Repeated, but not acute, stress suppresses inflammatory plasma extravasation

Abstract

Clinical findings suggest that inflammatory disease symptoms are aggravated by ongoing, repeated stress, but not by acute stress. We hypothesized that, compared with single acute stressors, chronic repeated stress may engage different physiological mechanisms that exert qualitatively different effects on the inflammatory response. Because inhibition of plasma extravasation, a critical component of the inflammatory response, has been associated with increased disease severity in experimental arthritis, we tested for a potential repeated stress-induced inhibition of plasma extravasation. Repeated, but not single, exposures to restraint stress produced a profound inhibition of bradykinin-induced synovial plasma extravasation in the rat. Experiments examining the mechanism of inhibition showed that the effect of repeated stress was blocked by adrenalectomy, but not by adrenal medullae denervation, suggesting that the adrenal cortex mediates this effect. Consistent with known effects of stress and with mediation by the adrenal cortex, restraint stress evoked repeated transient elevations of plasma corticosterone levels. This elevated corticosterone was necessary and sufficient to produce inhibition of plasma extravasation because the stress-induced inhibition was blocked by preventing corticosterone synthesis and, conversely, induction of repeated transient elevations in plasma corticosterone levels mimicked the effects of repeated stress. These data suggest that repetition of a mild stressor can induce changes in the physiological state of the animal that enable a previously innocuous stressor to inhibit the inflammatory response. These findings provide a potential explanation for the clinical association between repeated stress and aggravation of inflammatory disease symptoms and provide a model for study of the biological mechanisms underlying the stress-induced aggravation of chronic inflammatory diseases. There is considerable evidence that stress can exacerbate a number of chronic inflammatory diseases. For example, repeated mild daily stressors have been associated with exacerbation of rheumatoid arthritis (1, 2), ulcerative colitis (3), inflammatory bowel disease (4), and asthma (5). Patients with rheumatoid arthritis (6) cite stress as the most frequent antecedent of symptom flares, and stress management interventions can reduce symptoms (7). Similarly, studies in animal models of arthritis (8, 9) demonstrate that stress can exacerbate disease activity. Very little is known, however, about the biological mechanisms by which stress may exert these effects.Acute stress (10, 11), as well as acute activation of neuroendocrine circuits known to be activated by stressful stimuli (12, 13), transiently suppresses the inflammatory response. However, exacerbation of inflammatory diseases has been correlated with chronic repeated exposure to stressful stimuli rather than with exposure to a single acute stressor (2-4). We hypothesized that, compared with single acute stressors, chronic repeated stress may engage differe...

Role of hypothalamic inputs in maintaining pituitary-adrenal responsiveness in repeated restraint

“…Restraint and immobilization are similar stimuli, differing in stimulus strength and technical details. Previous reports on repeated restraint used different strain, conditions, and timing, which might explain the variable adaptations in ACTH and corticosterone previously reported (9,11,19,26,43). Similar to our observations, Popovic (38) and Pitman et al (37) reported no adaptation to restraint during 18-21 days.…”

β2‐Adrenergic receptor regulation of human neutrophil function is sexually dimorphic

“…Many inflammatory diseases, such as rheumatoid arthritis and systemic lupus erythematosus, have a much greater incidence in women (Green, 1992;Da Silva, 1995;Gaillard et al, 1998;Castagnetta et al, 2002), and there is a similar sexual dimorphism in animal models of inflammatory disease (Wilder et al, 1982;Allen et al, 1983;Griffiths et al, 1994). We have shown that sex differences in the inflammatory response in rats are adrenal medulla dependent (Green et al, 1999), and that activation of the sympathoadrenal system by stress or noxious stimulation inhibits the inflammatory response (Green et al, 1997;Strausbaugh et al, 1999). It is likely that adrenaline plays an important role, since it is a principal adrenal medulla mediator and the inflammatory response can be regulated through b 2 -adrenergic receptor activation (Coderre et al, 1990;Ottonello et al, 1996;Barnes, 1999;Mills et al, 2000).…”

Effects of restraint stress on NALT structure and nasal IgA levels

“…Our results suggest that restraint stress for 4 d inhibited the HPA axis, and that with restraint stress for 8 d this axis was again normally activated. Several studies have reported habituation and adaptation of the corticosterone response to the same (homotypic) stressor, resulting in a decrease in corticosterone levels in the short run followed by a recovery of the same in the long run [33][34][35][36][37][38][39][40]. Contrarily, other studies have reported the pattern of continuous suppression of the corticosterone response to repeated stress [41][42][43][44].…”