Neuroimmunomodulation
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Neuroimmunomodulation · Jan 2005
Randomized Controlled TrialNuclear factor-kappaB- and glucocorticoid receptor alpha- mediated mechanisms in the regulation of systemic and pulmonary inflammation during sepsis and acute respiratory distress syndrome. Evidence for inflammation-induced target tissue resistance to glucocorticoids.
To test the hypothesis that the interaction between nuclear factor-kappaB (NF-kappaB) and glucocorticoid receptor alpha (GRalpha) is a key pathogenetic mechanism regulating the progression of systemic and pulmonary inflammation in sepsis and acute respiratory distress syndrome (ARDS), we used an ex vivo model of systemic inflammation. Naïve peripheral blood leukocytes (PBL) were exposed to longitudinal (days 1-10) plasma samples from ARDS patients divided into three groups based on physiological improvement and clinical outcome by days 7-10: improvers, nonimprovers-survivors, and nonimprovers-nonsurvivors. In a separate group of nonimprovers-survivors, we correlated the severity of lung histopathology with the intensity of NF-kappaB and GRalpha nuclear staining in immunohistochemistry analysis of lung tissue obtained by open lung biopsy. ⋯ In immunohistochemistry analyses, lung tissues of patients with severe versus mild ARDS had a higher intensity of NF-kappaB nuclear staining (13 +/- 1.3 vs. 7 +/- 2.9; p = 0.01) and a lower ratio of GRalpha:NF-kappaB in nuclear staining (0.5 +/- 0.2 vs. 1.5 +/- 0.2; p = 0.007). In conclusion, we demonstrated that the ability of GC-GRalpha to downregulate NF-kappaB activation is critical for the resolution of systemic and pulmonary inflammation in ARDS. The findings provide a rationale for the use of prolonged GC treatment in early ARDS.
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Cytokines mediate and control immune and inflammatory responses. Complex interactions exist between cytokines, inflammation and the adaptive responses in maintaining homeostasis, health, and well-being. Like the stress response, the inflammatory reaction is crucial for survival and is meant to be tailored to the stimulus and time. ⋯ Thus, a dysfunctional neuroendocrine-immune interface associated with abnormalities of the 'systemic anti-inflammatory feedback' and/or 'hyperactivity' of the local pro-inflammatory factors may play a role in the pathogenesis of atopic/allergic and autoimmune diseases, obesity, depression, and atherosclerosis. These abnormalities and the failure of the adaptive systems to resolve inflammation affect the well-being of the individual, including behavioral parameters, quality of life and sleep, as well as indices of metabolic and cardiovascular health. These hypotheses require further investigation, but the answers should provide critical insights into mechanisms underlying a variety of common human immune-related diseases.
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A placebo is a sham treatment, such as a pill, liquid, or injection without biological activity, used in pharmacology to control for the activity of a drug. However, in many cases this placebo induces biological or psychological effects in the human. Two theories have been proposed to explain the placebo effect: the conditioning theory, which states that the placebo effect is a conditioned response, and the mentalistic theory, which sees the patient's expectation as the primary cause of the placebo effect. ⋯ Brain imaging has demonstrated that placebos can mimic the effect of the active drugs and activate the same brain areas. This is the case for placebo-dopamine in Parkinson's disease, for placebo-analgesics or antidepressants, and for placebo-caffeine in the healthy subject. It remains to be understood how conditioning and expectation are able to activate memory loops in the brain that reproduce the expected biological responses.