A New Role for Glucocorticoids in Septic ShockBalancing the Immune Response
a Department of Endocrinology University of Düsseldorf Düsseldorf, Germanyx{)z\2, 百拇医药
b Department of Anesthesiology University of Munich Munich, Germanyx{)z\2, 百拇医药
Glucocorticoids are the most important immunosuppressive agents in medicine; they are an established therapy for a great variety of chronic inflammatory diseases as well as in transplantation medicine. In acute inflammation, particularly sepsis and/or septic shock, the use of high-dose corticosteroids has not improved overall survival and has even increased the risk of secondary infections (1). Therefore, this adjunctive treatment of sepsis and septic shock has been abandoned after a series of negative clinical trials. There now seems to be a new rationale for glucocorticoid treatment: recent evidence indicates that adrenocortical insufficiency may be more common in septic shock, and low-dose hydrocortisone regimens have shown promising results in patients with sepsis (2–4). Despite these promising data on clinical outcome, little is known about effects of this intervention on immunity.
In this issue of AJRCCM (pp. 512–520), Keh and coworkers (5) present the results of a comprehensive, double-blind, randomized, placebo-controlled crossover study on this topic in which they demonstrate that low-dose hydrocortisone (240–300 mg/day) can restore hemodynamic stability in patients suffering from septic shock. Hydrocortisone infusion increased blood pressure and systemic vascular resistance and decreased heart rate, cardiac index, and catecholamine requirement (5). This study also provides important insights into the immunologic mechanisms underlying the beneficial effects of low-dose hydrocortisone therapy in septic shock (5). This communication clarifies the primarily antiinflammatory and immune-balancing, rather than immunosuppressive, role that low-dose hydrocortisone plays in acute sepsis. In agreement with previous studies on hydrocortisone in patients suffering from septic shock (6) and methylprednisolone treatment in patients with acute respiratory distress syndrome, there was a significant decrease in the level of proinflammatory cytokines, such as interleukin-6 and -8 (7). Antiinflammatory mediators such as interleukin-10 and soluble tumor necrosis factor receptors were attenuated, whereas interleukin-4 levels did not change (5). The results demonstrated an increase in in vitro phagocytosis and the monocyte-activating cytokine, interleukin-12, thus even suggesting an immunoenhancing role for hydrocortisone in the organisms' first line of defense in sepsis. With respect to effector cell function, stress hormones have been shown to enhance macrophage production of acute-phase proteins, complement factors, macrophage migration inhibitory factor, and sialoadhesin. Moreover, glucocorticoid hormones have been shown to act synergistically with interferons to induce Fc receptors on human monocytic cell lines and peritoneal macrophages; glucocorticoid induction of high-affinity Fc receptor expression on human monocytes and mouse macrophages is correlated with increased phagocytosis (8). Therefore, the data in this paper agree with previous studies in suggesting a positive acute effect of glucocorticoids on the immune system (9, 10). In further support of this concept, we recently demonstrated a broad immunoenhancing effect of glucocorticoids on human genes of the innate immune system by genomic profiling using microarray technology (11). In cells activated by T cell receptor cross-linking, glucocorticoids downregulated the expression of specific genes that were previously upregulated in resting cells, suggesting possible new mechanisms by which they could exert both positive and negative effects (11). In this context, it is of particular interest that interleukin-12 increased during hydrocortisone treatment in the present study in patients with sepsis, whereas inhibition of interleukin-12 synthesis has been demonstrated under nonseptic conditions (5).
