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published_or_final_version / Medicine / Doctoral / Doctor of Philosophy

Sepsis, a life-threatening organ dysfunction caused by dysregulated host immune response to infection, is one of the leading causes of death within intensive care units (ICUs) in the United States. Developing specific therapies to treat sepsis is a current challenge for translational research, where over 100 drugs developed to target pro- and anti-inflammatory pathways in sepsis have failed to pass clinical trials. The recent challenge in translating effective sepsis pharmaceuticals from animals to humans has led some researchers to question the overall viability of using specific pathogen free (SPF) mice as an animal model for sepsis in human beings. SFP mice are raised in a barrier facility designed to prevent exposure to specific pathogens, while humans are exposed to a wide range of pathogens on a daily basis. Acknowledging the influence that prior environmental pathogen exposure has on the immune system’s response to future infections, researchers have developed the cohoused (CoH) mouse model as a potential alternative to SPF mice for use in research on immunological diseases such as sepsis. CoH mice are SPF mice cohoused with “dirty” pet store mice for 60 days, which increases their pathogen exposure and results in mice with immune experience more comparable to humans. Although the CoH model shows promise, a recent study conducted by Huggins et al shows increased sepsis-induced morbidity and mortality of CoH mice compared to SPF mice when using the lipopolysaccharide (LPS) and cecal ligation and puncture (CLP) models of sepsis. The experiments described in this thesis aim to further compare the inflammatory response of SPF, CoH, and pet store mice after intra-peritoneal injections of either LPS or cecal slurry (CS) to identify potential differences among these mouse groups and better understand why CoH mice experience increased mortality during sepsis. A baseline experiment was performed on each of these mice groups for comparison. Our baseline experiments demonstrate significant elevations in peritoneal immune cells within CoH mice compared to SPF mice. CS experiments demonstrate a significantly higher infiltration of immune cells in CoH mice following cecal slurry injection compared to SPF mice, suggesting that environmental pathogen exposure influences host inflammatory response within the peritoneum. However, LPS experiments were largely inconclusive. No significant differences were observed between SPF and CoH mice in regard to immune cell infiltration within the peritoneum, while blood analysis showed significant elevations in Tumor Necrosis Factor alpha (TNFa) and Interleukin 6 (IL-6) with increasing environmental pathogen exposure. Since the inflammatory response within the peritoneum to LPS was not significantly different between SPF and CoH mice, future studies could expand upon these results by investigating other tissue compartments in SPF and CoH mice following LPS injection into the peritoneum to provide a more complete comparison between these mice during LPS induced sepsis.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24883号 / 医博第5017号 / 新制||医||1068(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 中島 貴子, 教授 石見 拓, 教授 中山 健夫 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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A artrite reumatoide (AR) é uma doença crônica autoimune que afeta as articulações e causa uma persistente inflamação sinovial e destruição da cartilagem e osso. A artrite induzida por pristane (PIA) em camundongos é um modelo experimental utilizado em muitos trabalhos, pois se assemelha à artrite reumatoide. MicroRNAs (miRNA) têm sido bastante estudados por sua participação no desenvolvimento da artrite. As linhagens de camundongos AIRmax e AIRmin, diferem quanto a susceptibilidade/resistência à PIA. Nós analisamos o perfil de expressão gênica de mRNA e miRNAs das células peritneais dessas linhagens e avaliamos sua participação no desenvolvimento da PIA. A linhagem AIRmax mostrou uma maior modulação de genes (2025) com relação aos AIRmin (1043) no início dos sintomas. Os miRNAs 132-3p/212-3p e 130b-3p foram, os miRNAs mais significativamente modulados nos animais sensíveis e mostraram correlações negativas com alguns de seus genes alvos preditos. Nosso estudo mostrou que a expressão de mRNAs e miRNAs é modificada nas linhagens AIRmax e AIRmin durante a PIA. / Rheumatoid arthritis is a chronic autoimmune disease that affects joints and it is characterized by synovial inflammation and articular cartilage and bone destruction. Pristane-induced arthritis (PIA) in mice is an experimental model that has been used in many studies, since it resembles rheumatoid arthritis. MiRNAs has been extensively studied in the development of arthritis. AIRmax and AIRmin lines, differ in their susceptibility/resistance to PIA. We analyzed the miRNA and gene expression profile of mRNA in peritoneal cells of these lines in order to evaluate their involvement in PIA development. AIRmax mice showed a high gene modulation (2025) than AIRmin mice (1043) at the onset of disease symptoms. The 132-3p/212-3p and 130b-3p miRNAs were the most significant in susceptible animals showing negative correlations with some of their predicted target genes. Our study showed that the global gene and miRNA expressions are modified in the peritoneal cells of AIRmax and AIRmin lines during pristane-induced arthritis.

