The basis for treatment in multiple sclerosis

Contemporary licensed treatments for multiple sclerosis fail to provide a solution for the disease because their effects are limited to a modest reduction in the frequency of new episodes. They do not reduce disability or materially influence the progressive phase of the disease. A contemporary strategy for management requires a more detailed analysis of the separate contributions to the clinical features and overall course made by inflammation, axonal injury, compensatory mechanisms, and remyelination. From this formulation emerges the need either for early and fully effective suppression of the inflammatory response, limiting the damage to all components of the axon-glial unit; or the development of strategies for axonal and myelin repair that solve the issues of controlled differentiation, delivery and timing of these cell and growth factor-based interventions.     

Chemoattractant-induced firm adhesion of leukocytes to vascular endothelium in vivo is critically dependent on initial leukocyte rolling

Leukocyte rolling and firm adhesion at the venular endothelium are two discrete events in the cellular inflammatory response mediated via selectin and integrin adhesion molecules, respectively. The dependency of chemoattractant-induced firm leukocyte adhesion on the preceding rolling interaction was investigated in rat mesenteric microvessels through use of intravital microscopy. Leukocyte rolling was dose-dependently inhibited by systemic treatment with the sulphated polysaccharide fucoidin. The firm leukocyte adhesion following stimulation with the chemotactic peptide fMLP was similarly inhibited when fMLP challenge was performed subsequent to inhibition of leukocyte rolling by fucoidin. Thus, based on paired observations in single venules before and after fucoidin treatment, reduced rolling leukocyte flux prior to fMLP challenge was paralleled over a wide range by a proportional decrease in fMLP-induced leukocyte adhesion. The results demonstrate quantitatively a close relationship between the extent of leukocyte rolling and the magnitude of the subsequent firm adhesion response, and, that an initial rolling interaction is a precondition for firm adhesion to occur at physiological blood flow rates in vivo.     

Lymphoid tissues induce NGF-dependent and NGF-independent neurite outgrowth from rat superior cervical ganglia explants in culture

Induction of neurite outgrowth from superior cervical ganglia (SCG) by rat lymphoid tissues was studied using a tissue culture model. Neonatal rat SCG were cultured with 6–12-week-old rat thymus, spleen, or mesenteric lymph node (MLN) explants in a Martrigel layer, in defined culture medium without exogenous nerve growth factor (NGF). SCG were also co-cultured with neonatal rat heart (as positive control) or spinal cord (SC; as negative control). To determine whether inflammation affects the ability of lymphoid tissues to induce neurite outgrowth, we also examined MLN at various times after infecting rats with Nippostrongylus brasiliensis (Nb-MLN). In one series of experiments, a single lymphoid tissue explant was surrounded by four SCG at a distance of 1 mm. The extent of neurite outgrowth was determinded by counting the number of neurites 0.5 mm away from each ganglion at several time points. Adult thymus and, to a lesser extent, spleen had strong stimulatory effects on neurite outgrowth from SCG after 12 hr or more in culture. For thymus tissue, this was similar to the positive control heart explants. MLN from normal rats had minimal effect on neurite outgrowth; however, Nb-MLN showed a time-dependent enhancement of the neurite outgrowth, maximal at 3 weeks after infection. The relative efficacy of neurite outgrowth induction (heart ≥ thymus ≥ Nb-MLN ≥ spleen ≥ MLN ≥ SC) was confirmed in a second series of experiments where one SCG was surrounded by three different tissue explants. We then examined the role of 2.5S NGF, a well-known trophic factor for sympathetic nerves, in the lymphoid tissue-induced neurite outgrowth. Anti-NGF treatment of co-cultures of SCG and heart almost completely blocked the neurite outgrowth. Anti-NGF also significantly inhibited thymus- and spleen-induced neurite outgrowth, but not as effectively as heart-induced neuritogenesis (93,80, and 77% inhibition at 24 hr; 86,70, and 68% inhibition at 48 hr for heart, thymus, and spleen, respectively). On the other hand, anti-NGF inhibited only 8% of neurite outgrowth induced by 3-week post-infection Nb-MLN at 24 hr, and 41% at 48 hr. These data show that several adult rat lymphoid tissues exert neurotrophic/tropic effects. The predominant growth factor in thymus and spleen is NGF, while Nb-MLN produces factor(s) which is (are) immunologically distinguishable from NGF. These neurotrophic/tropic factors are produced during the reactive lymphoid hyperplasia that forms part of the inflammatory response against the nematode, N. brasiliensis. This suggests the possibility that cytokines produced by lymphocytes or other inflammatory cells may stimulate sympathetic neurite outgrowth in vivo. © 1994 Wiley-Liss, Inc.     

