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Intestinal inflammation is associated with enteric nervous system alterations, at both inflamed and noninflamed sites. The perception of stimuli from the GI tract is enhanced during inflammatory conditions, but it is unknown whether visceral hypersensitivity is limited to the inflamed area or diffuse throughout the entire GI tract. Moreover, although stress can reactivate inflammatory processes in the gut, it is unknown if this can alter perception from the GI tract. Our aim was to determine if patients with ulcerative colitis (UC) have increased esophageal sensitivity to distention and whether this is modified by experimental stress.Ten UC patients and 12 healthy volunteers (HVs) underwent gradual balloon distension of the esophagus to assess their visceral sensitivity. Perceptive and pain thresholds were evaluated in basal conditions and after induction of experimental stress (cold water pressure test) while blood pressure and heart rate were monitored.Patients with UC had perceptive thresholds to distension similar to HVs (14.8+/-2.0 ml of air vs 14.5+/-3.0 ml); in contrast, the volume increment needed to evoke pain was significantly lower in UC patients than in HVs (58.9% vs 149.9%, p0.05). Physical stress caused a similar decrease in perceptive thresholds in HVs (-29.1+/-8.4%) and patients (-17.7+/-9.1%), but pain thresholds were significantly decreased only in HVs (-28.3+/-7.1% vs -11.5+/-12.3%).UC is characterized by increased esophageal sensitivity, indicating the existence of diffuse hyperalgesia during intestinal inflammatory processes. This increased sensitivity may account for the frequent upper GI symptoms these patients complain of when in clinical remission.

Expulsion of intestinal nematode parasites and the associated increased contraction by intestinal muscle are T cell dependent, since both are attenuated in athymic rodents. The CD4 T-cell subset has been strongly associated with worm expulsion; however, the relationship between these cells, antigen presentation, and worm expulsion is not definitive and the role of these factors in intestinal muscle hypercontractility has not been defined. We infected C57BL/6, athymic, CD4-deficient, CD8α-deficient, and major histocompatibility complex class II (MHC II)-deficient (C2d) mice with Trichinella spiralis larvae. We examined intestinal worm numbers, longitudinal muscle contraction, and MHC II expression. Numerous MHC II-positive cells were identified within the muscularis externa of infected but not uninfected C57BL/6 mice. C57BL/6 and CD8α-deficient mice developed large increases in muscle contraction, expelling the parasite by day 21. Athymic and C2d mice exhibited much smaller increases in muscle contraction and delayed parasite expulsion. CD4-deficient mice exhibited intermediate levels of muscle contraction and delayed parasite expulsion. To further examine the role of MHC II and CD4 T cells, we irradiated C2d mice and reconstituted them with C57BL/6 bone marrow alone or with C57BL/6 CD4 T cells. C57BL/6 bone marrow alone did not affect muscle function or worm expulsion in recipient C2d mice. Partial CD4 T-cell reconstitution was sufficient to restore increased muscle contraction but not worm expulsion. Thus, hematopoietic MHC II expression alone is insufficient for the development of muscle hypercontractility and worm expulsion, but the addition of even small numbers of CD4 T cells was sufficient to induce intestinal muscle pathophysiology.

Macrophages playa critical role in host defence and cel1-mediated immunity. Previously, we have shown that the absence of infiltrating macrophages resulted in a more severe colitis induced by hapten in mice. However, the mechanisms underlying this unexpected finding are unknown. In the present study, we explored this observation by studying colitis in mice lacking mature macrophages as a result of a spontaneous mutation in the macrophage-colony stimulating factor (M-CSF) encoding gene. Macrophage-deficient mice (op/op), as well as their M-CSF expressing littermates (op/+), received 3 mg of the hapten dinitrobenzensulfonic acid (DNBS) in 50% ethanol intrarectally. Mice were euthanized at days I and 3 post colitis and were evaluated for: macroscopic damage of the colon, for myeloperoxidase activity (MPO), for the presence of F4/80+ve macrophages by immunohistochemistry, and for levels of the chemokine MIP-la, which is involved in the recruitment of inflammatory. In paral1el experiments, mice received daily intraperitoneal injections of human recombinant M-CSF (hr M-CSF) prior to and during the colitis.In op/+ mice, DNBS-induced colitis was accompanied by an abundant transmural macrophagic infiltrate, while in M-CSF deficient mice only a few F4/80 + cel1s were evident. The severity of colitis was substantial1y greater in M-CSF deficient mice compared to op/+ mice at both days I and 3 post colitis (macroscopic score day I in op/+ mice = 4.4+0.9, in op/op mice = 7.2+0.8; at day 3 in op/+ mice = 3.3+0.5, in op/op mice = 7.3+0.5). Also, MPO activity was significantly higher in op/op mice at day I post colitis (op/+ mice = 1.9+0.3, op/op mice = 3.7+1.0). Colitis was accompanied by an increase in MIP-Ia levels, which were 10 times higher in op/op mice compared to opl+ mice at both days I and 3 post colitis. Treatment with hrM-CSF restored the macrophage infiltrate, reversed the increase in MPO activity observed in op/op mice, and ameliorated the macroscopic damage at day 3 but not at day I post colitis. Thus, in the absence of macrophages, there is a compensatory local overproduction MIP-I «.leading to an exaggerated neutrophilic infiltration and a greater degree of colonic damage. The ability of hr-MCSF to improve damage in op/op mice on day 3, but not on day I post colitis, indicates that additional factors are required for the early influx of macrophages to the inflamed bowel. Supported by MRC Canada.