Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 4 uppsatser.

Diss. (sammanfattning) Linköping : Univ., 2004. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Thesis (M.Sc. (Physiology))--Mahidol University, 1982.

Thesis (Ph.D.)--University of Alabama at Birmingham, 2009. / Title from PDF title page (viewed on Sept. 9, 2009). Includes bibliographical references.

O desmame precoce (DP) consiste na abrupta substituição do leite pela dieta sólida e este padrão de alimentação pode ter impacto sobre o crescimento do estômago. Esta situação é também estressante para os filhotes e eleva os níveis de corticosterona que age ligando-se ao receptor de glicocorticoide (GR). Estudamos a expressão e a distribuição do GR na mucosa gástrica de ratos amamentados (C) e em DP. A expressão de GR foi maior aos 17 dias no grupo C e aumentou do 17º para o 18º dia no grupo em DP (p<0,05). O DP diminuiu o nível de GR, principalmente aos 18 dias (p<0,05), porém não alterou sua distribuição tecidual. Em termos de localização subcelular o GR, ficou mais concentrado no citoplasma no C (p<0,05), enquanto no DP, a distribuição foi similar entre os compartimentos, com uma redução no citoplasma (p<0,05), e um sutil aumento no núcleo. Sugerimos que a resposta de GR ao DP indica a alteração um elemento essencial na atividade da corticosterona, e essa modificação pode ser importante na coordenação do crescimento da mucosa gástrica durante o desmame precoce. / Early weaning (EW) is the abrupt change from suckling (S) to solid food and it can impair stomach development. This is a stressful situation for pups and it augments corticosterone levels, which acts through glucocorticoid receptor (GR). We studied GR expression, tissue and subcellular distribution in the gastric mucosa of S and EW pups. GR expression was higher at 17 d in S pups (p<0,05), whereas in EW group, it increased from the 17th to 18th d (p<0,05). GR protein levels decreased throughout EW, mainly at 18 d (p<0,05). However, EW did not alter tissue distribution of GR along the gastric gland. As for GR subcellular distribution, we found that in S group GR was more concentrated in the cytoplasm, (p<0,05), whereas in EW pups, GR was similarly distributed between compartments, though we detected a decrease in the cytoplasm (p<0.05) and a slight increase in the nucleus. We suggest that GR response to EW indicates the change of an essential element of corticosterone cascade, and such alteration might be important in the coordination of gastric mucosa growth.

Sucralfate is a drug that effectively heals duodenal, gastric and oesophageal ulcers. It is not absorbed systemically and it has been shown to act locally by coating the ulcer base. However when it was also shown to prevent stress ulcers and ethanolinduced gastric mucosa! lesions, it seemed likely that it acted in some way to improve the effectiveness of the gastric mucosa! barrier. Some investigators suggested that it did so by stimulating local prostaglandin release. The Slomiany group, on the basis of in vitro work on the effects of Sucralfate on pig gastric mucus, claimed that Sucralfate acted by altering the physico-chemical properties of mucus to increase the viscosity and retard the back diffusion of H+ ions. The work described in this dissertation set out to verify, in vivo, these claimed effects on mucus, using an experimental porcine model of peptic ulceration, the bile duct ligated pig. In addition, the effects of Sucralfate were compared with those of Famotidine and Misoprostol, and changes in mucous prostaglandins, gastric juice pepsin and gastric flora were sought. By way of introduction, the known and postulated actions of Sucralfate, current understanding of gastric mucus physiology and pathogenesis of peptic ulceration, have been reviewed, as have experimental animal models of peptic ulceration, in order to justify using the bile duct ligated pig model.