It has always been paradoxical and simplistic to assume that organisms would have evolved to suppress immune function at a time when an active immune response may be critical for survival—such as during acute sepsis. We therefore need to reconsider the dogmatic view that corticosteroids are pure immunosuppressive agents and acknowledge the active role played by these compounds in the acute immune defense system. This can be accomplished by permissive and suppressive effects of glucocorticoids on immunity (9). On the basis of these findings, it is not surprising that glucocorticoid withdrawal will have a strong rebound effect in patients with sepsis, as has been described earlier and has been confirmed in the studies of Keh and coworkers and Briegel and coworkers (5, 12). High-dose and time-limited use of glucocorticoids can be disastrous if proinflammatory cytokines rise after glucocorticoid withdrawal in the presence of receptors that are still upregulated (10, 11).nr}*%, 百拇医药
Finally, the study of Keh and coworkers (5) provides further insight into the critical role of the endocrine stress system in sepsis (7, 13). Although adrenocortical function testing was not performed, hydrocortisone treatment allowed a decline in catecholamine requirement. There is a close functional interdependence between the glucocorticoid and catecholamine systems (14). A defect in adrenocortical cortisol production is always associated with impaired adrenal catecholamine release. On the other hand, the autonomic nervous system regulates adrenocortical function, and catecholamines facilitate the action of glucocorticoids on target cells (14, 15). Inflammatory cytokines, such as interleukin-1 and -6, stimulate directly the release of corticosteroids from the adrenal gland, whereas other cytokines such as tumor necrosis factor inhibit steroidogenesis (14). Therefore, in addition to pituitary adrenocorticotropin, there are other extrapituitary factors regulating adrenal steroidogenesis in septic shock. These interactions need to be considered when new immune therapies are used in patients with sepsis, and hydrocortisone therapy may become an even more logical component in the treatment strategy.
In conclusion, the study of Keh and coworkers (5) adds further evidence to support low-dose glucocorticoid therapy during sepsis. It also provides new insights into the immunologic mechanisms underlying such a positive effect. During sepsis, we are learning that immune-endocrine crosstalk is not an epiphenomenon but is critical to the organism's capacity to cope with severe stress. Further study is needed to identify the correct individual dosages, timing, mode of administration (boluses or continuous infusion), duration of treatment, assessment of the necessity (and appropriate time points) for adrenocortical function testing, the concomitant use of mineralocorticoids, and the emerging role of adrenal androgens (16). It is the art of medicine that trains us in constant reinvention, adaptation, and modification of our own concepts.i&aier, 百拇医药
REFERENCESi&aier, 百拇医药
Sprung CL, Caralis PV, Marcial EH, Pierce M, Gelbard MA, Long WM, Duncan RC, Tendler MD, Karpf M. The effects of high-dose corticosteroids in patients with septic shock: a prospective, controlled study. N Engl J Med 1984;311:1137–1143.
Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, Capellier G, Cohen Y, Azoulay E, Troche G, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288:862–871.ep, 百拇医药
Briegel J, Forst H, Haller M, Schelling G, Kilger E, Kuprat G, Hemmer B, Hummel T, Lenhart A, Heyduck M, et al. Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single-center study. Crit Care Med 1999;27:723–732.ep, 百拇医药
Bollaert PE, Charpentier C, Levy B, Debouverie M, Audibert G, Larcan A. Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Crit Care Med 1998;26:645–650.ep, 百拇医药
Keh D, Boehnke T, Weber-Cartens S, Schulz C, Ahlers O, Bercker S, Volk H-D, Doecke W-D, Falke KJ, Gerlach H. Immunologic and hemodynamic effects of "low-dose" hydrocortisone in septic shock: a double-blind, randomized, placebo-controlled, crossover study. Am J Respir Crit Care Med 2003;167:512–520.ep, 百拇医药
Briegel J, Jochum M, Gippner-Steppert C, Thiel M. Immunomodulation in septic shock: hydrocortisone differentially regulates cytokine responses. J Am Soc Nephrol 2001;12:S70–S74.
Meduri GU, Tolley EA, Chrousos GP, Stentz F. Prolonged methylprednisolone treatment suppresses systemic inflammation in patients with unresolving acute respiratory distress syndrome: evidence for inadequate endogenous glucocorticoid secretion and inflammation-induced immune cell resistance to glucocorticoids. Am J Respir Crit Care Med 2002;165:983–991.m, 百拇医药
Warren MK, Vogel SN. Opposing effects of glucocorticoids on interferon-gamma-induced murine macrophage Fc receptor and Ia antigen expression. J Immunol 1985;134:2462–2469.m, 百拇医药
Dhabhar FS, Satoskar AR, Bluethmann H, David JR, McEwen BS. Stress-induced enhancement of skin immune function: a role for gamma interferon. Proc Natl Acad Sci USA 2000;97:2846–2851.m, 百拇医药
Munck A, Guyre PM, Holbrook NJ. Physiological functions of glucocorticoids in stress and their relation to pharmacological actions. Endocr Rev 1984;5:25–44.m, 百拇医药
Galon J, Franchimont D, Hiroi N, Frey G, Boettner A, Ehrhart-Bornstein M, O'Shea JJ, Chrousos GP, Bornstein SR. Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells. FASEB J 2002;16:61–71.
