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K S Madden

Publications and source records attributed to K S Madden.

35 records · Page 2Linked to original sources
PubMed1994

Sympathetic nervous system modulation of the immune system. III. Alterations in T and B cell proliferation and differentiation in vitro following chemical sympathectomy.

Functional changes in lymph node (LN) and spleen lymphocytes were examined following sympathetic denervation of adult mice with 6-hydroxydopamine (6-OHDA). Sympathectomy reduced in vitro proliferation to concanavalin A (ConA) by LN cells and decreased LN Thy-1+ and CD4+ T cells. At the same time, ConA-induced interferon-gamma (IFN-gamma) production was increased, but interleukin-2 (IL-2) production was not altered. After sympathectomy, lipopolysaccharide (LPS)-stimulated proliferation of LN B cells was enhanced, in parallel with an increase in the proportion of sIgM+ cells. LPS-induced polyclonal IgM secretion was decreased, whereas polyclonal IgG secretion was dramatically enhanced. In the spleen, ConA and LPS responsiveness was reduced after sympathectomy, as was IL-2 and IFN-gamma production. The decreased proliferation was not associated with changes in splenic T and B cell populations. The uptake blocker desipramine prevented the 6-OHDA-induced changes in spleen and LN, indicating that these alterations were dependent upon neuronal destruction. These results provide evidence for heterogeneity of sympathetic nervous system regulation of T and B lymphocyte function and for organ-specific influences on immune function.

Animals↗
PubMed1993

CD36 is a receptor for oxidized low density lipoprotein.

The oxidation of low density lipoprotein (LDL) in the arterial wall is thought to contribute to human atherosclerotic lesion formation, in part by the high affinity uptake of oxidized LDL (OxLDL) by macrophages, resulting in foam cell formation. We have utilized cloning by expression to identify CD36 as a macrophage receptor for OxLDL. Transfection of a CD36 clone into 293 cells results in the specific and high affinity binding of OxLDL, followed by its internalization and degradation. An anti-CD36 antibody blocks 50% of the binding of OxLDL to platelets and to human macrophage-like THP cells. Furthermore, like mouse macrophages, 293 cells expressing CD36 recognize LDL which has been oxidized only 4 h, whereas more extensive oxidation of the LDL is required for recognition by the other known OxLDL receptors, the acetylated LDL (AcLDL) receptor and Fc gamma RII-B2. CD36 may play a role in scavenging LDL modified by oxidation and may mediate effects of OxLDL on monocytes and platelets in atherosclerotic lesions.

Animals↗
PubMed1993

Neonatal sympathetic denervation alters development of natural killer (NK) cell activity in F344 rats.

The development of natural killer (NK) cell activity was assessed in Fischer 344 (F344) rats sympathectomized as neonates with the neurotoxin, 6-hydroxydopamine (6-OHDA). No NK cell activity was detected in sympathectomized or vehicle-injected control animals at 7 days of age. At 10 and 14 days of age, NK cell activity was reduced in spleens from sympathectomized male and female rats. At 21 days of age, a reduction in NK cell activity was detected only in sympathectomized male rats. Sympathectomy did not alter NK cell activity at 28 and 42 days of age in either gender. At 56 days of age, NK cell activity was increased in neonatally sympathectomized females; rats of both genders acutely sympathectomized at 56 days of age also showed enhanced NK cell activity. No differences were observed at 90 days of age in neonatally or acutely sympathectomized males of females. Prior treatment with desipramine, which blocks uptake of 6-OHDA into nerve terminals and prevents the destruction of sympathetic nerve terminals, prevented these 6-OHDA-induced effects, suggesting that sympathectomy, and not direct toxic effects of 6-OHDA treatment of NK cells, accounted for the alterations in NK cell activity. Together, these results indicate that the sympathetic nervous system is an integral component of the developing lymphoid and hematopoietic microenvironment.

Aging↗
PubMed1993

Fundamental aspects of neural-immune signaling.