Hormone replacement therapy is associated with increased C-reactive protein in women with Type 2 diabetes in the Diabetes Heart Study.

AIMS: Increased levels of inflammatory biomarkers, especially C-reactive protein (CRP), are associated with increased risk for cardiovascular disease (CVD) events, such as myocardial infarction, stroke, peripheral vascular disease, and sudden cardiac death. Medical interventions that increase CRP levels, such as hormone replacement therapy (HRT) in post-menopausal women, are under increasing scrutiny. The effect of HRT on CRP levels in women with Type 2 diabetes (T2DM) is not well documented, and conflicting conclusions have been reported. The aim of this study was to determine the influence of HRT on women with diabetes in a large cross-sectional study. METHODS: Three hundred and twenty-seven post-menopausal women with T2DM from the Diabetes Heart Study participated. Current use of HRT was determined and serum CRP levels were measured using a high-sensitivity ELISA kit. Generalized estimating equation methods were used to assess the relationship of multiple clinical and lifestyle (e.g. smoking) measures on CRP levels including differences between women taking HRT (HRT+) and not taking HRT (HRT-). RESULTS: Overall serum CRP levels were strongly associated with body mass index (P < 0.0001) and age (P < 0.0001). Of the women, 243 were not using HRT and 84 were using HRT. HRT+ and HRT- women did not differ significantly in measures of clinical traits, with the exception of higher mean low-density lipoprotein cholesterol in HRT- women (P = 0.004). In all models tested, HRT+ women had significantly higher circulating CRP levels, with P-values ranging from 0.0045 to 0.010. CONCLUSIONS: In this study of serum CRP concentration as a function of HRT in women with Type 2 diabetes, there was consistent evidence for increased circulating CRP levels in women receiving oestrogen-containing HRT. Whether HRT-induced increases in CRP can account for the adverse cardiovascular effects of HRT remains to be established; however, based on these data, there is little reason to believe that diabetic women would be spared from such an effect.     

Role of intercellular adhesion molecule-1 in a murine model of toluene diisocyanate-induced asthma

BACKGROUND: Adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) are thought to contribute to the airway inflammation and airway hyper-responsiveness (AHR) of allergic asthma. Some differences from allergic asthma have been noted, including airway neutrophilia, and the involvement of ICAM-1 in toluene diisocyanate (TDI) asthma is currently unclear. OBJECTIVE: We utilized mice lacking ICAM-1 expression (ICAM-1(-/-)) to investigate the role of ICAM-1 in airway inflammation and AHR in TDI-induced asthma. METHODS: Male C57BL/6J mice (ICAM-1(+/+)) and ICAM-1(-/-) mice were intranasally sensitized to TDI solution or solvent alone. Airway inflammation, AHR and cytokine secretion were assessed 24 h after challenge by TDI or solvent. The production of antigen-specific IgG and IgE by TDI sensitized and non-sensitized mice was determined. RESULTS: TDI challenge to ICAM-1(+/+) mice induced an increase in airway inflammatory cell numbers, AHR and cytokine secretion of TNF-alpha, macrophage inflammatory protein-2 (MIP-2), IL-4, IL-5 and IFN-gamma into the bronchoalveolar lavage fluid. All these pathophysiological changes were reduced in ICAM-1(-/-) mice. Serum levels of TDI-specific IgG and IgE of ICAM-1(-/-) and ICAM-1(+/+) mice were comparable. CONCLUSION: These results suggest that ICAM-1 plays an essential role in airway inflammation and AHR in TDI-induced asthma.     

