Combined administration of secretin and oxytocin inhibits chronic colitis and associated activation of forebrain neurons.

BACKGROUND: The pathogenesis of inflammatory bowel disease is unknown; however, the disorder is aggravated by psychological stress and is itself psychologically stressful. Chronic intestinal inflammation, moreover, has been reported to activate forebrain neurons. We tested the hypotheses that the chronically inflamed bowel signals to the brain through the vagi and that administration of a combination of secretin (S) and oxytocin (OT) inhibits this signaling. METHODS: Three daily enemas containing 2,4,6-trinitrobenzene sulfonic acid (TNBS), which were given to rats produced chronic colitis and ongoing activation of Fos in brain neurons. KEY RESULTS: Fos was induced in neurons in the paraventricular nucleus of the hypothalamus, basolateral amygdala, central amygdala, and piriform cortex. Subdiaphragmatic vagotomy failed to inhibit this activation of Fos, suggesting that colitis activates forebrain neurons independently of the vagi. When administered intravenously, but not when given intracerebroventricularly, in doses that were individually ineffective, combined S/OT prevented colitis-associated activation of central neurons. Strikingly, S/OT decreased inflammatory infiltrates into the colon and colonic expression of tumor necrosis factor-alpha and interferon-gamma. CONCLUSIONS & INFERENCES: These observations suggest that chronic colonic inflammation is ameliorated by the systemic administration of S/OT, which probably explains the parallel ability of systemic S/OT to inhibit the colitis-associated activation of forebrain neurons. It is possible that S and OT, which are endogenous to the colon, might normally combine to restrict the severity of colonic inflammatory responses and that advantage might be taken of this system to develop novel means of treating inflammation-associated intestinal disorders.

Substance P promotes expansion of human mesenteric preadipocytes through proliferative and antiapoptotic pathways.

White adipose tissue is intimately involved in the regulation of immunity and inflammation. We reported that human mesenteric preadipocytes express the substance P (SP)-mediated neurokinin-1 receptor (NK-1R), which signals proinflammatory responses. Here we tested the hypothesis that SP promotes proliferation and survival of human mesenteric preadipocytes and investigated responsible mechanism(s). Preadipocytes were isolated from mesenteric fat biopsies during gastric bypass surgery. Proliferative and antiapoptotic responses were delineated in 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS), bromodeoxyuridine (BrdU), caspase-3, and TUNEL assays, as well as Western immunoanalysis. SP (10(-7) M) increased MTS and proliferation (BrdU) and time dependently (15-30 min) induced Akt, EGF receptor, IGF receptor, integrin alphaVbeta3, phosphatidylinositol 3-kinase, and PKC-theta phosphorylation. Furthermore, pharmacological antagonism of Akt and PKC-theta activation significantly attenuated SP-induced preadipocyte proliferation. Exposure of preadipocytes to the proapoptotic Fas ligand (FasL, 100 microM) resulted in nuclear DNA fragmentation (TUNEL assay), as well as increased cleaved poly (ADP-ribose) polymerase, cleaved caspase-7, and caspase-3 expression. Cotreatment with SP almost completely abolished these responses in a NK-1R-dependent fashion. SP (10(-7) M) also time dependently stimulated expression 4E binding protein 1 and phosphorylation of p70 S6 kinase, which increased protein translation efficiency. SP increases preadipocyte viability, reduces apoptosis, and stimulates proliferation, possibly via cell cycle upregulation and increased protein translation efficiency. SP-induced proliferative and antiapoptotic pathways in fat depots may contribute to development of the creeping fat and inflammation characteristic of Crohn's disease.

Expression and developmental regulation of oxytocin (OT) and oxytocin receptors (OTR) in the enteric nervous system (ENS) and intestinal epithelium.

