Ulm, Univ., Diss., 2001.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / IntroduÃÃo: MGI à o termo que descreve os efeitos da quimioterapia antineoplÃsica nas mucosas, podendo acometer o trato alimentar de maneira global ou localizada. 15 a 40% dos pacientes em quimioterapia apresentam algum grau de mucosite. Muito da fisiopatologia da MGI permanece desconhecido. A IL-18 à uma citocina pleiotrÃpica, com funÃÃo regulatÃria sobre o sistema imune e envolvimento nas fases iniciais da inflamaÃÃo. Objetivo: Avaliar o envolvimento de IL-18 na patogÃnese da MGI induzida por CPT-11. Materiais e MÃtodos: camundongos Balb/C IL-18Wt ou IL-18KO, machos, foram tratados durante quatro dias consecutivos com CPT-11 (60mg/Kg, i.p.) ou veÃculo (0,5 mL, i.p.). Um grupo de animais IL-18Wt recebeu, alÃm do CPT-11, a proteÃna ligante de IL-18 (IL-18Bp; 200 Âg, i.p.). Os seguintes parÃmetros foram avaliados: diarrÃia, leucograma, sobrevida, anÃlise histopatolÃgica, atividade de mieloperoxidade (MPO), dosagem de citocinas (TNF-α, IL-1β ) por ELISA e imunoistoquÃmica para TNF-α e IL-1β nas mucosas ileais. Resultados: CPT-11 induziu diarrÃia significante e promoveu alteraÃÃes intestinais exuberantes (encurtamento de vilos, achatamento e vacuolizaÃÃo de enterÃcitos, necrose em criptas e infiltrado inflamatÃrio de leucÃcitos polimorfonucleares e cÃlulas mononucleares) Observou-se aumento da atividade de MPO e dos nÃveis tissulares de TNF-α e IL-1β dosados por ELISA e intensa imunomarcaÃÃo com anticorpos anti-TNFα e anti-IL-1β nesses animais. AlÃm disso, tais animais apresentaram resposta contrÃtil intestinal exacerbada ao estÃmulo com colinÃrgicos (acetilcolina e betanecol). Os animais IL-18KO tratados com CPT-11 apresentaram diarrÃia estatisticamente menos severa e menor intensidade de alteraÃÃes morfomÃtricas e histolÃgicas. NÃo houve aumento de TNF-α, mas houve de IL-1β , a atividade de MPO nÃo diferiu da observada nos animais que receberam veÃculo e nÃo houve aumento de resposta contrÃtil ao estÃmulo colinÃrgico. Os animais que receberam CPT-11 e IL-18Bp apresentaram diarrÃia estatisticamente menos intensa que aqueles que receberam apenas CPT-11, resposta contrÃtil estatisticamente menos acentuada e menor atividade de MPO. Entretanto, as alteraÃÃes morfomÃtricas e histolÃgicas nÃo diferiram das encontradas nos animais tratados sà com CPT-11. ConclusÃo: IL-18 està envolvida na patogÃnese da MGI induzida por CPT-11. IL-18Bp atenua os eventos envolvidos na MGI induzida por CPT-11 e à um possÃvel candidato a modulador farmacolÃgico desse processo. As alteraÃÃes contrÃteis no intestino promovidas pelo CPT-11 parecem ter um componente inflamatÃrio / Introduction: The term GIM refers to the adverse effects of cancer chemotherapy on mucosal surfaces, affecting different portions of the alimentary tract. 15% to 40% of patients in chemotherapy present some degree of mucositis. By now, much of GIM pathophysiology remains unknown. IL-18 is a pleiotropic cytokine that exerts regulatory functions over the immune system and is also involved in inflammation. Purpose: The aim of the present study was to elucidate the involvement of IL-18 in the pathogenesis of CPT-11-induced mucositis. Materials and methods: Male IL-18 wild type (Wt) or IL-18 knockout (KO) Balb/C mice received CPT-11 (60mg/kg/day, i.p.) or vehicle (0.5ml, i.p.) in a four day schedule. A group of IL-18Wt also received IL-18 binding protein (IL-18Bp, 200 Âg, i.p., 1h before CPT-11). Animals were sacrificed on the fifth day. The following parameters were assessed: histologycal analysis, diarrhea, survival curve, leucogram, myeloperoxidase (MPO) activity assay, ileum levels of TNF-α and IL-1β by ELISA, immunohistochemistry for TNF-α and IL-1β and contractility assay. Results: IL-18Wt animals receiving CPT-11 presented diarrhea and intense histological alterations in the ileum (shortening of villi, flattening and vacuolization of enterocytes, cript necrosis and the presence of inflammatory infiltrate). There was also increased MPO activity, increased levels of TNF-α and IL-1β and strong immunostaining for TNF-α and IL-1β in the ileum. In addition, the CPT-11 treated mice presented increased intestinal contractility when stimulated with cholinergic drugs (bethanecol, BCh and acetylcholine, ACh). In contrast, IL-18KO animals treated with the same dose of CPT-11 presented less diarrhea and less intestinal histological alterations. There was no increase in MPO activity nor in TNF levels, but in IL-1 levels. In addition, TNFα and IL-1β immunostaining was weaker IL-18KO animals. Also, the intestinal contractility in IL-18KO animals was not exarcerbated after a cholinergic challenge. IL-18Wt animals receiving CPT-11 and IL-18Bp did not present significant diarrhea and there was no significant alterations on intestinal contractility after Ach administration. Although MPO activity was not increased in IL-18Bp treated animals, the ileal mucosa presented moderate to severe histological alterations. Conclusion: IL-18 participates in the CPT-11-induced GIM. IL-18Bp attenuates some inflammatory (cell infiltrate) and functional (diarrhea and contractility) events of CPT-11-induced GIM. The contractility alterations in CPT-11 treated animals seem to have an inflammatory related component

