Stress in autoimmune disease models.

The release of endogenous glucocorticoids is critical in regulating the severity of disease activity in patients with inflammatory conditions such as rheumatoid arthritis (RA). Blocking cortisol production results in a flare-up in disease activity in RA patients, and surgical removal of the adrenals in patients with Cushing's disease has been reported to exacerbate autoimmune disease. In adjuvant-induced arthritis (AA; a rat model of RA), there is an activation of the hypothalamo-pituitary-adrenal (HPA) axis associated with the development of inflammation. In addition, there are profound changes in peptides within the paraventricular nucleus, which are responsible for regulating the HPA axis. These changes have profound implications on the ability of AA rats to respond to acute stress. Understanding the regulation of the HPA axis in health and disease holds out the promise of targeted therapy to alleviate inflammatory conditions. This article will consider the impact of stress on an individual and his or her susceptibility to inflammation. We wish to question the idea that stress is "all bad." As we shall see, exposure to a single acute stressor can alter the phenotype of the rat to change it from being susceptible to resistant in autoimmune disease models. This alteration in susceptibility takes days to manifest itself, but can last for weeks, suggesting beneficial effects of exposure to an acute stressor.

[Analysis of gastric emptying dynamics in relationship to qualitative composition of intake. Comparison between normal-weight and obese subjects]. / Análisis de la dinámica de vaciamiento gástrico en relación con la composición cualitativa de la ingesta. Comparación entre sujetos con normopeso y obesos.

AIMS: To analyze whether the gastric emptying profile could define obesity and to study the impact of macronutrients diet composition on gastric emptying in obese and non obese people. MATERIAL AND METHODS: 47 subjects were selected (12 non obese and 35 obese). The study was organized in 4 visits. In each visit the subject was given isocaloric breakfast differing in macronutrient composition, (either equilibrated, or lipid, protein or carbohydrate rich) quantitative gastric emptying assay was done realized, every 15 minutes for two hours using a radionuclide technique. The week prior to the visit, the subject followed a standard 1,800 cal/day diet. RESULT: A significant interaction between time and diet composition is shown regardless of the group (obese or non-obese) the subject belongs to. The different macronutrient composition differentially affected gastric emptying only in the obese group. Post hoc analysis of the results showed significant differences after 45 min post breakfast between protein and carbohydrate rich breakfast. CONCLUSIONS: Gastric emptying in obese but not in non obese subjects, was significantly modified depending on the intake qualitative composition. These differences are clear when protein rich (significantly slower emptying) is compared versus hydrocarbon enriched diet (significantly faster emptying). A significant difference in gastric emptying between obese and non-obese subjects cannot be established.

Análisis de la dinámica de vaciamiento gástrico en relación con la composición cualitativa de la ingesta. Comparación entre sujetos con normopeso y obesos / Analysis of gastric emptying dynamics in relationship to qualitative composition of intake. Comparison between normal weight and obese subjects

Objetivos. Analizar si el perfil de vaciamiento gástrico podría ser característico en obesidad y estudiar el impacto que la relación de macronutrientes en la dieta tiene sobre el vaciamiento gástrico y las diferencias entre obesos y normopesos. Material y método. Se seleccionan 47 sujetos (12 normopeso y 35 obesos), que realizan 4 visitas durante el estudio. En cada una se administraba un desayuno isocalórico con distinta composición de macronutrientes (equilibrados, lipídico, proteico o hidrocarbonato). Se realizaron estudios cuantitativos de vaciamiento gástrico cada 15 minutos durante dos horas usando la técnica de gammagrafía. La semana previa a cada visita todos los sujetos realizaron una dieta estándar de 1.800 cal/día. Resultados. Se observa una interacción significativa entre los factores tiempo y dieta. Sin embargo, el mismo análisis no demostró esta tendencia al estudiar la evolución del vaciamiento en relación con el grupo al que pertenecía el sujeto (normopeso u obeso). La composición cualitativa de la dieta sólo influyó sobre el vaciamiento gástrico en obesos. El estudio post hoc demostró diferencias significativas fundamentalmente a partir de los 45 minutos postingesta, y entre ingestas ricas en hidratos de carbono y proteínas. Conclusiones. La composición cualitativa de la ingesta ha influido de forma significativa sobre la velocidad de vaciamiento gástrico en sujetos obesos, pero no en normopesos. Esta influencia se hace más evidente en la dieta hidrocarbonada (vaciamiento significativamente más rápido) y proteica (vaciamiento significativamente más lento). No puede establecerse una diferencia significativa de la velocidad de vaciamiento gástrico entre sujetos obesos o normopeso

