Antiinflammatory Action of Glucocorticoids — New Mechanisms for Old Drugs
20 Oct 2005-The New England Journal of Medicine (Massachusetts Medical Society)-Vol. 353, Iss: 16, pp 1711-1723
TL;DR: This review summarizes the understanding of how glucocorticoids inhibit inflammation and give rise to side effects.
Abstract: Glucocorticoids are among the most common therapeutic agents used in medical practice, yet their mechanisms of action are only partly understood. This review summarizes our understanding of how glu...
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TL;DR: Preliminary data from patients with inflammatory disorders, as well as medically healthy depressed patients, suggest that inhibiting proinflammatory cytokines or their signaling pathways may improve depressed mood and increase treatment response to conventional antidepressant medication.
3,084 citations
Cites background from "Antiinflammatory Action of Glucocor..."
...Regarding the HPA axis, cortisol is one of the most potent anti-inflammatory hormones in the body (58); yet, in the context of chronic stress or depression, as noted above, the immune system can become glucocorticoid resistant....
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...Given the potential effects of cytokines on GR signaling and the well-established inhibitory effect of glucocorticoids on inflammation (58), several studies have examined the relationship between inflammatory biomarkers and GR function in patients with major depression....
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TL;DR: Current understanding of the mechanisms by which the innate and adaptive immune systems interact with neurotransmitters and neurocircuits to influence the risk for depression are detailed.
Abstract: Crosstalk between inflammatory pathways and neurocircuits in the brain can lead to behavioural responses, such as avoidance and alarm, that are likely to have provided early humans with an evolutionary advantage in their interactions with pathogens and predators. However, in modern times, such interactions between inflammation and the brain appear to drive the development of depression and may contribute to non-responsiveness to current antidepressant therapies. Recent data have elucidated the mechanisms by which the innate and adaptive immune systems interact with neurotransmitters and neurocircuits to influence the risk for depression. Here, we detail our current understanding of these pathways and discuss the therapeutic potential of targeting the immune system to treat depression.
2,133 citations
TL;DR: This Review highlights recently gained mechanistic insights into the development and maintenance of the blood-brain barrier (BBB), and discusses how BBB disruption can cause or contribute to neurological disease.
Abstract: The interface between the blood circulation and the neural tissue features unique characteristics that are encompassed by the term 'blood-brain barrier' (BBB). The main functions of this barrier, namely maintenance of brain homeostasis, regulation of influx and efflux transport, and protection from harm, are determined by its specialized multicellular structure. Every constituent cell type makes an indispensable contribution to the BBB's integrity. But if one member of the BBB fails, and as a result the barrier breaks down, there can be dramatic consequences and neuroinflammation and neurodegeneration can occur. In this Review, we highlight recently gained mechanistic insights into the development and maintenance of the BBB. We then discuss how BBB disruption can cause or contribute to neurological disease. Finally, we examine how this knowledge can be used to explore new possibilities for BBB repair.
1,616 citations
TL;DR: A biologically plausible, multilevel theory is proposed that describes neural, physiologic, molecular, and genomic mechanisms that link experiences of social-environmental stress with internal biological processes that drive depression pathogenesis and may shed light on several important questions including how depression develops, why it frequently recurs, and why it is strongly predicted by early life stress.
Abstract: Major life stressors, especially those involving interpersonal stress and social rejection, are among the strongest proximal risk factors for depression. In this review, we propose a biologically plausible, multilevel theory that describes neural, physiologic, molecular, and genomic mechanisms that link experiences of social-environmental stress with internal biological processes that drive depression pathogenesis. Central to this social signal transduction theory of depression is the hypothesis that experiences of social threat and adversity up-regulate components of the immune system involved in inflammation. The key mediators of this response, called proinflammatory cytokines, can in turn elicit profound changes in behavior, which include the initiation of depressive symptoms such as sad mood, anhedonia, fatigue, psychomotor retardation, and social-behavioral withdrawal. This highly conserved biological response to adversity is critical for survival during times of actual physical threat or injury. However, this response can also be activated by modern-day social, symbolic, or imagined threats, leading to an increasingly proinflammatory phenotype that may be a key phenomenon driving depression pathogenesis and recurrence, as well as the overlap of depression with several somatic conditions including asthma, rheumatoid arthritis, chronic pain, metabolic syndrome, cardiovascular disease, obesity, and neurodegeneration. Insights from this theory may thus shed light on several important questions including how depression develops, why it frequently recurs, why it is strongly predicted by early life stress, and why it often co-occurs with symptoms of anxiety and with certain physical disease conditions. This work may also suggest new opportunities for preventing and treating depression by targeting inflammation.
1,361 citations
Cites background from "Antiinflammatory Action of Glucocor..."
...It is therefore a prototype for some of the most effective anti-inflammatory drugs (Pace, Hu, & Miller, 2007; Rhen & Cidlowski, 2005)....
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References
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TL;DR: Severe sepsis is a common, expensive, and frequently fatal condition, with as many deaths annually as those from acute myocardial infarction, and is especially common in the elderly and is likely to increase substantially as the U.S. population ages.
Abstract: ObjectiveTo determine the incidence, cost, and outcome of severe sepsis in the United States.DesignObservational cohort study.SettingAll nonfederal hospitals (n = 847) in seven U.S. states.PatientsAll patients (n = 192,980) meeting criteria for severe sepsis based on the International Classification
7,888 citations
TL;DR: The rate of sepsis due to fungal organisms increased by 207 percent, with gram-positive bacteria becoming the predominant pathogens after 1987, and the total in-hospital mortality rate fell, yet the total number of deaths continued to increase.
Abstract: Background Sepsis represents a substantial health care burden, and there is limited epidemiologic information about the demography of sepsis or about the temporal changes in its incidence and outcome. We investigated the epidemiology of sepsis in the United States, with specific examination of race and sex, causative organisms, the disposition of patients, and the incidence and outcome. Methods We analyzed the occurrence of sepsis from 1979 through 2000 using a nationally representative sample of all nonfederal acute care hospitals in the United States. Data on new cases were obtained from hospital discharge records coded according to the International Classification of Diseases, Ninth Revision, Clinical Modification. Results Review of discharge data on approximately 750 million hospitalizations in the United States over the 22-year period identified 10,319,418 cases of sepsis. Sepsis was more common among men than among women (mean annual relative risk, 1.28 [95 percent confidence interval, 1.24 to 1.32]...
5,704 citations
Book•
01 Jan 1988
TL;DR: This poster describes the cellular components of Inflammation, the mechanisms of response to inflammation, and the role of cytokines in the regulation of these components.
Abstract: I: Cellular Components of Inflammation II: Mediators of Inflammation III: Cellular Mechanisms IV: Responses to Inflammation V: Clinical Correlates VI: Therapeutic Modulation of Inflammation Inde
2,103 citations
TL;DR: This review summarizes the current knowledge of the most important GC-mediated side effects from a clinical to a molecular perspective and should be helpful in predicting the potential advantages of selective GR agonists in comparison to classical GCs.
1,624 citations