Noradrenergic and peptidergic nerve fibers abundantly innervate the parenchyma of both primary (bone marrow) and secondary (spleen, lymph nodes) lymphoid organs. Nerve fibers distribute within the parenchyma of these organs, as well as along smooth muscle compartments. Both noradrenaline and peptides such as substance P have been shown to fulfill the basic criteria for neurotransmission with lymphocytes, macrophages, and other immunocytes as targets. Denervation or pharmacological manipulation of these neurotransmitters can profoundly alter immunological reactivity at the individual cellular level, at the level of complex multicellular interactions (such as antibody response), and at the level of host response to a disease-producing challenge. The characteristic and mechanisms of bidirectional neural-immune signaling may provide a novel approach to immunologically-mediated disease, both pharmacologically and behaviorally.

Female↗
PubMed1991

Neonatal sympathetic denervation alters the development of in vitro spleen cell proliferation and differentiation.

The ontogeny of spleen cell proliferation to T and B cell mitogens and immunoglobulin secretion, measured in vitro, was examined in neonatally sympathectomized Fischer 344 (F344) rats, administered the neurotoxic drug 6-hydroxydopamine (6-OHDA) from 1 to 3 days of age. Compared to cells from age-matched controls, spleen cells from neonatally sympathectomized animals, aged 7-14 days, exhibited a shift in the proliferative response to the T cell mitogen, concanavalin A (Con A), with reduced proliferation in the presence of low doses of Con A, but increased proliferation with higher doses. During the same period, from 7 to 14 days, the B cell mitogen STM/DxS inhibited proliferation by spleen cells from all rats, and no effect of sympathectomy was observed. As adult-like patterns of mitogen responsiveness emerged from 21 to 42 days of age, neonatally sympathectomized rats showed reduced proliferative responses of both T and B cells. This effect dissipated by 56 days of age. Polyclonal immunoglobulin (Ig) production by B cells was assessed in vitro in the presence or absence of STM/DxS. Neonatal sympathectomy resulted in reduced spontaneous IgM production throughout development. From 28 to 42 days of age, when mitogen-triggered IgM secretion first developed, neonatal sympathectomy decreased the magnitude of the response. By 56 days of age, mitogen-induced IgM secretion was no longer affected by sympathectomy, similar to the proliferative response. Gender influenced the time course of sympathectomy-induced changes in spleen cell proliferation and differentiation; however, the magnitude and direction of these changes were similar in both males and females. Desipramine, administered prior to 6-OHDA, prevented both sympathetic denervation and the 6-OHDA-induced changes in spleen cell responsiveness. This indicates that the alterations in immune function were dependent on NA nerve fiber destruction and were not simply the result of direct 6-OHDA action on other cells. The results of this study suggest that sympathetic innervation may play an important potentiating role in the development of the lymphoid system, through effects on lymphocyte proliferation and differentiation.

Animals↗
PubMed1989

Sympathetic neural modulation of the immune system. I. Depression of T cell immunity in vivo and vitro following chemical sympathectomy.

Chemical sympathectomy of adult mice with 6-hydroxydopamine (6-OHDA) either prior to or following epicutaneous sensitization with the trinitrophenyl (TNP) hapten decreased the delayed hypersensitivity (DH) response to ear challenge. To determine if uptake of 6-OHDA into sympathetic nerve terminals, and their subsequent destruction, was required for suppression of DH, the catecholamine uptake blocker, desipramine, was employed to block 6-OHDA-induced sympathetic denervation. Pretreatment with desipramine prevented the depression of DH. In vivo treatment with the beta blocker, propranolol, did not alter the 6-OHDA effect, eliminating the potential contribution of released catecholamines, acting on beta-adrenoceptors, to DH reduction. Sympathectomy before sensitization also diminished hapten-specific T cell reactivity of sensitized lymph node (LN) cells, as measured in vitro by IL-2 production and CTL generation. In vivo DNA synthesis in draining LN in response to immunization was modestly decreased following 6-OHDA. Thus, sympathetic denervation appears to impair T cell activity in vivo and in vitro. Overall, these results indicate the SNS plays a role in generation of cell-mediated immunity.

Animals↗
PubMed1987

Regulation of the immune system by sympathetic neural mechanisms.