Aims. To analyze whether the gastric emptying profile could define obesity and to study the impact of macronutrients diet composition on gastric emptying in obese and non obese people. Material and methods. 47 subjects were selected (12 non obese and 35 obese). The study was organized in 4 visits. In each visit the subject was given isocaloric breakfast differing in macronutrient composition, (either equilibrated, or lipid, protein or carbohydrate rich) quantitative gastric emptying assay was done realized, every 15 minutes for two hours using a radionuclide technique. The week prior to the visit, the subject followed a standard 1,800 cal/day diet. Result. A significant interaction between time and diet composition is shown regardless of the group (obese or non obese) the subject belongs to. The different macronutrient composition differentialy affected gastric emptying only in the obese group. Post hoc analysis of the results showed significant differences after 45 min post breakfast between protein and carbohydrate rich breakfast. Conclusions. Gastric emptying in obese but not in non obese subjects, was significantly modified depending on the intake qualitative composition. These differences are clear when protein rich (significantly slower emtying) is compared versus hydrocarbon enriched diet (significantly faster emptying). A significant difference in gastric emptying between obese and non obese subjects cannot be stablished

The effect of stress on inflammation.

Stress can either enhance or suppress aspects of the immune response, depending on the nature, duration, timing and intensity of the stressor. This paper focuses on the effects on inflammation of two behavioural stress paradigms: learned helplessness (La) and the open-field test (OF), and of the immunological stressor lipopolysaccharide (LPS). We have observed that the onset and severity of inflammation in adjuvant-induced arthritis (AA) in the rat can be altered by experience of the LH paradigm, or by priming with LPS, but not by OF.In the LH test, some rats escape (LH(-)) and others do not (LH(+)). Despite the LH(-) group demonstrating a greater corticosterone response to the LH stressor compared to the LH(+)rats, they exhibited earlier onset and greater seventy of AA. In contrast, intraperitoneal injection of LPS several weeks prior to induction of AA protected against inflammation. These results provide further evidence that environmental factors influence the etiology of at least one type of inflammation. The modulation of inflammation by a defined stressor suggests that understanding of the underlying mechanisms may provide a potential for novel therapies.

Onset and severity of inflammation in rats exposed to the learned helplessness paradigm.

OBJECTIVE: To test the hypothesis that there is an association between susceptibility to inflammation and a hyporesponsive hypothalamo-pituitary-adrenal (HPA) axis. METHODS: Animals were separated on the basis of behaviour in the learned helplessness (LH) paradigm into groups of LH(+) (i.e. animals which did not escape footshock) and LH(-) animals. Adjuvant-induced arthritis (AA) was subsequently induced in the LH(+) and LH(-) animals. RESULTS: Plasma corticosterone was significantly increased in response to the LH test in the LH(-) compared with the LH(+) rats. We observed an earlier onset and increased inflammation in the LH(-) rats in spite of the greater corticosterone response to the acute stress. We noted lower levels of plasma testosterone in the LH(-) animals suggesting a possible influence for this protective factor in AA. CONCLUSION: These data suggest that increased onset and severity of inflammation in AA is not a simple consequence of an attenuated HPA axis response to stress as proposed in the Lewis rat. Indeed we have observed the converse. Together these data suggest that the balance of pro- and anti-inflammatory factors released in response to stress may influence the progress of AA.

Effects of stress on susceptibility and severity of inflammation in adjuvant-induced arthritis.