Histamine differentially interacts with tumor necrosis factor-α and thrombin in endothelial tissue factor induction: the role of c-Jun NH2-terminal kinase

BACKGROUND: Histamine plays an important role in vascular disease. Tissue factor (TF) expression is induced in vascular inflammation and acute coronary syndromes. OBJECTIVES: This study examined the effect of histamine on tumor necrosis factor-alpha- (TNF-alpha-) vs. thrombin-induced endothelial TF expression. METHODS AND RESULTS: Histamine (10(-8)-10(-5) mol L-1), TNF-alpha (5 ng mL-1), and thrombin (1 U mL-1) induced TF expression in human endothelial cells. Although TF expression by TNF-alpha and thrombin was identical, histamine augmented TNF-alpha-induced expression 7.0-fold, but thrombin-induced expression only 2.6-fold. Similar responses occurred with TF activity. The H1-receptor antagonist mepyramine abrogated these effects. Differential augmentation by histamine was also observed at the mRNA level. Histamine-induced p38 activation preceded a weak second activation to both TNF-alpha and thrombin. Histamine-induced c-Jun NH2-terminal kinase (JNK) activation was followed by a strong second activation to TNF-alpha, and less to thrombin. Selective inhibition of this second JNK activation by SP600125 reduced TF induction to histamine plus TNF-alpha by 67%, but to histamine plus thrombin by only 32%. Histamine augmented TNF-alpha- and thrombin-induced vascular cell adhesion molecule 1 (VCAM-1) expression to a similar extent. Consistent with this observation, VCAM-1 induction to TNF-alpha and thrombin was mediated by p38, but not by JNK. CONCLUSIONS: Histamine differentially augments TNF-alpha- vs. thrombin-induced TF expression and activity, which is mediated by the H1-receptor, occurs at the mRNA level, and is related to differential JNK activation.     

Topical treatment with aqueous solutions of rofleponide palmitate and budesonide in a pollen-season model of allergic rhinitis

BACKGROUND: Rofleponide palmitate is an esterified glucocorticosteroid pro-drug with a promising pre-clinical profile designed to deliver topical airway treatment for allergic rhinitis and asthma in a novel manner. Thus, the rofleponide palmitate pro-drug is designed to provide topical exposure of the mucosa to the inactive lipophilic drug, which would be locally metabolized to the more hydrophilic and readily cleared drug rofleponide. OBJECTIVE: To examine whether rofleponide palmitate affects nasal symptoms and peak inspiratory flow (PIF) in a pollen-season model of allergic rhinitis and to compare any such effects with those of another glucocorticosteroid (i.e., budesonide). METHODS: During the pollen-free season, 40 patients with strictly seasonal allergic rhinitis received topical nasal spray treatment with an aqueous solution of rofleponide palmitate 400 microg and an aqueous solution of budesonide 128 microg once daily for 10 days in a double-blind, placebo-controlled, and crossover study. After 3 days of drug treatment, individualized allergen challenges were given once daily for 7 days while the treatment continued. The washout periods between each of the challenge series were 2 weeks. Nasal symptoms and PIF were recorded in the morning and evening, as well as 10 and 20 min after each allergen challenge. The mean recordings obtained during the last 3 days of the allergen-challenge series, when symptoms were established and when the treatment had lasted for 8-10 days, were used in the analysis. RESULTS: Both active treatments reduced nasal symptoms and improved nasal PIF compared with placebo (P<0.01-0.001). There was no overall difference in efficacy between rofleponide palmitate 400 microg and budesonide 128 microg. CONCLUSIONS: Topical treatment with aqueous solutions of rofleponide palmitate attenuates nasal symptoms and improves nasal PIF in allergic rhinitis. The overall efficacy of 400 microg of rofleponide palmitate is similar to that of 128 microg of budesonide in the pollen-season model used in this study.     