Although oxytocin (OT) and oxytocin receptor (OTR) are known for roles in parturition and milk let-down, they are not hypothalamus-restricted. OT is important in nurturing and opposition to stress. Transcripts encoding OT and OTR have been reported in adult human gut, and OT affects intestinal motility. We tested the hypotheses that OT is endogenous to the enteric nervous system (ENS) and that OTR signaling may participate in enteric neurophysiology. Reverse transcriptase polymerase chain reaction confirmed OT and OTR transcripts in adult mouse and rat gut and in precursors of enteric neurons immunoselected from fetal rats. Enteric OT and OTR expression continued through adulthood but was developmentally regulated, peaking at postnatal day 7. Coincidence of the immunoreactivities of OTR and the neural marker Hu was 100% in the P3 and 71% in the adult myenteric plexus, when submucosal neurons were also OTR-immunoreactive. Co-localization with NeuN established that intrinsic primary afferent neurons are OTR-expressing. Because OTR transcripts and protein were detected in the nodose ganglia, OT signaling might also affect extrinsic primary afferent neurons. Although OT immunoreactivity was found only in approximately 1% of myenteric neurons, extensive OT-immunoreactive varicosities surrounded many others. Villus enterocytes were OTR-immunoreactive through postnatal day 17; however, by postnatal day 19, immunoreactivity waned to become restricted to crypts and concentrated at crypt-villus junctions. Immunoelectron microscopy revealed plasmalemmal OTR at enterocyte adherens junctions. We suggest that OT and OTR signaling might be important in ENS development and function and might play roles in visceral sensory perception and neural modulation of epithelial biology.

Role of neuropeptides in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic, relapsing condition involving complex interactions between genes and the environment. The mechanisms triggering the initial attack and relapses, however, are not well understood. In the past several years the enteric nervous system (ENS) has been implicated in the pathophysiology of IBD. Both the ENS and the central nervous system (CNS) can amplify or modulate aspects of intestinal inflammation through secretion of neuropeptides that serve as a link between the ENS and CNS. Neuropeptides are defined as any peptide released from the nervous system that serves as an intercellular signaling molecule. Neuropeptides thought to play a potentially key role in IBD include substance P, corticotropin-releasing hormone, neurotensin, vasoactive intestinal peptide, mu-opioid receptor agonists, and galanin. This review focuses on the role of these neuropeptides in the pathophysiology of IBD and discusses the cell types and mechanisms involved in this process. The available evidence that neuropeptide blockade may be considered a therapeutic approach in both Crohn's disease and ulcerative colitis will also be discussed.

Pulmonary function and exercise response in patients with pectus excavatum after Nuss repair.

BACKGROUND/PURPOSE: The Ravitch repair of pectus excavatum removes segments of abnormal costal cartilages after which the sternum is elevated and stabilized. Some investigators have found a worsening in total lung capacity postoperatively. Recently, a technique has been used in which the costal cartilages are preserved, and the sternum is elevated with an internal steel bar (Nuss repair). The authors hypothesized that placement of a substernal bar in the first stage of the Nuss repair will not adversely affect pulmonary and exercise function. METHODS: Patients who presented to the Children's Hospital of Buffalo for surgical repair of pectus excavatum from June 1997 through June 2000 underwent pulmonary function and exercise testing before and 6 to 12 months after the first stage of a Nuss repair. RESULTS: Ten patients were studied (all boys; mean age at operative repair, 13.4 +/- 3 years). Mean baseline pulmonary function was normal, and no significant differences were seen before and after placement of the intrathoracic bar. Peak oxygen consumption was near normal, although work at VO2max was less than predicted (mean, 68.2% before v. 71.8% after surgery). V(E) was below normal and Vt/FVC was below the expected 50% to 60% level both before and after surgery (41.3% +/- 3 SE and 41.6% +/- 3 SE pre- and postoperatively, respectively). CONCLUSIONS: Placement of a substernal steel bar in the first stage of the Nuss procedure for repair of pectus excavatum does not cause adverse effects on either static pulmonary function or on the ventilatory response to exercise.