male when injected into healthy BALB/cByJ, but not C57BL/6J, mice induced behaviors similar to those of lupus-prone NZM88 mice. This monoclonal antibody, which is specific to dynamin-1, binds preferentially in BALB/cByJ cortex and induces substantial expression of cytokines mainly in the hypothalamus. Thus, an antibody to just one brain antigen can induce multiple behavioral changes, and multiple autoantibodies to different brain antigens exist in lupus-prone mice; however, susceptibility to the induction of neurobehavioral deficits is dependent on host genetics.

Animals↗

PubMed2006

Deterministic hydrodynamics: taking blood apart.

We show the fractionation of whole blood components and isolation of blood plasma with no dilution by using a continuous-flow deterministic array that separates blood components by their hydrodynamic size, independent of their mass. We use the technology we developed of deterministic arrays which separate white blood cells, red blood cells, and platelets from blood plasma at flow velocities of 1,000 microm/sec and volume rates up to 1 microl/min. We verified by flow cytometry that an array using focused injection removed 100% of the lymphocytes and monocytes from the main red blood cell and platelet stream. Using a second design, we demonstrated the separation of blood plasma from the blood cells (white, red, and platelets) with virtually no dilution of the plasma and no cellular contamination of the plasma.

Blood Platelets↗

PubMed2006

Death-receptor activation halts clathrin-dependent endocytosis.

Endocytosis is crucial for various aspects of cell homeostasis. Here, we show that proapoptotic death receptors (DRs) trigger selective destruction of the clathrin-dependent endocytosis machinery. DR stimulation induced rapid, caspase-mediated cleavage of key clathrin-pathway components, halting cellular uptake of the classic cargo protein transferrin. DR-proximal initiator caspases cleaved the clathrin adaptor subunit AP2alpha between functionally distinct domains, whereas effector caspases processed clathrin's heavy chain. DR5 underwent ligand-induced, clathrin-mediated endocytosis, suggesting that internalization of DR signaling complexes facilitates clathrin-pathway targeting by caspases. An endocytosis-blocking, temperature-sensitive dynamin-1 mutant attenuated DR internalization, enhanced caspase stimulation downstream of DRs, and increased apoptosis. Thus, DR-triggered caspase activity disrupts clathrin-dependent endocytosis, leading to amplification of programmed cell death.

Apoptosis↗

PubMed2006

Serum antibodies from Parkinson's disease patients react with neuronal membrane proteins from a mouse dopaminergic cell line and affect its dopamine expression.

Evidence exists suggesting that the immune system may contribute to the severity of idiopathic Parkinson's disease (IPD). The data presented here demonstrates that antibodies in the sera of patients with IPD have increased binding affinity to dopaminergic (DA) neuronal (MN9D cell line) membrane antigens in comparison to antibodies in sera from healthy controls. In general, the degree of antibody reactivity to these antigens of the mouse MN9D cell line appears to correlate well with the disease severity of the IPD patients contributing sera, based on the total UPDRS scores. Surprisingly, the sera from IPD patients enhanced the DA content of MN9D cells differentiated with n-butyrate; the n-butyrate-differentiated MN9D cells had a greater concentration of DA (DA/mg total protein) than undifferentiated MN9D cells, especially early in culture. Although the IPD sera did not directly harm MN9D cellular viability or DA production, in the presence of the N9 microglial cell line, the amount of DA present in cultures of untreated or n-butyrate-treated MN9D cells was lowered by the IPD sera. The results suggest the involvement of antibodies in the decline of dopamine production and, thus, the potential of immune system participation in IPD.

Journal Article↗

PubMed2005

On-chip micro-biosensor for the detection of human CD4(+) cells based on AC impedance and optical analysis.

The current study was undertaken to fabricate a small micro-electrode on-chip to rapidly detect and quantify human CD4(+) cells in a minimal volume of blood through impedance measurements made with simple electronics that could be battery operated implemented in a hand held device. The micro-electrode surface was non-covalently modified sequentially by incubation with solutions of protein G', human albumin, monoclonal mouse anti-human CD4, and mouse IgG. The anti-human CD4 antibody served as the recognition and capture molecule for CD4(+) cells present in human blood. The binding of these biomolecules to the micro-electrodes was verified by impedance and cyclic voltammetry measurements. An increase in impedance was detected for each layer of protein adsorbed onto the micro-electrode surface. This process was shown to be highly repeatable. Increased impedance was measured when CD4(+) cells were captured on the micro-electrode, and the impedance also increased as the number of captured cells increased. Fluorescence microscopy of captured cells immunolabeled with anti-human CD4, CD8, and CD19 antibodies, and the nuclear label DAPI, confirmed that only CD4(+) cells were captured. The results were highly dependent on the specimen preparation method used. We conclude that the on-chip capture system can efficiently quantify the number of CD4(+) cells.

