Annals of the New York Academy of Sciences
-
Ann. N. Y. Acad. Sci. · May 1998
ReviewNeuroimmunomodulation in inflammatory bowel disease. How far from "bench" to "bedside"?
The chronic inflammatory bowel diseases (BID), Crohn's disease and ulcerative colitis, are characterized by recurrent periods of inflammation and tissue destruction. The clinical course is influenced by genetics, environmental factors, and the immune system. Recent insights (bench trials) benefiting from advances in genetic engineering and molecular biology have contributed to clinical care (bedside) in terms of actual or potential therapies. ⋯ Compelling anecdotal reports exist that "stress" affects disease activity in terms of the frequency and severity of IBD flares (bedside), but the mechanisms underlying these observations are unknown. Evidence that neuroendocrine factors play a significant role in immunomodulation is progressing (bench). (i) Trinitrobenzene sulfonic acid (TNB)-induced colitis, although similar in unstressed Fisher and Lewis rats, shows marked worsening in stressed Lewis rats. (ii) Early studies of rectal pain perception suggest there are specific differences in neuroimaging studies (PET scans) in IBD patients compared to controls. (iii) Levels of substance P (SP) and its receptor are altered. (iv) Preliminary clinical studies with SP receptor antagonists show a trend toward improvement. (v) Importantly, the placebo response in clinical trials is as high as 45%. Evidence that neuroendocrine systems significantly modulate local inflammation is rapidly accumulating (bench), which will facilitate enhanced coordination of clinically relevant therapies (bedside).
-
Ann. N. Y. Acad. Sci. · May 1998
ReviewEvidence for and pathophysiologic implications of hypothalamic-pituitary-adrenal axis dysregulation in fibromyalgia and chronic fatigue syndrome.
Chronic fatigue syndrome (CFS) is characterized by profound fatigue and an array of diffuse somatic symptoms. Our group has established that impaired activation of the hypothalamic-pituitary-adrenal (HPA) axis is an essential neuroendocrine feature of this condition. The relevance of this finding to the pathophysiology of CFS is supported by the observation that the onset and course of this illness is excerbated by physical and emotional stressors. ⋯ In order to provide a more refined view of the nature of the HPA dusturbance in patients with CFS, we have studied the detailed, pulsatile characteristics of the HPA axis in a group of patients meeting the 1994 CDC case criteria for CFS. Results of that work are consistent with the view that patients with CFS have a reduction of HPA axis activity due, in part, to impaired central nervous system drive. These observations provide an important clue to the development of more effective treatment to this disabling condition.
-
Fever is induced in response to the entrance of pathogenic microorganisms into the body and is thought to be mediated by cytokines. Because these pathogens most commonly invade the body through its natural barriers and because body temperature is regulated centrally, these mediators are presumed to be produced peripherally and transported by the bloodstream to the brain, to act. It is generally considered that their febrigenic messages are further modulated there by prostaglandin E2 (PGE2). ⋯ LPS, and that i.v. LPS rapidly stimulates the release of norepinephrine (NE) and, hence, of PGE2 in their preoptic-anterior hypothalamus (POA, the brain region containing the thermoregulatory controller). Based on these and other data in the literature, we hypothesize that LPS fever may be initiated as follows: i.v., LPS-->complement-->Kupffer cells-->cytokines?-->vagal afferents -->n. tractus solitarius?-->A1/A2 cell groups?-->ventral noradrenergic bundle? -->POA-->NE-->PGE2-->fever.