Universiẗat, Diss.--Jena, 2004.

Thesis (Ph.D.)--University of Tennessee Health Science Center, 2009. / Title from title page screen (viewed on August 19, 2009). Research advisor: Edward Rosloniec, Ph.D. Document formatted into pages (xi, 126 p. : ill.). Vita. Abstract. Includes bibliographical references (p. 103-117).

O objetivo desse estudo foi avaliar o efeito do tratamento não-cirúrgico sobre os níveis da IL-18 em sítios inflamados de pacientes com doença periodontal. Foram avaliados 14 pacientes com doença periodontal, sendo 9 pacientes com periodontite crônica generalizada (media 48,8 DP 7,4 anos) e 5 pacientes com gengivite (43,6 DP 11,8 anos). Nos pacientes com periodontite, os sítios foram divididos em: sem (GP) e com perda de inserção clínica (PP). Os sítios de pacientes com gengivite foram denominados GG. Os pacientes foram avaliados no dia 0, receberam tratamento periodontal não-cirúrgico, e foram novamente avaliados 30 dias depois. Os parâmetros clínicos utilizados no dia 0 e dia 30 foram: Índice de Placa (IP), Índice gengival (IG), Índice de placa visível (IPV), sangramento gengival a sondagem, profundidade de bolsa à sondagem (PBS) e nível de inserção (NI). Foram realizadas coletas de fluido gengival (FG) em 5 sítios GP, 5 sítios PP e em 5 sítios GG por paciente no dia 0 e dia 30. IPV reduziu significantemente de 33,7% para 10,7%. A % de sitos comPBS >4 mm reduziu significantemente de 81,7% para 53,4%. Quando todos os sítios (GG, GP, PP) foram analisados juntos, houve uma redução significante para os níveis de IL-18, IP, IG e PBS. Sendo assim, podemos concluir que houve uma redução significante dos níveis de IL-18 nos sítios inflamados de pacientes com doença periodontal acompanhado por uma melhora significante nos parâmetros clínicos periodontais. / The aim of that study was to evaluate the effect of the non surgical treatment on the levels of the IL-18 in inflamed sites from patients with periodontal disease. 14 patient with disease periodontal were appraised, being 9 patient with chronic periodontitis (mean age 48,8, SD 7,4 years) and 5 patient with gingivitis (mean age: 43,6 SD 11,8). The patients were divided in: gingivitis sites from periodontitis patients (sites GP), periodontitis sites from periodontitis patients (sites PP), and gingivitis sites from gingivitis patients (sites GG). The patients were evaluated at the baseline, they received non surgical periodontal treatment, and they were evaluated again 30 days after. The clinical parameters used at the baseline and 30 was: Plaque Index (PI), gingival Index (GI), visible plaque Index (VPI), bleeding on probing (BOP), pocket depth (PD) and attachment loss (AL). Collections of fluid gengival were accomplished (FG) in 5 sites GP, 5 sites PP and in 5 sites GG for patient at the baseline and 30 days. VPI reduced significantly from 33,7% to 10,7%. The % of sites with PBS >4 mm it reduced significantly from 81,7% to 53,4%. When all sites (GG, GP, PP) was analyzed together, there was a significant reduction for the levels of IL-18, PI, GI and PD. It was concluded that there was a significant reduction of the levels of IL-18 in inflamed sites from patients with periodontal disease accompanied by a significant improvement in the parameters clinical periodontais.

