La cirrhose hépatique et ses conséquences il y a longtemps intriguent le médecin, surtout, par l’engagement multisystémique et parce que la science médicinal n’a pas encore dévoilé bonne partie des aspects biochimies et du métabolisme cellulaire, qui sont affectés par la disfonction hépatique chronique. Bien que décrite il y a plus de cent ans sous une forme de même qu’empirique, la syndrôme hépatopulmonaire est un objet d’étude et d’intérêt progressivement plus grands dans les dernières décades. Ses altérations et ses trouvailles commencent, cependant, seulement il y a quelques ans, a être bien définies. Nonobstant le mécanisme biochimie et étiopathologène persiste dans la sphére de la spéculation. La présence d’hypoxemie arterielle ne la cirrhose hépatique cést un fait bien documenté. Les mécanismes physiopathogènes sont en train d’être étudiés. On admet qu’il ya des altérations dans la vasculature pulmonaire que déterminent petits et innombrables “shunts” artério-veineux. La présence de “shunts”anatomiques intrapulmonaires quoique présents et bien documentés sont en petite quantité et difficilement expliqueraient si bas niveaux d’oxygénation artériel. On postule que surviennent des altérations dans la dynamique pulmonaire et que la diffusion des gaz peut être compromis. Ce travail met en évidence les aspects afférents à la fonction pulmonaire et aux niveaux d’oxygénation artériel. Initialement sélectione patients avec diagnostic de cirrhose hépatique, excluant comorbité pulmonaire, cardiaque, ou hematologie graves. Postérieurement sont soumis à une évaluation de la fonction pulmonaire au travers de la mesure de la capacité vital forcée, volume expiratoire forcé, et volume résiduel, bien comme mesure de la diffusion avec monoxyde de carbone. Finalement évalue l’oxygénation artériel au travers de la réalisation de gazométries artérielles em repos et avec oxygène à 100%. L’analyse des resultats obtenus a permis d’observer la présence de flux et volumes pulmonaires normaux ( moyenne de : CVF = 104, 6%; VEF 1 = 101,7%; volume résiduel = 114,3 % ), et diffusion diminuée ( moyenne = 70,48%) en relation au prévu. L’evaluation des gaz artériels a constaté une PaO2 moyenne de 82,48 mmHg au repos et de 518,2 mmHg quand l’oxygène a été inspiré à 100%. N’ont été observées correlations entre les niveaux de PaO2 ( repos et avec oxygène ) et diffusion. Dans cette étude, le flux et volumes pulmonaires ont été normaux en relation au prévu; cependant la diffusion avec monoxyde de carbone s’est montré diminuée. Cette diffusion diminuée permis de corroborer à l’idée jusqu’au présent existant de l’appelé trouble diffusion-perffusion, comme un des mécanismes enveloppés dans la physiopathogénie de la syndrôme hépatopulmonaire, même sans évidence de “shunt” artério-veineux morphologique intrapulmonaire. / A cirrose hepática e suas conseqüências há muito intrigam o médico, sobretudo pelo comprometimento multissistêmico e, também, porque a ciência médica ainda não desvendou boa parte dos aspectos bioquímicos e do metabolismo celular, que são afetados pela disfunção hepática crônica. Embora descrita há mais de 100 anos sob uma forma um tanto empírica, a síndrome hepatopulmonar tem sido objeto de estudo e de interesse progressivamente maiores nas últimas décadas. Suas alterações e seus achados começaram, no entanto, a ser bem definidos somente há alguns anos. Não obstante, o mecanismo bioquímico etiopatogênico persiste na esfera da especulação. A presença de hipoxemia arterial na cirrose hepática é fato bem documentado. Os mecanismos fisiopatogênicos estão sendo muito estudados. Admite-se que haja, acompanhando a doença do fígado, alterações na vasculatura pulmonar que determinem pequenos e inúmeros “shunts” artério-venosos. A presença de “shunts”anatômicos intrapulmonares, embora bem documentada, ocorre em pequena quantidade e dificilmente explicaria tão baixos níveis de oxigenação arterial, vistos nos pacientes cirróticos. Postula-se que ocorram alterações na dinâmica pulmonar e que a difusão dos gases possa estar comprometida. Esse trabalho focaliza os aspectos