Expression of tyrosine hydroxylase and neuropeptide tyrosine in mouse sympathetic airway-specific neurons under normal situation and allergic airway inflammation

BACKGROUND: The traditional neurotransmitter catecholamine and the neuropeptide tyrosine in sympathetic airway nerves have been proposed to be involved in the pathogenesis of airway diseases. OBJECTIVE: The aim of the present study was to investigate the effect of allergic airway inflammation on the expression of catecholamine enzyme tyrosine hydroxylase (TH), neuropeptide tyrosine (NPY) and tachykinins in mouse sympathetic airway ganglia. METHODS: Using neuronal tracing in combination with immunohistochemistry, the present study was designed to characterize TH, NPY and tachykinin profiles of superior cervical (SCG) and stellate ganglia after allergen challenge. RESULTS: The vast majority of fast blue-labelled SCG neurons (allergen: 97.5+/-1.22% (mean+/-SEM) vs. controls: 94.5+/-1.48%, P=0.18) and stellate neurons (allergen: 95.3+/-1.01% vs. controls: 93.6+/-1.33%, P=0.34) were immunoreactive for TH. Of the TH immunoreactive and fast blue-labelled SCG neurons, 52.0+/-1.01% allergen vs. 51.2+/-3.58% controls (P=0.83) and stellate neurons, 57.3%+/-0.97 allergen vs. 56.4+/-1.65% controls (P=0.64) were positive for TH only but not NPY, whereas 45.3+/-1.05% allergen vs. 43.3+/-1.18% controls (P=0.47) of fast blue-labelled SCG neurons and 37.9+/-0.86% allergen vs. 37.1+/-1.24% controls (P=0.62) of fast blue-labelled stellate neurons were immunoreactive for both TH and NPY immunoreactivities. There was a trend of an increase, but not significant one, in the percentage of TH-/NPY-immunoreactive and fast blue-labelled neurons in allergen-treated animals in comparison with the controls. Tachykinins, however, were not expressed by sympathetic neurons and were also not induced in sympathetic neurons after allergen challenge. CONCLUSION: The present study indicates that allergic airway inflammation does not alter the expression of noradrenalin and NPY in sympathetic ganglia and also shows that sympathetic neurons do not respond to allergic airway inflammation with tachykinins induction. However, a participation of catecholamine and NPY in the pathogenesis of allergic airway inflammation cannot be excluded in the present study as a higher neurotransmitter output per neuron following allergen challenge could be possible.     

Low-dose endotoxin in allergic asthmatics: effect on bronchial and inflammatory response to cat allergen

BACKGROUND: Endotoxin was proposed to increase the severity of asthma. Endotoxin levels greatly differ according to settings. In domestic environments, airborne concentrations may be dramatically low compared with levels reported in occupational settings. OBJECTIVE: Our first objective was therefore to assess the effect of inhalation of low-level lipopolysaccharide (LPS) on the immediate and late-phase asthmatic bronchial response. Our second objective was to evaluate the effect of exposure to LPS on the local and systemic inflammatory response. METHODS: Nineteen asthmatics sensitized to cat underwent on two separate occasions a bronchial challenge test to cat allergen (cat BCT) preceded randomly by a pre-exposure to either saline or LPS (2 microg). Methacholine challenge test was performed 24 h before exposure to LPS or saline. The Borg scale for dyspnoea and lung function were recorded before and after exposure to LPS or saline, and before and after cat BCT. Induced sputum and blood samples were collected before and after cat BCT, and analysed for cell counts and eosinophil cationic protein (ECP) levels. RESULTS: Inhalation of 2 microg LPS did not induce any changes in forced expiratory volume in 1 s (FEV1), peak expiratory flow (PEF), FEF 25-75 and Borg scale of dyspnoea. It neither modified Fel d 1 PD20 (45.03 ng as compared with 87.03; P=0.42). As well, there was no significant difference in late-phase reaction. Pre-exposure to LPS did not influence eosinophil counts or ECP levels in blood and sputum. CONCLUSION: Our study demonstrated that pre-exposure to LPS at low levels, which may be encountered in domestic environment, had no significant effect on the immediate and late-phase bronchial response to cat allergen. It neither modified local and systemic eosinophilic inflammation.