We have utilized the open field and learned helplessness (LH) models of psychological stress to determine whether a differential response to stress can affect the severity of adjuvant-induced arthritis (AA) within a single rat strain. In response to open field stress, the corticosterone response of the low emotivity rats was significantly lower than that of the high emotivity rats. In spite of the differential corticosterone response to stress, no significant difference was found in paw volumes between the AA high and low emotivity groups. In another study, rats were subjected to a learned LH paradigm and separated into two groups based on failed (LH+) or successful (LH-) avoidance. Plasma corticosterone levels in response to avoidable foot shock in the LH- rats were significantly greater than in the LH+ group. Following injection with adjuvant, paw inflammation occurred earlier and was more severe in the LH- rats compared to the LH+ group. These data show that rats with a greater tendency to avoid foot shock have more severe inflammation, despite having a greater corticosterone response to stress. We conclude that an increased corticosterone response to stress does not affect susceptibility to or severity of inflammation in AA. Indeed, in the LH model a more robust response to stress is associated with increased inflammation and earlier onset of the disease.

A differential response to stress is not a prediction of susceptibility or severity in adjuvant-induced arthritis.

It has been suggested that glucocorticoid insufficiency consequent to a blunted hypothalamo-pituitary-adrenal (HPA) axis response to stress may be associated with increased susceptibility to certain experimentally induced autoimmune diseases. We have developed a model which allows this hypothesis to be tested within a single population of rats, using the open field stress. Following the open field stress, rats were divided into groups of high or low emotivity on the basis of faecal pellet count. High and low emotivity groups exhibited significantly elevated plasma corticosterone following the open field stress compared to pre-stress levels, but the corticosterone response of the low emotivity rats was significantly lower than that of the high emotivity rats (p < 0.01). Four hours following termination of the stress, groups of high or low emotivity rats were further divided into two groups and given either an intradermal injection of Mycobacterium butyricum or vehicle for the induction of arthritis. Fourteen days after injection of adjuvant, paw volumes in the arthritic high and low emotivity groups were significantly greater than their respective vehicle-injected non-arthritic controls. However, in spite of the differential corticosterone response to stress, there was no significant difference in paw volumes between the arthritic high and low emotivity groups. These data show that an attenuated response to stress is not associated with enhanced susceptibility to the inflammatory disease of adjuvant-induced arthritis, or with increased severity of inflammation as measured by paw volume on day 14. This experimental paradigm can be more widely applied to extend our observations on the relationship between the HPA axis response to stress and susceptibility to inflammation in other models of experimentally induced autoimmune disease.

Antinociception produced by the peptidase inhibitor, RB 101, in rats with adrenal medullary transplant into the spinal cord.

This study was undertaken to investigate the effects induced by the systemic administration of RB 101 [N-[(R,S)-2-benzyl-3[(S)(2-amino-4-methylthio)butyl dithio]-1-oxoprpyl]-L-phenylalanine benzyl ester], a mixed inhibitor of the enkephalin catabolism able to cross the blood-brain barrier, in antinociception produced by adrenal medullary tissue transplanted in the rat spinal subarachnoid space. For this purpose, the antinociceptive responses induced by intravenous (i.v.) administration of RB 101 were evaluated in the tail-flick in rats transplanted 28 and 56 days before the test. Systemic administration of RB 101 induced antinociceptive effects in sham-operated rats, as previously reported. RB 101 also enhanced significantly the antinociception produced by the autotransplant 28 and 56 days after surgery. The antinociceptive responses of RB 101 in both sham-operated and autotransplanted rats were blocked by naloxone, but were not modified by the noradrenergic antagonist, phentolamine, suggesting a selective involvement of opioid mechanisms. The present results indicate that the inhibitors of enkephalin catabolism enhance the antinociception induced by adrenal medullary transplants.

Interleukin-1 beta-induced effects on plasma oxytocin and arginine vasopressin: role of adrenal steroids and route of administration.

The effects of cytokines in stimulating neurohypophysial hormone release have not been well characterized. In the present study, we have investigated the effect of intraperitoneal injection of recombinant human interleukin (IL)-1 beta on oxytocin release in sham-operated controls, adrenalectomized (ADX) rats and ADX rats given either low or high doses of the synthesis glucocorticoid dexamethasone. In a second study, we determined the effect of central injection of IL-1 beta on both oxytocin and arginine vasopressin (AVP) release in sham-operated and ADX rats. We were unable to demonstrate an increase in plasma oxytocin in intact rats in response to intraperitoneal injection of IL-1 beta. In contrast, we found a substantial and sustained increase in plasma oxytocin concentrations in ADX rats. This stimulation was abolished by treatment with dexamethasone at both the low and high doses. Following central injection of IL-1 beta, we were unable to demonstrate any increase in either oxytocin or AVP, despite the ability of this dose of cytokine to stimulate the hypothalamo-pituitary-adrenal axis, as evidenced by increased circulating corticosterone. It appears that circulating glucocorticoids may exert a tonic inhibitory effect on the release of oxytocin in response to peripheral stimulation by IL-1 beta.