<p>Liver cancer is a devastating disease that is the 5th most common cancer in men, 7th most common cancer in women, and the 3rd leading cause of cancer-related mortality. This disease arises from multiple etiological factors, including hepatitis viruses, environmental toxins, alcohol abuse, and metabolic syndrome, which induce a state of chronic inflammation. This diseased liver tissue background is a drastically different microenvironment from the healthy liver, especially with regards to immune cell prevalence and presence of mediators of immune function. It has been well-established that this altered tissue background contributes significantly to the tumorigenic process, yet its effects on the progression of the disease are more poorly understood. </p><p>To better understand the consequences of liver disease on tumor growth and the interplay with its microenvironment, we first utilized two standard methods of fibrosis induction and orthotopic implantation of tumors into the inflamed and fibrotic liver to mimic the liver condition in human HCC patients, and examined the immune infiltrate. Compared to non-diseased controls, tumor growth is significantly enhanced under fibrotic conditions. The immune cells that infiltrated the tumors are also drastically different, with decreased proportions of natural killer cells but greatly increased numbers of immune-suppressive CD11b+ Gr1hi myeloid cells in both models of fibrosis. In addition, there are model-specific differences: increased proportions of CD11b+ myeloid cells and CD4+ CD25+ T-cells are found in tumors in the bile duct ligation model but not in the carbon tetrachloride model. Importantly, the skewed immune infiltration into the tumor, while having some commonalities with the non-tumor tissue, had several distinct, tumor-specific populations. Induction of fibrosis also alters the cytokine production of implanted tumor cells, which could have far-reaching consequences on the immune infiltrate and its functionality. Taken together, this work demonstrates that the combination of fibrosis induction with orthotopic tumor implantation results in a markedly different tumor microenvironment and tumor growth kinetics. </p><p>Appreciating that the altered immune microenvironment dramatically shifts tumor progression, we sought to further explore the effects of individual inflammatory mediators on the development of the disease. Interleukin 18 (IL-18) is an inflammatory cytokine that is markedly increased in the circulation of patients with HCC correlated with poor prognosis. However, the precise role for IL-18 in HCC remains unclear, with reports presenting both pro- and anti-tumorigenic activities. To answer this question definitively, we interrogated in more detail the expression profiles of IL-18 in tissue specimens from HCC patients and conducted experimentation using multiple clinically relevant mouse models to explore the functional role of this cytokine in the context of HCC. Our results indicate that IL-18 exerts a tumor-suppressive effect mediated in large part by alterations in survival and functionality of T-lymphocytes which infiltrated the tumor microenvironment. This tumor-suppressive effect is however dependent upon the inflammatory milieu: In the absence of an inflammatory environment, whether from a chemical carcinogenesis model or a fibrosis induction model, loss of IL-18 signaling does not affect tumor growth. This effect is also stage-dependent. Taken together, our findings establish a tumor-suppressive role for IL-18 in established HCC and provide a mechanistic explanation for the complex relationship between its expression pattern and HCC prognosis. </p><p>In summary, this work demonstrates a dramatic shift in the microenvironment of developing HCC tumors in the presence of chronic inflammatory stimuli. This microenvironment, which more accurately models the situation in which tumors develop and progress in patients, alters the presence and functionality of many immune mediators. In particular, IL-18 signaling is a powerful mediator of tumor progression, however observation of its functionality is dependent on an inflammatory context. This work provides new insight into the complex processes underlying HCC tumor progression, and emphasizes the necessity for more accurate modeling of HCC progression in mice which takes into account the drastic changes in the tissue caused by chronic liver disease.</p> / Dissertation