Biosensing Techniques↗

PubMed2005

The paradoxical effects of lead in interferon-gamma knockout BALB/c mice.

It has been reported that lead (Pb) exposure enhances interleukin (IL)-4 and inhibits interferon-gamma (IFNgamma) production in wild-type (WT) BALB/c mice. Here, we examined Pb effects on immunity in IFNgamma knockout (KO) mice. Lead significantly enhanced serum IgG1 anti-keyhole limpet hemocyanin (KLH) levels in WT mice compared to the controls; Pb also increased serum IgG2a anti-KLH levels, but the IgG1:IgG2a ratio was greater with Pb. In addition, total serum IgE levels, but not IgE anti-KLH levels, were increased. In the KO mice, the serum IgG1, IgG2a, IgE anti-KLH, and total IgE levels were significantly lower than those of WT mice. Surprisingly, Pb significantly enhanced IgG1 and IgG2a anti-KLH levels in the KO mice. However, for these mice, unlike the WT mice, Pb caused a greater percentage change in IgG2a than in IgG1 anti-KLH, indicating less skewing toward type-2 immunoglobulins. Lead also enhanced the delayed-type hypersensitivity (DTH) response in WT mice. Not surprisingly, very low DTH occurred in the KO mice; however, Pb induced a strong KLH-specific DTH response. The in vivo Pb exposure significantly increased in vitro production of IL-4, IL-5, and IL-10, but not IFNgamma, IL-2 and IL-12, by KLH-induced WT and KO spleen cells. In contrast to KLH, dinitrofluorobenzene contact hypersensitivity (DNFB CHS) was detected in all groups, and Pb did not affect this response, which suggests that Pb has only a slight effect on CD8+ T cell-related responses. As previously reported, Pb enhances Th2 responses in WT mice; however, in the KO mice, Pb enhanced Th1-related anti-KLH production and a Th2-related DTH. The Pb enhancement of DTH in IFNgamma-deficient mice is likely due to promotion of type-2 cytokines and enhancement of major histocompatibility complex (MHC) class II expression.

Animals↗

PubMed2005

Gene expression influences on metal immunomodulation.

Heavy metals in the environment originate from both human activities and natural processes. Exposure to these metals can result in important changes to immune activity. Depending on the metal and dose, these changes can result in enhanced immune function, diminished immune responses, or altered responses that produce autoimmune disease. One of the intriguing aspects of these various phenomena are the multiple points of interaction with cellular machinery at which metals elicit these changes. The individual sections of this review serve to underscore the variety of targets that can be altered by exposure to heavy metals, and provide some comparisons between the effects of specific heavy metals on the immune system. These observations may ultimately lead us to a comprehensive understanding of the mechanisms by which metals alter the immune system, and may enable the development of countermeasures to offset these effects.

Animals↗

PubMed2005

Neonatal lead exposure changes quality of sperm and number of macrophages in testes of BALB/c mice.

BALB/c mice were exposed to 0.1 ppm lead acetate in the drinking water from postnatal day (PND) 1 for 6 weeks. Until PND21, lead exposure was from mother's milk; thereafter, it was directly from the drinking water. The blood lead levels were the highest in pups before weaning (59.5+/-0.9 microg/dL) and significantly lower between PND21 and PND42 (20.3+/-4.7 microg/dL). At PND42, lead-exposed male mice were tested for fertility, sperm DNA, and macrophage number. Mating of lead-treated males with non-treated females confirmed the reduction of fertility in the exposed males. Flow cytometric studies of testicular preparations indicated that the sperm count was not different between lead-exposed and control males; however, the lead-treated mice had a significant increase in the number of testicular cells having a < 1n amount of DNA, which coincided with a decrease in the number of testicular cells with a 2n and 4n amount of DNA. The number of testicular macrophages also was decreased in lead-exposed males, which could reflect altered levels of CSF-1 or response to CSF-1, as previously reported [Kowolenko, M., Tracy, L., Lawrence, D.A., 1989. Lead-induced alterations of in vitro bone marrow cell responses to colony stimulating factor-1. J. Leukoc. Biol. 45, 198-206]. Our study showed that exposure to 0.1 ppm of lead during the neonatal and adolescent period is sufficient to reduce fertility in adult male mice; however, it did not affect sperm count on PND42. The presence of an increased number of apoptotic (< 1n amount of DNA) testicular cells may be diagnostic of defective sperm function. Thus, an administered dose of 0.1 ppm via drinking water ingestion by neonatal male BALB/c mice sufficient to produce PbB of 20-60 mg/dL compromised reproductive function in these mice as adults.