An investigation of the effects of interleukin-1 beta on plasma arginine vasopressin in the rat: role of adrenal steroids.

While the effects of cytokines on the hypothalamo-pituitary-adrenal axis have received a great deal of attention in recent years the effects of cytokines on posterior pituitary hormone release has been less well characterized. In the present study we have investigated the effects of a single i.p. injection of interleukin (IL)-1 beta on circulating levels of vasopressin (AVP) in the rat. We have found that the ability of IL-1 beta to increase plasma AVP is strongly influenced by circulating levels of glucocorticoid steroids. IL-1 beta did not affect plasma AVP in sham-operated control animals over the 4 h period of study. In contrast, following adrenalectomy we were able to stimulate AVP substantially with increases over the 4 h period. This effect was reduced by treatment of adrenalectomized rats with a low dose of dexamethasone and abolished with a high dose. These data suggest an inverse relationship between circulating levels of glucocorticoids and the ability of IL-1 beta to stimulate plasma AVP.

Role of central catecholamines in the modulation of corticotrophin-releasing factor mRNA during adjuvant-induced arthritis in the rat.

The development of adjuvant-induced arthritis in the rat is associated with an activation of the hypothalamo-pituitary-adrenal axis. In the Piebald-Viral-Glaxo strain of rat there is however a paradoxical decrease in corticotrophin-releasing factor (CRF) mRNA in the hypothalamic paraventricular nucleus (PVN) and a decrease in CRF-41 peptide release into the hypophysial portal blood with increasing severity of disease. In the present study we have investigated the role of endogenous catecholamines within the PVN as possible inhibitory factors acting on CRF neurons during adjuvant-induced arthritis. Noradrenaline (NA) concentrations were approximately doubled in the PVN of arthritic animals. Depletion of endogenous catecholamines following direct 6-OHDA lesions of the PVN resulted in a significant depletion in PVN NA. The increase in NA observed in arthritic animals appears to have a protective role since depletion of NA increased the severity of the disease. Neither the increase in circulating levels of corticosterone nor the decrease in CRF mRNA in the PVN were prevented following NA depletion. Our results suggest that modification of central neurotransmitter systems are able to influence the severity of adjuvant-induced arthritis.

Effect of adrenalectomy and stress on interleukin-1 beta-mediated activation of hypothalamic corticotropin-releasing factor mRNA.

We have investigated the effect of (a) stress and (b) steroid feed-back on the interleukin-1 beta (IL-1 beta)-mediated increase of corticotropin-releasing factor (CRF) mRNA in the hypothalamic paraventricular nucleus. Both IL-1 beta and stress resulted in increased levels of CRF mRNA and when both were given together, the combination resulted in an additive effect on the increase in CRF transcripts. The effect of IL-1 beta was blunted by adrenalectomy, but returned when a replacement dose of dexamethasone was administered. The IL-1 beta-induced increase in CRF mRNA is dependent on the presence of circulating glucocorticoids, and its mechanism of action on CRF mRNA appears to be distinct from that activated in response to stress.

Action of interleukin-2 and interleukin-4 on CRF mRNA in the hypothalamus and POMC mRNA in the anterior pituitary.

We have used the technique of in situ hybridization histochemistry to determine corticotropin-releasing factor (CRF) mRNA in the hypothalamic paraventricular nucleus (PVN) and proopiomelanocortin (POMC) mRNA in the anterior pituitary of rats given a single ip injection of either interleukin (IL)-2 or IL-4. IL-2 increased POMC mRNA in the anterior pituitary in a dose-dependent manner. The effect was apparent both at 4 and 24 h after injection. No effect of IL-2 on CRF mRNA in the PVN was detected in these animals, suggesting that the increase in POMC mRNA was not driven by an increase in CRF. IL-4 was without effect at the hypothalamic level although this cytokine did result in a decrease in POMC mRNA in the anterior pituitary.