Made available in DSpace on 2014-06-11T19:22:21Z (GMT). No. of bitstreams: 0 Previous issue date: 2013-01-24Bitstream added on 2014-06-13T20:28:36Z : No. of bitstreams: 1 leal_lm_me_jabo.pdf: 1027361 bytes, checksum: f297c3a731a9e77d6a7d1becc046d08f (MD5) / Na busca de material biológico alternativo para a realização de implantes, objetivou-se com o presente estudo avaliar comparativamente a implantação do peritônio de paca, uma nova opção de biomaterial, conservado em solução supersaturada de açúcar a 300% e conservado em glicerina a 98% na parede abdominal de ratos wistar. Foram utilizados 60 ratos, machos, da linhagem Wistar pesando entre 150 e 200 gramas organizados nos seguintes grupos experimentais: grupo controle (GI), grupo peritônio conservado em solução supersaturada de açúcar a 300% (GII) e grupo peritônio conservado em glicerina a 98% (GIII), cada um com 20 animais. Os grupos GII e GIII receberam o enxerto de peritônio da paca conservado em solução de açúcar 300% e glicerina 98% respectivamente, e o grupo GI não recebeu a membrana. Cinco ratos de cada grupo foram submetidos à eutanásia em quatro momentos distintos: sete, 15, 30 e 60 dias de pós-operatórios para avaliações clínicas, macroscópicas, histológicas e estereológicas da interface implante-tecido nativo. Apesar de reações adversas observadas em 57,5% dos animais do grupo GII e GIII, em 95% dos animais destes grupos houve boa cicatrização da membrana. Na análise histológica, verificou-se a presença de grande infiltrado inflamatório nos períodos iniciais (sete e 15 dias) e grande presença de tecido conjuntivo nos momentos finais (30 e 60 dias). Mediante análise estereológica verificou-se que o número de células mononucleares diminuiu no decorrer dos momentos de avaliação. Concluiu-se que o peritônio da paca como membrana biológica conservado nos meios estudados pode ser utilizado com segurança na parede abdominal de ratos; ainda, que sua conservação em solução supersaturada de açúcar a 300% permitiu melhor maleabilidade no ato cirúrgico e também que a conservação em glicerina a 98% possibilitou, microscopicamente, menor resposta inflamatória / In the search for alternative biological material to perform implants, this study aimed to compare the implantation of paca peritoneum, a new option biomaterial, preserved in supersaturated sugar solution 300% and preserved in glycerin 98% in the abdominal wall of Wistar rats. A total of 60 male rats of Wistar strain weighing between 150 and 200 grams housed into three diferent experimental groups: control group (GI), peritoneum preserved in supersaturated sugar solution 300% group (GII) and peritoneum preserved in glycerin 98% group (GIII), with 20 animals each one. The GII and GIII received the paca peritoneum graft preserved in sugar solution 300% and glycerin 98%, respectively and the group GI did not receive any membrane. Five rats from each group were euthanized at four different times: seven, 15, 30 and 60 days post-surgery to macroscopic, microscopic and stereological evaluations in graft-native tissue interface. Despite the adverse reactions observed in 57,5% of GII and GIII, there was good healing of the membrane in 95% of the animals of these groups. On histological examination, there was a large presence of inflammatory infiltrates in the initial periods (seven and 15 days) and large presence of connective tissue in the final stages (30 and 60). By stereology, it was found that the number of mononuclear cells decreased throughout the evaluation times. It was concluded that the paca peritoneum as biological membrane preserved as presented in this study can be used safely in the abdominal wall of rats, the preservation in supersaturated sugar solution 300% allowed better flexibility during surgery and conservation in glycerin 98% allowed, microscopically, less inflammatory response

Thesis (M. Sc.)--University of Adelaide, 1984. / Includes bibliographical references (leaves 111-137).