Administration, Oral↗

PubMed2005

Mercury impairment of mouse thymocyte survival in vitro: involvement of cellular thiols.

Heavy metals are well known to be able to induce immunotoxicity, but comparative metal studies related to apoptosis have not been conducted. In the present study, the effects of arsenic, cadmium, gold, lead, manganese, and mercury on thymocytes from BALB/c mice were analyzed. Thymic cells were cultured for 3-24 h in vitro in the absence or presence of metal, and markers of apoptosis or cell death, including annexin V binding, DNA loss/oligonucleosomal fragmentation, 7-amino-actinomycin D uptake (loss of impermeance), changes of the mitochondrial membrane potential (JC-1 fluorescence), and Western analysis of cellular thiols, were assayed. Mercury (Hg) was the only metal shown to be consistently toxic with the dose and times utilized. Cadmium (Cd) was the only other metal tested that also produced some significant level of DNA loss; however, the induction of apoptosis by Cd was not as consistent as that observed with Hg. When Hg was added with 2-mercaptoethanol (2-ME), Hg produced greater toxicity. Endogenous DNA synthesis by thymocytes was immediately inhibited by Hg and Hg + 2-ME. The Hg + 2-ME-induced apoptosis appeared to be associated with altered levels of cellular thiols, in that glutathione (GSH) depletion was significant in comparison to the non-metal control and Hg alone. The increased Hg-induced toxicity in the presence of 2-ME likely was due to the ability of 2-ME to enhance (10- to 20-fold) the cellular uptake of Hg. Western analysis with biotin maleimide demonstrated that Hg + 2-ME and to a lesser extent the positive control dexamethasone eliminated many reactive thiols; the major thiol-reactive protein still reactive with the maleimide probe had an approximate Molecular Mass of 45 kD. Surprisingly, Hg alone enhanced the expression of this thiol-expressing protein, which by Mass Spectrometry (MS)/MS analysis was shown to be beta-actin. Hg also produced the appearance of yet to be identified new proteins. Based on the results with Hg + 2-ME, it is suggested that numerous protein thiols participate in maintenance of cell survival and their loss is associated with apoptosis. The increased expression of new thiol-reactive proteins or thiol-reactive proteins with altered electrophoretic profiles needs to be further investigated. However, the enhanced toxicity attributed to Hg + 2-ME suggests that increased intracellular oxidative stress, observed as increased depletion of GSH, is responsible for the accelerated cell death.

Animals↗

PubMed2005

Selective knockdown of the long variant of cellular FLICE inhibitory protein augments death receptor-mediated caspase-8 activation and apoptosis.

Death receptors trigger apoptosis by activating the apical cysteine proteases caspase-8 and -10 within a death-inducing signaling complex (DISC). c-FLIP (cellular FLICE inhibitory protein) is an enzymatically inactive relative of caspase-8 and -10 that binds to the DISC. Two major c-FLIP variants result from alternative mRNA splicing: a short, 26-kDa protein (c-FLIP(S)) and a long, 55-kDa form (c-FLIP(L)). The role of c-FLIP(S) as an inhibitor of death receptor-mediated apoptosis is well established; however, the function of c-FLIP(L) remains controversial. Although overexpression of transfected c-FLIP(L) inhibits apoptosis, ectopic expression at lower levels supports caspase-8 activation and cell death. Simultaneous ablation of both c-FLIP variants augments death receptor-mediated apoptosis, but the impact of selective depletion of c-FLIP(L) on caspase-8 activation and subsequent apoptosis is not well defined. To investigate this, we developed small interfering RNAs that specifically knock down expression of c-FLIP(L) in several cancer cell lines and studied their effect on apoptosis initiation by Apo2L/TRAIL (Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand). Knockdown of c-FLIP(L) augmented DISC recruitment, activation, processing, and release of caspase-8, thereby enhancing effector-caspase stimulation and apoptosis. Thus, endogenous c-FLIP(L) functions primarily as an inhibitor of death receptor-mediated apoptosis.