The immune system is made up of primary and secondary lymphoid organs, containing lymphocytes and several accessory cell types, which are the key agents of immunological reactivity. Some of the basic features of immune responses are reviewed. Several pathways from the CNS to the immune system are of potential importance in physiological regulation. The sympathetic nervous system innervates all lymphoid organs with noradrenergic fibers. Furthermore, lymphocytes have receptors for sympathetic neurotransmitters, e.g., beta adrenoceptors. Sympathetic denervation by pharmacologic treatment with 6-hydroxydopamine has a marked affect on several immune responses, including antibody production, delayed hypersensitivity, and generation of cytotoxic T lymphocytes. Norepinephrine, epinephrine, and synthetic adrenergic agonists potentiate cytotoxic T lymphocyte responses in vitro. This appears to be mediated via beta 2 adrenoceptors. Studies with adrenoceptor blockers also indicate a possible role for alpha receptors. In sum, our studies indicate that intact noradrenergic innervation is required for normal immune function. Sympathetic neural influence, via norepinephrine release, may be exerted at the cellular (activation, proliferation, secretion of products) as well as the physiologic (antigen localization, lymphocyte migration) levels.

Animals↗
PubMed1985

Indomethacin, prostaglandin E2 and transmission at the frog neuromuscular junction.

The effects of indomethacin on transmission at the frog neuromuscular junction were studied using intra- and extracellular voltage recordings. The drug had two dose-dependent effects on spontaneous and evoked quantal acetylcholine release. Low doses (less than or equal to 30 microM) irreversibly decreased and high doses (greater than or equal to 300 microM) reversibly increased release. Indomethacin also increased the latencies of evoked responses by increasing synaptic delays and usually increasing nerve action potential conduction times. Low doses are thought to inhibit cyclo-oxygenase specifically. To determine whether this single action might account for the presynaptic effects of the drug, other treatments that affect prostaglandin concentrations were also studied: 1) potassium 5,8,11,14-eicosatetraynoate (3 microM) and phenylbutazone (80 micron or 1 mM), two additional, molecularly different synthesis inhibitors; 2) prostaglandin E2 (30 nM-30 microM); and 3) sodium arachidonate (30 nM-30 microM), the essential fatty acid precursor of prostaglandin E2. Each treatment altered transmission, but perturbations in endogenous prostaglandin concentrations cannot account for all of their presynaptic effects.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1981

4-Aminopyridine does not increase m.e.p.p. frequencies at junctions depolarized by potassium.

4-aminopyridine (4-AP) is known to produce large increases in quantal acetylcholine release from stimulated motor nerve terminals. It has been suggested that the drug might act directly on Ca2+ channels to increase Ca2+ influx. This possibility was tested at frog neuromuscular junctions depolarized in elevated [K+]out. The 4-AP did not increase miniature end-plate potential frequencies. Also, 4-AP did not alter the increase in frequency that follows a rise in [Ca2+]out at a depolarized junction. Therefore, under these conditions, 4-AP does not appear to change Ca2+ entry into or elimination from the nerve terminal. The results support the hypothesis that 4-AP acts by lengthening the nerve terminal action potential.

4-Aminopyridine↗
PubMed1978

Surface charges and the effects of calcium on the frequency of miniature end-plate potentials at the frog neuromuscular junction.

1. When motor nerve terminals are slightly depolarized with increased [K+]o, progressive increases in [Ca2+]o raise min.e.p.p. frequencies until a maximum is reached; further increases then produce a depression (Cook & Quastel, 1973; Matthews & Wickelgren, 1977). 2. Increases in [Mg2+]o also produce the depression. 3. It has been suggested that the depression results from this sequence of events: (a) the divalent cations screen the fixed negative surface charges on the outer face of the nerve terminal, which (b) decreases the negativity of the surface potential, which (c) increases the voltage gradient within the membrane itself, which (d) tends to shut depolarization-gated channels for Ca2+ entry, which (e) decreases min.e.p.p. frequency. 4. In agreement with the interpretation, in frog neuromuscular junctions slightly depolarized with 11 mM-[K+]o, min.e.p.p. frequency is a monotonically increasing function of [Ca2+]o, as long as the sum of [Ca2+]o plus [Mg2+]o is kept constant. 5. The decrease in min.e.p.p. frequency caused by raising [Mg2+]o by 5 mM can be counterbalanced by raising [K+]o by about 9 mM. Using the Grahame equation (1947), assuming that the elevated divalent cations act solely by screening and have no effect on conductance, the negative surface charge is estimated to be roughly 1 electronic charge/75 A2.