referentes à função pulmonar e aos níveis de oxigenação arterial, em pacientes com cirrose hepática, nos quais excluem-se comorbidez pulmonar, cardíaca, ou hematológica graves. Posteriormente, eles foram submetidos à avaliação da função pulmonar através da medida da capacidade vital forçada, volume expiratório forçado e volume residual, bem como medida de difusão do monóxido de carbono. Finalmente, avaliou-se a oxigenação arterial através da realização de gasometrias arteriais em repouso e com oxigênio a 100%. A análise dos resultados obtidos permitiu observar a presença de fluxos e volumes pulmonares normais ( médias de: CVF = 104,6 %; VEF 1 = 101,7 %; Volume Residual = 114,3% ) e difusão diminuída ( média = 70,48 % ) em relação ao previsto. A avaliação dos gases arteriais constatou uma PaO2 média de 82,48mmHg ao repouso e de 518,2mmHg quando inspirado oxigênio a 100 %. Não foram observadas correlações entre os níveis de PaO2 ( repouso e com oxigênio ) e a difusão. Nesse estudo, os fluxos e volumes pulmonares foram normais em relação ao previsto; porém, a difusão do monóxido de carbono mostrou-se diminuída. Essa difusão diminuída permite corroborar a idéia até então existente do chamado distúrbio difusão-perfusão, como um dos mecanismos envolvidos na fisiopatogenia da síndrome hepatopulmonar, mesmo sem evidência de “shunt”artério-venoso morfológico intrapulmonar. / Hepatic cirrhosis and its consequences have intrigued doctors for a long time, specially by its multi-systemic extent and also because the Medical Science has not yet revealed a great part of the aspects of biochemical and cellular metabolism which are affected by chronic hepatic malfunction. Although written more than a hundred years ago in a rather empirical way, hepatopulmonary syndrome has been studied and progressively focused over the last decades. Its modifications and findings, however, were well defined only some years ago. Nevertheless, the aetiopathogenic biochemical mechanism is still being speculated. The presence of arterial hypoxaemia in hepatic cirrhosis is a welldocumented fact. The physiopathogenic mechanisms are being widely studied. It is assumed that there are alterations on the pulmonary vascularity which determine small and numerous arterial-venous shunts. The presence of anatomic intrapulmonary shunts, although present and well documented, is low in quantity and they could hardly explain such low levels of arterial oxigenation in cirrhotic patients. It is a premise that alterations occur in the pulmonary dynamics and that the diffusion of gases may be altered. This paper focuses on the aspects related to the pulmonary function and to the arterial oxygenation levels, in patients diagnosed of hepatic cirrhosis, without serious pulmonary, cardiac or haematologic morbidity. They are later submitted to a pulmonary function evaluation through the measurement of the forced vital capacity, forced expiratory volume and residual volume as well as diffusion measurement of carbon monoxide. Finally, it evaluates the arterial oxygenation through arterial gasometry in resting condition and with oxygen to 100%. The analysis of the results obtained allowed us to observe the presence of normal pulmonary fluxes and volumes ( average quantities of: FVC = 104,6 %; FEV 1 = 101,7%; Residual Volume = 114,3% ), and diffusion was diminished ( average = 70,48% ) in relation to what was expected. The evaluation of the arterial gases came to an average PaO2 of 82,48 mmHg in resting condition and 518, 2 mmHg when oxygen is inspired at 100%. No correlations among the PaO2 ( in resting conditions and with oxygen ) and diffusion capacity were observed. In this study, the fluxes and pulmonary volumes were normal in relation to was expected; however, the diffusion of carbon monoxide presented itself diminished. This diminished diffusion corroborates the existing idea of the so-called diffusion-perfusion disturbance as one of the mechanisms involved in the physiopathogeny of the hepatic pulmonary syndrome, even without evidence of intrapulmonary morphological arterial-venous shunt.