Alternative Splicing↗

PubMed2005

Influence of polychlorinated biphenyls and turning preference on striatal dopamine metabolism.

Male BALB/c mice, assessed for spontaneous nocturnal rotation that has been linked with functional differences in striatal dopamine (DA) content, were divided into right (R), left (L), and no turning preference (NP) groups. Both total turning activity and turning in the preferred direction were greatest in the R mice. To determine whether turning preference influences the response to exposure to an environmental toxicant known to reduce striatal DA function, striatal tissues from R, L, or NP mice were exposed to polychlorinated biphenyls (PCBs). In vitro exposure of striata from these mice to varying concentrations of PCBs for 4 h concentration-dependently decreased tissue DA content and increased the concentrations of DA and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the media, a phenomenon already observed, although of smaller magnitude, with rat tissues. These effects were independent of the turning preference of the mice. Although the DA content initially did not differ among the striatal tissue from R, L, and NP mice, following 4 h of incubation in control medium (without PCBs), there was significantly greater DA content in striata from R mice in comparison to that from either L or NP mice. This difference was also apparent after 6 h of incubation, and it was not due to differences in DA turnover or cytotoxicity. Rather, the greater DA content in the striata of R mice was due to increased DA synthesis, since tyrosine hydroxylase (TH) activity was greater in striata from R mice than in striata from either L or NP mice. These differences in striatal DA synthesis, if present in vivo, may explain the observed greater nocturnal turning activity of the R mice. Additionally, the in vitro analyses suggest that striata from R mice have differential responses to stress compared with striata from L or NP mice. With regard to the effects of PCBs, however, it appears that (1) striata derived from mice with different turning preference are equally sensitive to this dopaminergic toxicant and (2) mice appear more sensitive to PCBs than rats.

Animals↗

PubMed2004

Manganese potentiates in vitro production of proinflammatory cytokines and nitric oxide by microglia through a nuclear factor kappa B-dependent mechanism.

Recent evidence suggests that the mechanism of manganese (Mn) neurotoxicity involves activation of microglia and/or astrocytes; as a consequence, neurons adjacent to the activated microglia may be injured. Mn modulation of proinflammatory cytokine expression by microglia has not been investigated. Therefore, the objectives of this research were to (1) assess whether Mn induces proinflammatory cytokine expression and/or modulates lipopolysaccharide (LPS)-induced expression of proinflammatory cytokines and (2) investigate possible mechanisms for such an induction. N9 microglia were exposed in vitro to increasing concentrations (50-1000 microM) of Mn in the presence or absence of LPS (10, 100, or 500 ng/ml). After various incubation times (up to 48 h), media levels of several cytokines and nitric oxide (NO) were determined, as was the expression of the inducible form of NO synthase (iNOS). Lactate dehydrogenase (LDH) release into the medium and the cellular uptake of Neutral Red were used as general measures for cytotoxicity. In the absence of LPS, Mn moderately increased interleukin-6 and tumor necrosis factor alpha (TNF-a) production only at higher Mn concentrations, which were cytotoxic. At all LPS doses, however, proinflammatory cytokine production was dose-dependently increased by Mn. Similarly, LPS-induced NO production and iNOS expression were substantially enhanced by Mn. Pharmacological manipulations indicated that nuclear factor kappa B (NFkappaB) activation is critical for the observed enhancement of cytokine and NO production. Within the context of inflammation, increased production of proinflammatory cytokines and NO by Mn could be an important part of the mechanism by which Mn exerts its neurotoxicity.

Acetylcysteine↗

PubMed2004

Splenic norepinephrine and serum corticosterone level fluctuations associated with bacteria-induced stress.