Briegel J, Kellermann W, Forst H, Haller M, Bittl M, Hoffmann GE, Buchler M, Uhl W, Peter K. Low-dose hydrocortisone infusion attenuates the systemic inflammatory response syndrome: the Phospholipase A2 Study Group. Clin Investig 1994;72:782–787.na+}, 百拇医药
Schroeder S, Wichers M, Klingmuller D, Hofer M, Lehmann LE, von Spiegel T, Hering R, Putensen C, Hoeft A, Stuber F. The hypothalamic-pituitary-adrenal axis of patients with severe sepsis: altered response to corticotropin-releasing hormone. Crit Care Med 2001;29:310–316.na+}, 百拇医药
Bornstein SR, Chrousos GP. Clinical review 104: adrenocorticotropin (ACTH)- and non-ACTH-mediated regulation of the adrenal cortex: neural and immune inputs. J Clin Endocrinol Metab 1999;84:1729–1736.na+}, 百拇医药
Roth M, Johnson PR, Rudiger JJ, King GG, Ge Q, Burgess JK, Anderson G, Tamm M, Black JL. Interaction between glucocorticoids and beta(2) agonists on bronchial airway smooth muscle cells through synchronised cellular signalling. Lancet 2002;360:1293–1299.na+}, 百拇医药
Marx C, Petros S, Wendt M, Weise M, Menschikowsky M, Bornstein SR, Engelmann L, Höffken G. Adrenocortical hormones in survivors and non-survivors of servere sepsis: time-dependent diversity of dehydroepiandrosterone, dehydroepi-androsterone-sulfate, acortisol, and adrenocorticotropin. Crit Care Med (In press).(Stefan R. Bornstein, M.D. and Josef Briegel, M.D.)
b Department of Anesthesiology University of Munich Munich, Germanyx{)z\2, 百拇医药
Glucocorticoids are the most important immunosuppressive agents in medicine; they are an established therapy for a great variety of chronic inflammatory diseases as well as in transplantation medicine. In acute inflammation, particularly sepsis and/or septic shock, the use of high-dose corticosteroids has not improved overall survival and has even increased the risk of secondary infections (1). Therefore, this adjunctive treatment of sepsis and septic shock has been abandoned after a series of negative clinical trials. There now seems to be a new rationale for glucocorticoid treatment: recent evidence indicates that adrenocortical insufficiency may be more common in septic shock, and low-dose hydrocortisone regimens have shown promising results in patients with sepsis (2–4). Despite these promising data on clinical outcome, little is known about effects of this intervention on immunity.