Objetivo: Estudo transversal prospectivo para determinar as alterações ultraestruturais do miocárdio devido a hipoxemia crônica secundária à anemia decorrente da doença renal crônica em pacientes em programa dialítico. Material e métodos: Foram selecionados quatorze pacientes urêmicos, sendo doze pacientes anêmicos e dois não anêmicos em uso de eritropoietina humana recombinante. Dois pacientes não urêmicos serviram como controle. Todos os pacientes utilizaram com critério de exclusão obstrução coronariana ≥ 70% à cineangiocoronariografia. Realizaram-se biópsias de septo interventricular esquerdo do miocárdico que foram avaliadas por microscopia óptica e eletrônica de transmissão. Utilizou-se o método de Carnoy para contagem e medidas das ultraestruturas do miocárdio. Foram consideradas estatisticamente significativas as diferenças cujo valor de p fosse ≤ 0,05. Resultados: Nos 16 pacientes incluídos no estudo, a média dos hematócritos e hemoglobinas dos pacientes urêmicos e não urêmicos foram 29,3±5,4% e 46,5±0,7% e 9,5±1,9 g% e 15,5±0,35 g%, respectivamente (p< 0,05). Dos quatorze pacientes urêmicos, doze eram anêmicos e dois não anêmicos, a média dos hematócritos e hemoglobinas foram 27,7±3,7% e 39,0±4,2% e 9,0±1,3 g% e 12,8±1,7 g%, respectivamente (p<0,05). As demais variáveis: idade, sexo, fração de ejeção e outras, não diferiram entre os grupos estudados. O número de mitocôndrias foi significativamente maior quando comparou-se os grupos de pacientes urêmicos com os não urêmicos (p<0,05), o mesmo ocorrendo quando comparou-se os grupos de pacientes urêmicos anêmicos com os não anêmicos (p<0,05). Nas alterações na forma das mitocôndrias, houve diferença com significância estatística entre os grupos de pacientes urêmicos e não urêmicos (p<0,05), porém esta não ocorreu quando comparou-se os grupos de pacientes urêmicos anêmicos com os não anêmicos (p>0,05). Na análise das fibras miocárdicas observou-se alterações morfológicas das bandas Z e H comparando-se os pacientes urêmicos com os não urêmicos (p<0,05) e os pacientes urêmicos anêmicos com os não anêmicos (p<0,05). Encontrou-se uma correlação inversa e forte entre o número de mitocôndrias, com os níveis de hematócrito e hemoglobina (r=-0,70, p<0,001 e r=-0,69, p<0,001), respectivamente. Conclusões: Nesta amostra de pacientes com doença renal crônica em programa de terapia renal substitutiva e com diferentes níveis de hematócrito e hemoglobina, encontrou-se alterações ultra-estruturais, na forma e número das mitocôndrias e na morfologia das bandas Z e H das células miocárdicas, possivelmente como uma conseqüência adaptativa à hipoxemia crônica secundária a anemia decorrente da insuficiência renal crônica.

Arterial desaturation in fit athletes, during exercise at an intensity greater than or equal to 90% of VO₂ max has been reported by a number of authors yet the etiology of these changes remain obscure. Inadequate pulmonary ventilation due to a blunted respiratory drive, or lung mechanics has been implicated as a factor in the etiology of this phenomenon. It was the purpose of this experiment to investigate the relationship between arterial desaturation and ventilatory response to hypoxia (HVR). Twelve healthy male subjects ( age = 23.8 ± 3.6 yrs., height = 181.6 ±₋₁ 5.6 cms., Weight = 73.7 ± 6.2 kg., VO₂ max = 63.2 ± 2.2 ml .kg . -1 2 .min⁻¹) performed a five minute exercise test on a treadmill at 100% of VO₂ max. Arterial samples for pH, PCO₂, PO₂, and SaO₂ were withdrawn via an indwelling arterial cannula at rest and every 15s throughout the exercise test. The blood gas samples were analyzed with an Instrument Laboratories 1306 blood gas analyzer. Ventilation and VO₂ were measured by a Beckman metabolic measurement cart. On a separate occasion the ventilatory response to hypoxia (HVR) was determined by recording VE as progressive hypoxia was induced by adding N₂ to a mixing