Corticosterone (CORT) and norepinephrine (NE), two effector molecules of the hypothalamic-pituitary-adrenal (HPA) and the sympathetic-lymphoid (SL) axes, respectively, differentially influence murine host resistance to Listeria monocytogenes (LM). Serum CORT and splenic NE levels early (< or =24 h) after infection correlated positively with host resistance, as long as the LM burden did not exceed approximately 10(6) cfu LM per spleen. As previously reported, mice with right-circling preference (R-mice) have significantly greater host resistance to LM than those with left-circling preference (L-mice) and early after infection, R-mice had significantly higher serum CORT levels than L-mice. However, rapid pathogenesis with a high bacterial burden induced high activation of the HPA and SL axes, which prevented observable differences in the defense against LM, especially later in infection. With the high bacterial inoculum (10(5) LM), the splenic NE levels significantly increased, but no differences among R- and L-mice were discernible. We suggest that endogenous asymmetry of neuroimmune circuits contributes to differential host resistance, but the level of stress (bacterial inoculum) is critical. With regard to the neuroendocrine factors assessed, CORT, but not NE, levels significantly correlated with the enhanced defenses of R-mice in comparison to L-mice. The differential host resistance based on brain laterality seems to be more a function of the HPA axis and possibly other CNS effects on peripheral immunity than neurotransmitter release by the sympathetic innervation of the spleen.

Animals↗

PubMed2003

Shrinking the biologic world--nanobiotechnologies for toxicology.

Although toxicologic effects need to be considered at the organismal level, the adverse events originate from interactions and alterations at the molecular level. Cellular structures and functions can be disrupted by modifications of the nanometer structure of critical molecules; therefore, devices used to assess biologic and toxicologic processes at the nanoscale will allow important new research pursuits. In order to properly assess alterations at these dimensions, nanofabricated tools are needed to detect, separate, analyze, and manipulate cells or biologic molecules of interest. The emergence of laser tweezers, surface plasmon resonance (SPR), laser capture microdissection (LCM), atomic force microscopy (AFM), and multi-photon microscopes have allowed for these assessments. Micro- and nanobiotechnologies will further advance biologic, clinical, and toxicologic endeavors with the aid of miniaturized, more sensitive devices. Miniaturized table-top laboratory equipment incorporating additional innovative technologies can lead to new advances, including micro total analysis systems (microTAS) or "lab-on-a-chip" and "sentinel sensor" devices. This review will highlight several devices, which have been made possible by techniques originating in the microelectronics industry. These devices can be used for toxicologic assessment of cellular structures and functions, such as cellular adhesion, signal transduction, motility, deformability, metabolism, and secretion.

Animals↗

PubMed2003

Immune changes during acute cold/restraint stress-induced inhibition of host resistance to Listeria.

Experiments were conducted to delineate the cellular changes modulated by acute cold/restraint stress (ACRS), a physical and psychological stressor, in response to a Listeria monocytogenes(LM) infection. In addition to wild type (WT) BALB/c mice, CD4-deficient (CD4-/-) BALB/c mice, which have no effective adaptive immunity, were used to determine the involvement of adaptive versus innate immunity. ACRS-induced suppression of host resistance to LM was not observed in CD4-/- mice, suggesting the involvement of CD4+T cells in the acute cold/restraint stress (ACRS)-induced inhibition. The in vivo splenic leukocyte phenotypes and activities of WT BALB/c mice after infection and in vitro lymphocyte responses to heat-killed LM (HKLM) also were examined. There were no significant differences in the numbers of splenic T and B lymphocytes, natural killer cells, macrophages, or neutrophils between nonstressed and ACRS-treated WT mice. However, higher levels of activated T cells and non-T lymphocytes were observed in the ACRS-treated mice; beta-adrenergic receptor (beta-ADR) antagonists (propranolol and atenolol) eliminated these elevated levels of activation, as well as the ACRS-induced suppression of host resistance. ACRS and control mice also had equivalent activation of macrophages. With in vitro HKLM stimulation, splenocytes from ACRS-treated mice produced significantly higher levels of IFNgamma and slightly higher levels of IL-6 in comparison with the nonstressed mice, although equivalent levels of lymphocyte proliferation were obtained. Additionally, ACRS-treated mice showed comparable elevation of serum nitric oxide after infection, indicating macrophage bactericidal activity similar to nonstressed mice. Thus, it appears that ACRS inhibits host resistance through regulatory CD4+ T cells and/or effector cell functions downstream of CD4+ T cell activation, as well as through beta-ADR signaling, in that blockage of these receptors appears to aid host defenses by means other than elevation of helper T cell activity. Because CD4 T cell deficiency and beta-ADR blockage produced equivalent effects, beta-ADR+ CD4+ T cells may have a negative role on host defenses after ACRS.

Acute Disease↗