Made available in DSpace on 2014-06-11T19:23:43Z (GMT). No. of bitstreams: 0 Previous issue date: 2007-07-06Bitstream added on 2014-06-13T20:50:58Z : No. of bitstreams: 1 oliveira_tc_me_jabo.pdf: 2166341 bytes, checksum: 3506a5bd81e793c204aacdd18020a595 (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Neste estudo, implantou-se peritônio bovino ou biomembrana de látex natural em defeito (1,5 x 1,5 cm) induzido na parede ventral da bexiga de coelhos, com o intuito de se avaliar o processo de reparação tecidual no que se refere à biocompatibilidade, capacidade de reparação e possíveis complicações. Utilizaram-se 36 coelhos, albinos, raça Nova Zelândia Branco, adultos, machos inteiros, divididos em grupos experimentais: grupo Biomembrana (GB), grupo peritônio bovino (GP) e grupo controle (GC), cada um com 12 animais. Aos sete, 14, 30 e 60 dias de pós-operatório, os animais foram eutanasiados mediante o emprego de uma dose elevada de tiopental sódico para avaliações macroscópica e histopatológica da interface do implante com o tecido nativo. Macroscopicamente, em ambos os grupos (GB, GP e GC), observaramse, em todos os períodos, aderências de estruturas adjacentes ao local do implante, presença de cálculos e ausência de sinais de rejeição. No grupo biomembrana, aos 30 e 60 dias de pós-operatório, constatou-se a presença do biocompósito solto na luz vesical. Sob microscopia de luz, aos sete dias verificaram-se intensa reação inflamatória, neovascularização e presença de fibroblastos proliferados. Aos 14 dias não havia epitélio, porém observaram-se escassos feixes musculares, intensa neovascularização, fibroblastos e infiltrado inflamatório. No grupo GP, aos 30 dias de observação, o implante estava presente, havia fibroblastos, feixes de fibras musculares, moderada população inflamatórias e ausência de epitélio e de lâmina própria. No grupo GB, neste mesmo período, todas as camadas vesicais estavam reconstituídas. Em ambos os grupos, aos 60 dias de pós-operatório, todas as camadas vesicais encontravam-se reparadas e a membrana peritônio bovino não foi observada. No grupo GC, em todos os tempos de avaliação verificou-se integridade... / In this study, bovine peritoneum or biomembrane of natural latex were utilized to replace a section of ventral face of the bladder of rabbits, with purpose of evaluation of the tissue repair process in regard of its biocompatility, scar formation ability and possible complications. Thirty-six New Zealand rabbits, adult and entire males were divided in three experimental groups: biomembrane group (GB), bovine peritoneum group (GP) and control group (GC), each one with 12 animals. The animals were euthanized at seven, 14, 30 and 60 days post operative, by use of an elevated dosage of sodium tiopental, followed by macroscopic and histopathological analysis of the implant interface with the native tissue. Macroscopically, in both groups (GB, GP and GC), it was observed, in all time periods, structure adherence to the implant site, presence of calculi and absence of rejection signs. In the GB group, since 30 until 60 days of post operative, it was evidenced the presence of the biomembrane inside the bladder. Under light microscopy, at seven days, there were intense inflammatory reaction, new vessels and proliferated fibroblasts. In 14 days, there was no urotelium, however it saw muscle fibers, intense inflammatory cells, new vessels and fibroblasts. In the GP group, at 30 days the implant was still present, there were fibroblasts, muscle fibers, moderate population of inflammatory cells and absence of urotelium and sheath. In the GB group, in the same time period, all the vesical layers were reconstituted. In both groups, at 60 days of post operative, bladder wall was repaired and the bovine peritoneum membrane was not observed. In the GC group, all the evaluation times, integrity of the vesical wall was verified... (Complete abstract click electronic access below)