chamber. SaO₂ was measured using a Hewlett-Packard ear oximeter; to maintain isocapnia small ammounts of CO₂ were added to the open circuit system. ANOVA for repeated measured was used to evaluate changes in blood gases, ventilation, and VO₂. Simple linear regression and multiple linear regression was used to evaluate the relationship between the changes in SaO₂ and HVR and the descriptive variables. Subjects showed a significant decline in arterial saturation and PO₂ over the course of the test (p < 0.01,and p < 0.01). Four subjects (Mild) exhibited modest decreases in SaO₂ to (94.6 ± 1.9%), three (Moderate) showed an intermediate response (SaO₂ 91.6 ± 0.1%) and five (Marked) demonstrated a marked decrease in arterial saturation (SaO₂ = 90.0 + 1.2%). The differences in PO₂ and SaO₂ between Mild and Marked groups were significant ( p < 0.05, and p < 0.01); there were no significant differences between groups in VE, VO₂, pH or PCO . There was no significant correlation between the lowest SaO₂ reached and HVR, or any of the descriptive variables. Nine subjects did not reach maximal VE (as determined by the VO₂ max test) on the exercise test, two subjects 2 exhibited similar ventilation, and the remaining subject exceeded maximal VE, but fell into the Mild group with respect to desaturation. Oxygen uptake exceeded that recorded for the VO₂ max determination for four of the five subjects in the Marked group; the remaining subjects demonstrated lower or similar values. It was concluded that arterial desaturation was not related to blunted hypoxic drive. / Education, Faculty of / Curriculum and Pedagogy (EDCP), Department of / Graduate

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Orientador: Ana Carolina Firmino / Resumo: O encharcamento do solo é um problema comum em algumas áreas agricultáveis, inclusive em regiões sob cultivo de soja (Glycine max). Em solos encharcados, ocorre a depleção de O2 do solo pelos microrganismos aeróbicos e plantas, afetando os processos metabólicos e fisiológicos das plantas após sofrerem anoxia no tecido radicular. Outro fator prejudicial neste contexto, é o aumento exponencial da disponibilidade de ferro (Fe) no solo, o que pode resultar na absorção excessiva do Fe pelas plantas. No primeiro experimento, o objetivo foi avaliar a vulnerabilidade do aparato fotossintético e produção de biomassa de duas cultivares de soja no estágio fenológico V2, sob condição hídrica adequada e diferentes níveis de encharcamento do solo associada a uma concentração moderada e duas concentrações tóxicas de Fe. No segundo experimento, o objetivo foi avaliar o comportamento fisiológico e bioquímico da soja cultivar Agroeste 3680 associado ao desenvolvimento das vagens (estágio fenológico R3) sob solo não encharcado e encharcado combinado com uma concentração moderada e duas concentrações tóxicas de Fe. No primeiro experimento, o aparato fotossintético das cultivares de soja responderam diferentemente ao encharcamento e à disponibilidade de Fe no solo. Ambas cultivares foram vulneráveis ao encharcamento de 100% em todas as concentrações Fe, o que resultou em danos acentuados às trocas gasosas, concentração de clorofilas e, consequentemente, levou à diminuição da biomassa seca da part... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Soil waterlogging is a common problem in some agricultural areas, including regions under soybean (Glycine max) cultivation. In waterlogged soils, soil O2 depletion occurs due to aerobic microorganisms and plants, affecting the metabolic and physiological processes of plants after suffering anoxia in their root tissue. Another harmful factor of this situation is the exponential increase in the availability of iron (Fe) in the soil, which may result in excessive Fe uptake by plants. In the first experiment, the objective was to evaluate the vulnerability of the photosynthetic apparatus and