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Research Article

Repeated, but not acute, stress suppresses inflammatory plasma extravasation

Holly J. Strausbaugh, Mary F. Dallman, and Jon D. Levine
PNAS December 7, 1999 96 (25) 14629-14634; https://doi.org/10.1073/pnas.96.25.14629
Holly J. Strausbaugh
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Mary F. Dallman
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Jon D. Levine
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  1. Edited by James L. McGaugh, University of California, Irvine, CA, and approved October 14, 1999 (received for review September 1, 1999)

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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.

Footnotes

    • ↵§ To whom reprint requests should be addressed. E-mail: levine{at}itsa.ucsf.edu.

    • This paper was submitted directly (Track II) to the PNAS office.

  • Abbreviations

    BK,
    bradykinin;
    ACTH,
    corticotropin;
    NS,
    not significant;
    HPA,
    hypothalamic–pituitary–adrenal
    • Received September 1, 1999.
    • Copyright © 1999, The National Academy of Sciences
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    Repeated, but not acute, stress suppresses inflammatory plasma extravasation
    Holly J. Strausbaugh, Mary F. Dallman, Jon D. Levine
    Proceedings of the National Academy of Sciences Dec 1999, 96 (25) 14629-14634; DOI: 10.1073/pnas.96.25.14629

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    Repeated, but not acute, stress suppresses inflammatory plasma extravasation
    Holly J. Strausbaugh, Mary F. Dallman, Jon D. Levine
    Proceedings of the National Academy of Sciences Dec 1999, 96 (25) 14629-14634; DOI: 10.1073/pnas.96.25.14629
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    Proceedings of the National Academy of Sciences: 96 (25)
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