In this issue of AJRCCM (pp. 512–520), Keh and coworkers (5) present the results of a comprehensive, double-blind, randomized, placebo-controlled crossover study on this topic in which they demonstrate that low-dose hydrocortisone (240–300 mg/day) can restore hemodynamic stability in patients suffering from septic shock. Hydrocortisone infusion increased blood pressure and systemic vascular resistance and decreased heart rate, cardiac index, and catecholamine requirement (5). This study also provides important insights into the immunologic mechanisms underlying the beneficial effects of low-dose hydrocortisone therapy in septic shock (5). This communication clarifies the primarily antiinflammatory and immune-balancing, rather than immunosuppressive, role that low-dose hydrocortisone plays in acute sepsis. In agreement with previous studies on hydrocortisone in patients suffering from septic shock (6) and methylprednisolone treatment in patients with acute respiratory distress syndrome, there was a significant decrease in the level of proinflammatory cytokines, such as interleukin-6 and -8 (7). Antiinflammatory mediators such as interleukin-10 and soluble tumor necrosis factor receptors were attenuated, whereas interleukin-4 levels did not change (5). The results demonstrated an increase in in vitro phagocytosis and the monocyte-activating cytokine, interleukin-12, thus even suggesting an immunoenhancing role for hydrocortisone in the organisms' first line of defense in sepsis. With respect to effector cell function, stress hormones have been shown to enhance macrophage production of acute-phase proteins, complement factors, macrophage migration inhibitory factor, and sialoadhesin. Moreover, glucocorticoid hormones have been shown to act synergistically with interferons to induce Fc receptors on human monocytic cell lines and peritoneal macrophages; glucocorticoid induction of high-affinity Fc receptor expression on human monocytes and mouse macrophages is correlated with increased phagocytosis (8). Therefore, the data in this paper agree with previous studies in suggesting a positive acute effect of glucocorticoids on the immune system (9, 10). In further support of this concept, we recently demonstrated a broad immunoenhancing effect of glucocorticoids on human genes of the innate immune system by genomic profiling using microarray technology (11). In cells activated by T cell receptor cross-linking, glucocorticoids downregulated the expression of specific genes that were previously upregulated in resting cells, suggesting possible new mechanisms by which they could exert both positive and negative effects (11). In this context, it is of particular interest that interleukin-12 increased during hydrocortisone treatment in the present study in patients with sepsis, whereas inhibition of interleukin-12 synthesis has been demonstrated under nonseptic conditions (5).
It has always been paradoxical and simplistic to assume that organisms would have evolved to suppress immune function at a time when an active immune response may be critical for survival—such as during acute sepsis. We therefore need to reconsider the dogmatic view that corticosteroids are pure immunosuppressive agents and acknowledge the active role played by these compounds in the acute immune defense system. This can be accomplished by permissive and suppressive effects of glucocorticoids on immunity (9). On the basis of these findings, it is not surprising that glucocorticoid withdrawal will have a strong rebound effect in patients with sepsis, as has been described earlier and has been confirmed in the studies of Keh and coworkers and Briegel and coworkers (5, 12). High-dose and time-limited use of glucocorticoids can be disastrous if proinflammatory cytokines rise after glucocorticoid withdrawal in the presence of receptors that are still upregulated (10, 11).nr}*%, 百拇医药
Finally, the study of Keh and coworkers (5) provides further insight into the critical role of the endocrine stress system in sepsis (7, 13). Although adrenocortical function testing was not performed, hydrocortisone treatment allowed a decline in catecholamine requirement. There is a close functional interdependence between the glucocorticoid and catecholamine systems (14). A defect in adrenocortical cortisol production is always associated with impaired adrenal catecholamine release. On the other hand, the autonomic nervous system regulates adrenocortical function, and catecholamines facilitate the action of glucocorticoids on target cells (14, 15). Inflammatory cytokines, such as interleukin-1 and -6, stimulate directly the release of corticosteroids from the adrenal gland, whereas other cytokines such as tumor necrosis factor inhibit steroidogenesis (14). Therefore, in addition to pituitary adrenocorticotropin, there are other extrapituitary factors regulating adrenal steroidogenesis in septic shock. These interactions need to be considered when new immune therapies are used in patients with sepsis, and hydrocortisone therapy may become an even more logical component in the treatment strategy.
In conclusion, the study of Keh and coworkers (5) adds further evidence to support low-dose glucocorticoid therapy during sepsis. It also provides new insights into the immunologic mechanisms underlying such a positive effect. During sepsis, we are learning that immune-endocrine crosstalk is not an epiphenomenon but is critical to the organism's capacity to cope with severe stress. Further study is needed to identify the correct individual dosages, timing, mode of administration (boluses or continuous infusion), duration of treatment, assessment of the necessity (and appropriate time points) for adrenocortical function testing, the concomitant use of mineralocorticoids, and the emerging role of adrenal androgens (16). It is the art of medicine that trains us in constant reinvention, adaptation, and modification of our own concepts.i&aier, 百拇医药
REFERENCESi&aier, 百拇医药
Sprung CL, Caralis PV, Marcial EH, Pierce M, Gelbard MA, Long WM, Duncan RC, Tendler MD, Karpf M. The effects of high-dose corticosteroids in patients with septic shock: a prospective, controlled study. N Engl J Med 1984;311:1137–1143.
Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, Capellier G, Cohen Y, Azoulay E, Troche G, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288:862–871.ep, 百拇医药
Briegel J, Forst H, Haller M, Schelling G, Kilger E, Kuprat G, Hemmer B, Hummel T, Lenhart A, Heyduck M, et al. Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single-center study. Crit Care Med 1999;27:723–732.ep, 百拇医药
Bollaert PE, Charpentier C, Levy B, Debouverie M, Audibert G, Larcan A. Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Crit Care Med 1998;26:645–650.ep, 百拇医药
Keh D, Boehnke T, Weber-Cartens S, Schulz C, Ahlers O, Bercker S, Volk H-D, Doecke W-D, Falke KJ, Gerlach H. Immunologic and hemodynamic effects of "low-dose" hydrocortisone in septic shock: a double-blind, randomized, placebo-controlled, crossover study. Am J Respir Crit Care Med 2003;167:512–520.ep, 百拇医药
Briegel J, Jochum M, Gippner-Steppert C, Thiel M. Immunomodulation in septic shock: hydrocortisone differentially regulates cytokine responses. J Am Soc Nephrol 2001;12:S70–S74.
Meduri GU, Tolley EA, Chrousos GP, Stentz F. Prolonged methylprednisolone treatment suppresses systemic inflammation in patients with unresolving acute respiratory distress syndrome: evidence for inadequate endogenous glucocorticoid secretion and inflammation-induced immune cell resistance to glucocorticoids. Am J Respir Crit Care Med 2002;165:983–991.m, 百拇医药
Warren MK, Vogel SN. Opposing effects of glucocorticoids on interferon-gamma-induced murine macrophage Fc receptor and Ia antigen expression. J Immunol 1985;134:2462–2469.m, 百拇医药
Dhabhar FS, Satoskar AR, Bluethmann H, David JR, McEwen BS. Stress-induced enhancement of skin immune function: a role for gamma interferon. Proc Natl Acad Sci USA 2000;97:2846–2851.m, 百拇医药
Munck A, Guyre PM, Holbrook NJ. Physiological functions of glucocorticoids in stress and their relation to pharmacological actions. Endocr Rev 1984;5:25–44.m, 百拇医药
Galon J, Franchimont D, Hiroi N, Frey G, Boettner A, Ehrhart-Bornstein M, O'Shea JJ, Chrousos GP, Bornstein SR. Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells. FASEB J 2002;16:61–71.
Briegel J, Kellermann W, Forst H, Haller M, Bittl M, Hoffmann GE, Buchler M, Uhl W, Peter K. Low-dose hydrocortisone infusion attenuates the systemic inflammatory response syndrome: the Phospholipase A2 Study Group. Clin Investig 1994;72:782–787.na+}, 百拇医药
Schroeder S, Wichers M, Klingmuller D, Hofer M, Lehmann LE, von Spiegel T, Hering R, Putensen C, Hoeft A, Stuber F. The hypothalamic-pituitary-adrenal axis of patients with severe sepsis: altered response to corticotropin-releasing hormone. Crit Care Med 2001;29:310–316.na+}, 百拇医药
Bornstein SR, Chrousos GP. Clinical review 104: adrenocorticotropin (ACTH)- and non-ACTH-mediated regulation of the adrenal cortex: neural and immune inputs. J Clin Endocrinol Metab 1999;84:1729–1736.na+}, 百拇医药
Roth M, Johnson PR, Rudiger JJ, King GG, Ge Q, Burgess JK, Anderson G, Tamm M, Black JL. Interaction between glucocorticoids and beta(2) agonists on bronchial airway smooth muscle cells through synchronised cellular signalling. Lancet 2002;360:1293–1299.na+}, 百拇医药
Marx C, Petros S, Wendt M, Weise M, Menschikowsky M, Bornstein SR, Engelmann L, Höffken G. Adrenocortical hormones in survivors and non-survivors of servere sepsis: time-dependent diversity of dehydroepiandrosterone, dehydroepi-androsterone-sulfate, acortisol, and adrenocorticotropin. Crit Care Med (In press).(Stefan R. Bornstein, M.D. and Josef Briegel, M.D.)