biomass production of two soybean cultivars at the phenological stage V2, under optimal water condition and different levels of soil waterlogging, combined with one moderate and two toxic levels of Fe. While in the second experiment, the objective was to evaluate the physiological and biochemical behaviour of soybean cultivar Agroeste 3680, associated with the development of pods (at the phenological stage R3) in non-waterlogged and waterlogged soil, combined with one moderate and two toxic levels of Fe. In the first experiment, the photosynthetic apparatus of the two soybean cultivars responded differently to waterlogging and the availability of Fe in the soil. Both cultivars were vulnerable to waterlogging of 100% at all concentrations Fe, which resulted in damage to gas exchange and chlorophyll levels, and consequently, led to lower shoot and root biomass accumulation. The photosynthetic ... (Complete abstract click electronic access below) / Mestre

Indiana University-Purdue University Indianapolis (IUPUI) / Rationale: CD55 down-regulation on airway epithelium correlates with local complement activation observed in hypoxia-associated pulmonary diseases. Therefore, we hypothesized that induction of hypoxia inducible factor 1 alpha (HIF-1α) in hypoxic airway epithelium, mediates CD55 down-regulation. Methods: Chetomin and HIF-1α siRNA inhibited HIF-1α in hypoxic SAECs (1% O2), and mice lungs (10% O2). DMOG mediated HIF-1α stabilization in normoxic SAECs and mice lungs (21% O2). Transduction of SAECs with AdCA5 also stabilized HIF-1α. CD55 and CA9 transcripts were measured by RT-PCR. CD55 and HIF-1α protein expression was assessed by western blots. In vivo, immunohistochemistry (IHC) confirmed CD55 and HIF-1α expression. C3a and C5a levels in bronchoalveolar lavage fluid (BALF) were measured by ELISA. Results: HIF-1α was induced in 6 hour hypoxic SAECs (p<0.05), but CD55 transcripts were repressed (p&lt;0.05). CD55 protein was down-regulated by 72 hours (p<0.05). CA9 transcripts were elevated by 48 -72 hours (p<0.05 and p<0.01, respectively). In vivo, CD55 transcripts and protein were down- regulated by 24 hours post-hypoxia (p<0.01) which corresponded to complement activation (p<0.05) in BALF. However, CA9 was increased (p<0.01). Chetomin (100nM) treatment in 6 hour hypoxic SAECs, recovered CD55 transcripts (p<0.01) and protein (p<0.05), but down-regulated CA9 (p<0.05). Similarly, in vivo chetomin (1mg/ml) treatment recovered CD55 protein (p<0.01) and down-regulated CA9 (p<0.01). Silencing HIF-1α (50nM) in hypoxic SAECs restored CD55 transcripts by 6 hours (p<0.05), and protein expression by 24 hours (p<0.05). However, CA9 was repressed (p<0.01). In vivo silencing of HIF-1α (50µg) restored CD55 protein expression (p<0.05) but down-regulated CA9 (p<0.05). Stabilizing HIF-1α in normoxic SAECs via DMOG (1µM), down-regulated CD55 transcripts and protein (p<0.01), but increased CA9 within 6-24 hours (p<0.05 and p<0.01, respectively). HIF-1α induction by DMOG (1mg/ml) in normoxic mice lungs down-regulated CD55 transcripts (p<0.01) and protein (p<0.01), but increased CA9 (p<0.05). Induction of HIF-1α in AdCA5 (50 PFUs/cell) transduced normoxic SAECs, resulted in CD55 protein down-regulation (p<0.05), but increased CA9 (p<0.001). Conclusions: HIF-1α down-regulates CD55 on airway epithelium. Targeting this mechanism may be a potential therapeutic intervention for attenuating complement activation in hypoxic pulmonary diseases.

published_or_final_version / Physiology / Doctoral / Doctor of Philosophy