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 5 uppsatser.

München, Techn. Univ., Diss., 2004.

O objetivo desse estudo foi avaliar o efeito do tratamento não-cirúrgico sobre os níveis da IL-18 em sítios inflamados de pacientes com doença periodontal. Foram avaliados 14 pacientes com doença periodontal, sendo 9 pacientes com periodontite crônica generalizada (media 48,8 DP 7,4 anos) e 5 pacientes com gengivite (43,6 DP 11,8 anos). Nos pacientes com periodontite, os sítios foram divididos em: sem (GP) e com perda de inserção clínica (PP). Os sítios de pacientes com gengivite foram denominados GG. Os pacientes foram avaliados no dia 0, receberam tratamento periodontal não-cirúrgico, e foram novamente avaliados 30 dias depois. Os parâmetros clínicos utilizados no dia 0 e dia 30 foram: Índice de Placa (IP), Índice gengival (IG), Índice de placa visível (IPV), sangramento gengival a sondagem, profundidade de bolsa à sondagem (PBS) e nível de inserção (NI). Foram realizadas coletas de fluido gengival (FG) em 5 sítios GP, 5 sítios PP e em 5 sítios GG por paciente no dia 0 e dia 30. IPV reduziu significantemente de 33,7% para 10,7%. A % de sitos comPBS >4 mm reduziu significantemente de 81,7% para 53,4%. Quando todos os sítios (GG, GP, PP) foram analisados juntos, houve uma redução significante para os níveis de IL-18, IP, IG e PBS. Sendo assim, podemos concluir que houve uma redução significante dos níveis de IL-18 nos sítios inflamados de pacientes com doença periodontal acompanhado por uma melhora significante nos parâmetros clínicos periodontais. / The aim of that study was to evaluate the effect of the non surgical treatment on the levels of the IL-18 in inflamed sites from patients with periodontal disease. 14 patient with disease periodontal were appraised, being 9 patient with chronic periodontitis (mean age 48,8, SD 7,4 years) and 5 patient with gingivitis (mean age: 43,6 SD 11,8). The patients were divided in: gingivitis sites from periodontitis patients (sites GP), periodontitis sites from periodontitis patients (sites PP), and gingivitis sites from gingivitis patients (sites GG). The patients were evaluated at the baseline, they received non surgical periodontal treatment, and they were evaluated again 30 days after. The clinical parameters used at the baseline and 30 was: Plaque Index (PI), gingival Index (GI), visible plaque Index (VPI), bleeding on probing (BOP), pocket depth (PD) and attachment loss (AL). Collections of fluid gengival were accomplished (FG) in 5 sites GP, 5 sites PP and in 5 sites GG for patient at the baseline and 30 days. VPI reduced significantly from 33,7% to 10,7%. The % of sites with PBS >4 mm it reduced significantly from 81,7% to 53,4%. When all sites (GG, GP, PP) was analyzed together, there was a significant reduction for the levels of IL-18, PI, GI and PD. It was concluded that there was a significant reduction of the levels of IL-18 in inflamed sites from patients with periodontal disease accompanied by a significant improvement in the parameters clinical periodontais.