Animals↗
PubMed1975

Effect of secretin and cholecystokinin on small intestinal blood flow distribution.

The relative blood flow distribution within the small intestine of anesthetized cats was investigated during resting conditions and when superior mesenteric blood flow was increased 15--85% by the intravenous infusion of secretin, cholecystokinin (CCK), or isoproterenol. Radioactive microspheres of 15 mum diameter were injected into the superior mesenteric artery and shortly thereafter intestinal segments were removed and dissected into mucosal, submucosal, and muscularis fractions. Tissue weights and the radioactivity of each were determined. During secretin-induced mesenteric vasodilatation there was a significant redistribution of blood away from the jejunal mucosa to the submucosa. During CCK and isoproterenol infusions there were significant increases in mucosal and decreases in submucosal blood flow. No significant changes were observed in muscularis flow. There was no apparent relationship between the percent increase in SMBF and the relative blood flow distribution changes observed. The results indicate that while secretin, CCK, and isoproterenol increase superior mesenteric blood flow, they also affect blood flow distribution within the mucosa and submucosa.

Animals↗
PubMedDate not supplied

Age-associated alterations in sympathetic neural interactions with the immune system.

We have examined age-related alterations in sympathetic noradrenergic (NA) innervation in primary and secondary lymphoid organs from mouse and rat. As the thymus involuted with age, the density of NA innervation and norepinephrine (NE) concentration increased markedly. Total thymic NE was not altered significantly with age, suggesting that NA innervation is maintained as the thymus involutes. In the rat spleen, NA innervation and NE concentration were diminished with age. Enhanced antibody responses and in vitro proliferation to a T-dependent protein antigen were observed following selective destruction of NA nerve fibers with the neurotoxin 6-hydroxydopamine (6-OHDA), demonstrating that the diminished NA innervation in the aged spleen is capable of signaling the immune system. Plasticity of NA nerves in old rats was demonstrated following lesioning with 6-OHDA and in intact rats treated with L-deprenyl, a monoamine oxidase B inhibitor. These age-related alterations in NA innervation of lymphoid organs occur concurrently with age-associated changes in immune function. Understanding the functional relationship between these two physiological systems in aging will contribute to a greater understanding of sympathetic nervous system regulation of immune function.

Age Factors↗
PubMedDate not supplied

Inhibition of tumor growth by L-deprenyl involves neural-immune interactions in rats with spontaneously developing mammary tumors.

L-deprenyl, a monoamine oxidase-B inhibitor, has been shown to reverse the age-related decline in sympathetic noradrenergic innervation and immune function in old rats and enhance T cell and NK cell activity in tumor-bearing rats. The objective of the present study was to examine whether deprenyl treatment of old female rats with mammary tumors could augment sympathetic nervous system and immune responses to inhibit the tumor growth. Female Sprague-Dawley rats with spontaneous mammary tumors were administered 0, 2.5 mg, or 5.0 mg/kg body weight (BW)/day deprenyl for i.p. 9 weeks. Tumor diameter, tumor number and body weight were measured throughout the treatment period. At the end of the treatment period, norepinephrine (NE) concentration, interferon-gamma production (IFN-gamma), Con A-induced T lymphocyte proliferation, and percentage of T and B lymphocytes and natural killer cells were measured in the spleen, and the concentrations of monoamines were measured in the medial basal hypothalamus. Relative to saline-treated controls, treatment with deprenyl reduced tumor growth, increased NE concentration, IFN-gamma production and percentage of the CD8+ T lymphocytes in the spleen. In the medial basal hypothalamus, deprenyl treatment increased the concentrations of catecholamines and indoleamine. These results suggest that the anti-tumor effects of deprenyl on spontaneous rat mammary tumors may be achieved via neural-immune signaling in the spleen and medial basal hypothalamus.

Animals↗