Se ha evaluado el efecto del ketoprofeno sobre los valores hematológicos de 10 bovinos Jersey, machos, de 1 a 2 meses de edad, nacidos a nivel del mar (NM) y expuestos durante 30 días a 3 320m. de altitud (A), divididos en los grupos control (T1) y tratamiento con ketoprofeno (T2). Los resultados obtenidos a NM y a los 3 y 30 días de exposición en A fueron: Hematocrito (%) a NM: 28.50±5.09 y 26.60±4.10 para T1 y T2, respectivamente; al día 3 en A: 31.17±4.02 y 28.80±2.95 para T1 y T2, respectivamente y al día 30 en A: 39.50±4.28 y 38.00±2.94 para T1 y T2, respectivamente. Hemoglobina (g/dl) a NM: 8.37±1.63 y 7.96±1.33 para T1 y T2, respectivamente; al día 3 en A: 10.97±1.38 y 9.99±1.43 para T1 y T2, respectivamente y al día 30 en A: 13.72±1.09 y 14.04±1.68 para T1 y T2, respectivamente. Eritrocitos (x106/µl) a NM: 8.47±1.61 y 7.04±2.96 para T1 y T2, respectivamente; al día 3 en A: 8.41±1.52 y 8.99±2.54 para T1 y T2, respectivamente y al día 30 en A: 10.97±0.93 y 9.33±0.58 para T1 y T2, respectivamente. Volumen corpuscular medio (mm3) a NM: 34.03±4.90 y 41.20±11.13 para T1 y T2, respectivamente; al día 3 en A: 37.58±5.39 y 33.42±6.31 para T1 y T2, respectivamente y el día 30 en A: 36.17±4.39 y 41.01±5.61 para T1 y T2, respectivamente. Hemoglobina corpuscular media (ρg) a NM: 9.99±1.57 y 12.28±3.17 para T1 y T2, respectivamente; al día 3 en A: 13.27±2.19 y 11.50±2.04 para T1 y T2, respectivamente y al día 30 en A: 12.55±1.12 y 15.16±2.66 para T1 y T2, respectivamente. Concentración media de hemoglobina corpuscular (g/dl) a NM: 29.44±2.51 y 29.92±2.00 para T1 y T2, respectivamente; al día 3 en A: 35.23±1.34 y 34.56±2.02 para T1 y T2, respectivamente y al día 30 en A: 34.82±1.33 y 36.86±2.08 para T1 y T2, respectivamente. Leucocitos (x103/µl) a NM: 7.78±3.34 y 7.59±0.51 para T1 y T2, respectivamente; al día 3 en A: 12.90±3.43 y 12.00±1.88 para T1 y T2, respectivamente y al día 30 en A: 11.51±2.90 y 9.56±0.64 para T1 y T2, respectivamente. Se concluye que el tratamiento con ketoprofeno no tuvo efecto significativo (P>0.05) sobre los valores hematológicos de terneros Jersey, a los 30 días de exposición a 3 320m. de altitud. / The effect of ketoprofen upon the hematological values in 10 Jersey male calves from 1 to 2 months age, born at sea level (SL) and exposed at 3 320m. of altitude (A) during 30 days; they were divided in control (T1) and ketoprofen treatment (T2). The obtained values at SL and at the 3 and 30 days of exposure to A, were as follows: Hematocrit (%) at SL: 28.50±5.09 and 26.60±4.10 for T1 and T2 respectively; 3 days at A: 31.17±4.02 and 28.80±2.95 for T1 and T2, respectively and 30 days at A: 39.50±4.28 y 38.00±2.94 for T1 and T2, respectively. Hemoglobin (g/dl) at SL: 8.37±1.63 and 7.96±1.33 for T1 and T2 respectively; 3 days at A: 10.97±1.38 and 9.99±1.43 for T1 and T2, respectively and 30 days at A: 13.72±1.09 and 14.04±1.68 for T1 and T2, respectively. Erythrocytes (x106/µl) at SL: 8.47±1.61 y 7.04±2.96 for T1 and T2, respectively; 3 days at A: 8.41±1.52 y 8.99±2.54 for T1 and T2, respectively and 30 days at A: 10.97±0.93 and 9.33±0.58 for T1 and T2, respectively. Mean corpuscular volume (mm3) at SL: 34.03±4.90 and 41.20±11.13 for T1 and T2, respectively; 3 days at A: 37.58±5.39 and 33.42±6.31 for T1 and T2, respectively and 30 days at A: 36.17±4.39 and 41.01±5.61 for T1 and T2, respectively. Mean corpuscular hemoglobin (ρg) at SL: 9.99±1.57 and 12.28±3.17 for T1 and T2, respectively; 3 days at A: 13.27±2.19 and 11.50±2.04 for T1 and T2, respectively and 30 days at A: 12.55±1.12 and 15.16±2.66 for T1 and T2, respectively. Mean corpuscular hemoglobin concentration (g/dl) at SL: 29.44±2.51 and 29.92±2.00 for T1 and T2, respectively; 3 days at A: 35.23±1.34 and 34.56±2.02 for T1 and T2, respectively and 30 days at A: 34.82±1.33 and 36.86±2.08 for T1 and T2, respectively. Leukocytes (x103/µl) at SL: 7.78±3.34 and 7.59±0.51 for T1 and T2, respectively; 3 days at A: 12.90±3.43 and 12.00±1.88 for T1 and T2, respectively and 30 days at A: 11.51±2.90 and 9.56±0.64 for T1 and T2, respectively. In conclussion the ketoprofen treatment have not significative effect (P>0.05) upon the hematological values of Jersey calves, until 30 days of exposure to 3320m. of altitude.