The gastrointestinal (GI) tract is a crucial interface for the host, food derived antigens, the commensal microbiota and invasive pathogens. Here, the immune system must simultaneously protect against harmful pathogens and remain tolerogenic to commensal bacteria and nutrients. The intestinal mucosa of adult humans and mice is enriched for innate lymphoid cells (ILCs) that express the transcription factor RORγt (ILC3s). These cells are crucial for maintaining the delicate balance of tolerance and immunity in the GI tract. They serve protective roles in immune responses to infectious organisms, are essential for the formation of lymphoid tissues, and help maintain gut homeostasis via signaling to epithelial cells through interleukin 22 (IL-22). ILC3s in the GI tract can be further categorized into three main subsets with distinct and overlapping functional roles. These subsets can be identified by either the expression of CCR6, Nkp46, or by lacking both markers- double negative (DN), some of which also make IL-17A. Signals that mediate the development and function of the various ILC3 subsets are still an area of active investigation. Notch signaling is a highly conserved pathway that contributes to the development and function of many types of immune cells. There has been some investigation into the role Notch signaling plays in the development of ILC3, particularly in the transition from DN to Nkp46 ILC3. However, all three subsets of ILC3s express two Notch receptor isoforms (Notch1 and Notch2) the individual roles of these two receptors have not been dissected. We show signaling through Notch1 and Notch2 individually contribute to Nkp46 ILC3 development in a cell intrinsic manner. We also show Notch signaling, primarily through Notch2, reinforces the ILC3 program and suppresses the ILC1-like program in Nkp46 ILC3 by promoting the expression of RORγt, c-Maf, and IL-22, and suppressing the expression of T-bet and IFNγ. Notch signaling also supports ILC3-identity genes in CCR6 ILC3, promoting RORγt, IL-17A, and IL-22. We, therefore, identify a novel role for Notch signaling in ILC3 function. As such, Notch-deficient ILC3 fail to initiate proper immune response to enteric pathogen Citrobacter rodentium, leading to more severe infection. Our results show how a highly conserved signaling pathway contributes to ILC3 development, identity, and function. The GI tract is also enriched with helper CD4 T cells that express RORγt, IL-17A, and IL-22 (Th17), which share many phenotypic and functional features with ILC3. The relative contribution of ILC3 and Th17 cells to immune phenotypes remains poorly understood. Moreover, due to the lack of ILC3-specific depletion models, how ILC3 regulate mucosal protection in the presence of Th17 cells is not clear. Here, we examined non-redundant functions of ILC3 in intestinal immunity using novel ILC3-deficient mice that maintain endogenous T cells, Th17 cells, and secondary lymphoid organs. ILC3 depletion did not affect IL-22-production by CD4 T cells during homeostasis. However, despite the presence of IL-22-producing T cells, ILC3 and ILC3- derived IL-22 were required for maintaining homeostatic functions of the intestinal epithelium. ILC3 were dispensable for generation of Th17 and Th22 cell responses to pathogenic bacteria, though Th17 and Th22 responses were delayed in the absence of ILC3. ILC3- deficient mice were capable of pathogen clearance and survived infection with low dose Citrobacter rodentium in the presence of antigen-specific Th17 cells. However, ILC3 increased pathogen tolerance at early timepoints of infection by activating tissue-protective immune pathways. Consequently, ILC3 were indispensable for survival of high dose infection. We also assess the role of ILC3 and Th17 cell in metabolic syndrome, using our novel model. Our lab demonstrated commensal-specific Th17 cells are protective against metabolic syndrome and lost under high-fat, high-sugar diet. ILC3s drive the expansion of a commensal member, Faecalibaculum rodentium (F. rod), which displaces the Th17 cell-inducing commensal, segemented filamentous bacteria (SFB). Without ILC3s, SFB is not lost from the microbiota, commensal- specific Th17 cells are maintained and there is, therefore, no development of metabolic syndrome. Our results demonstrate crucial context- dependent roles for ILC3 in immune-sufficient animals during homeostasis, infection, and metabolic disease.

O leite é essencial para o desenvolvimento pós-natal da mucosa gástrica e durante o período de aleitamento, o jejum estimula a proliferação celular. Mostramos que o TGF<font face=\"Symbol\">b, reverte este efeito e p27 está envolvida neste mecanismo. Os níveis de p27 oscilam durante o ciclo celular, devido à sua fosforilação na Thr187, que leva à degradação pelo sistema UPS. Diferentes estudos relatam que TGF<font face=\"Symbol\">b pode aumentar p27, através do controle de sua degradação. Este estudo visa analisar o efeito do jejum e TGF<font face=\"Symbol\">b1, na regulação de p27 no epitélio gástrico de ratos lactentes. Para tanto, filhotes de 14 dias foram submetidos a jejum durante 90 min e receberam uma dose única de TGF<font face=\"Symbol\">b ou PBS, por gavagem. As amostras foram coletadas após 2 e 14 horas de tratamento. Analisamos a concentração proteica de p27, fosfo-p27, Skp2 e Cdh1. Observamos que durante o jejum houve a diminuição de p27 e Cdh1, paralelamente ao aumento de fosfo-p27 e Skp2. Enquanto que o tratamento com TGF<font face=\"Symbol\">b1, reverteu os efeitos do jejum em 2h e 14h em todas as proteínas analisadas. Além disso, o jejum aumentou a ubiquitinação e degradação de p27 e o tratamento com TGF<font face=\"Symbol\">b1 reverte esses efeitos. Desta forma, o TGF<font face=\"Symbol\">b1 do leite materno estabiliza os níveis de p27 e assim, influenciar a progressão do ciclo celular no epitélio gástrico. / Milk is essential for postnatal development of the gastric mucosa and during the suckling period fasting stimulates cell proliferation. We have shown that TGF<font face=\"Symbol\">b reverses this effect and p27 is involved in this mechanism. The levels of p27 oscillate during the cell cycle due to its phosphorylation at Thr187, which leads to its degradation by the UPS. Different studies reported that TGF<font face=\"Symbol\">b can increase p27, by controlling its degradation. This study aims to analyze the effect of fasting and TGF<font face=\"Symbol\">b1 in regulating p27 in lactating rats gastric epithelium. For such, the 14 days rats were fasted for 90 min and received a single dose of TGF<font face=\"Symbol\">b or PBS by gavage. Samples were collected after 2 and 14 hours of treatment. We analyzed the p27 protein concentration, phospho-p27, Skp2 and Cdh1. We found that during fasting, p27 and Cdh1 a decreased, at the same time to the increment of phospho-p27 and Skp2. The treatment with TGF<font face=\"Symbol\">b1, reversed the effects of fasting on 2h and 14h in all proteins analyzed. Moreover, the fasting increased the ubiquitination and the degradation of p27, while TGF<font face=\"Symbol\">b1 treatment reversed these effects. Thus the milk born TGF<font face=\"Symbol\">b1 can stabilize p27 levels and thus influences cell cycle progression in lactent rat gastric epithelium.