Nasopharyngeal cancer (NPC) is endemic in Southern China and Hong Kong. It has traditionally been treated by local radiotherapy with great success especially for early stage disease. However the treatment outcome in advanced stage disease is unsatisfactory. / Results from this series of combined clinical, translational and laboratory studies have redefined the role of hypoxia, angiogenesis and metastasis as new therapeutic targets in NPC. Novel biomarkers and new therapeutic approaches were developed based on these targets. / To develop new therapies in NPC, we demonstrated in a randomized controlled phase 2 clinical trial that sequential therapy of neoadjuvant chemotherapy followed by chemoradiotherapy was well tolerated with a manageable toxicity profile that allowed subsequent delivery of full dose chemoradiotherapy. This strategy reduced distant metastasis which translated into improved patient survival. In preclinical studies, the antiangiogenesis agent sunitinib demonstrated potent in vitro and in vivo growth inhibition in NPC. In a phase 2 clinical trial, sunitinib demonstrated modest clinical activity in heavily pretreated NPC patients. However, the unexpected high incidence of severe hemorrhage from upper aero-digestive tract in NPC patients who received prior high dose RT to the region is of concern. We propose to exclude NPC patients with disease recurrence within previous radiation field and/or with vascular invasion from future antiangiogenesis therapy. / To investigate potential new therapeutic targets and biomarkers in NPC, we first confirmed from the Hong Kong NPC study group of 2915 patients' database that distant metastasis was the leading cause of NPC failure after primary radiotherapy. We further showed that hypoxia induced broad changes of both up- and down-regulated gene expressions involved in diverse biological processes in NPC cells. Over-expression of biomarkers of hypoxia and angiogenesis (including HIF-1alpha, CA IX and VEGF) is common in NPC and is associated with poor prognosis. Elevated plasma osteopontin is a biomarker of distant metastasis, and pre-treatment plasma osteopontin level may be a useful biomarker of response to radiotherapy in NPC. / Hui, Pun. / "September 2010." / Adviser: Anthony Chan. / Source: Dissertation Abstracts International, Volume: 73-04, Section: B, page: . / Thesis (M.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 269-293). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web.

Publicación a texto completo no autorizada por el autor / El documento digital no refiere asesor / Compara la escala de dificultad respiratoria usada en Argentina (EDRAR) y la utilizada en Chile (EDRCH) y determina la correlación con la saturación de oxigeno. Se incluyen 300 pacientes menores de 24 meses con SBO, registrando SaO2 y los componentes de la EDRAR y de la EDRCH (taquipnea, taquicardia, tiraje, sibilancias, cianosis). Se evalúa la capacidad de los componentes de ambas escalas para predecir hipoxemia (SaO2 ≤95 y SaO2 ≤91) por regresión logística. Se estima correlación entre cada escala y SaO2. Se determina el mejor punto de las escalas para predecir hipoxemia por medio de curvas ROC. Se validan ambas escalas calculando sensibilidad, especificidad, valores predictivos y razones de verosimilitud. La EDRAR muestra aceptable correlación con SaO2 (Spearman -0,465; P < 0,001). En la regresión logística, sólo el tiraje es predictor independiente de hipoxemia, definida por diferentes niveles de SaO2 (≤95 y ≤91) (RR: 8,2, IC 95%: 1,78 – 56,4 p: < 0,001 y RR: 17,3 IC 95%: 1,88 – 147,3 p < 0,001 respectivamente). En SaO2 ≤ 91 la EDRAR muestra la mejor capacidad diagnóstica (auc=0,914). Un puntaje 5 es el mejor punto para predecir hipoxemia (Sensibilidad=100%). También se evalúa el desempeño de la EDRCH, demostrando un rendimiento ligeramente inferior a la EDRAR. Concluye que la EDRAR es suficientemente sensible para predecir hipoxemia (SaO2 ≤91) en un puntaje 5, pero no muestra especificidad que permita una correcta discriminación por encima de este punto. La EDRCH presenta un desempeño similar. Estas escalas de dificultad respiratoria sólo permiten identificar niños que no se beneficiarían con el uso de O2. / Trabajo académico

Choi, Siu Cheong. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2008. / Includes bibliographical references (leaves 132-148). / Abstracts in English and Chinese. / Acknowledgement --- p.i / Abstract --- p.ii / Abbreviation --- p.v / List of Figures --- p.viii / List of Tables --- p.xii / Table of Content --- p.xiii / Chapter Chapter 1: --- General Introduction / Chapter 1.1 --- Introduction --- p.1 / Chapter 1.1.1 --- Treatment resistance in cancer --- p.1 / Chapter 1.1.1.1 --- Surgery --- p.2 / Chapter 1.1.1.2 --- Chemotherapy --- p.3 / Chapter 1.1.1.3 --- Radiotherapy --- p.3 / Chapter 1.1.1.4 --- Hormonal therapy --- p.4 / Chapter 1.1.2 --- Hypoxia/reoxygenation and its correlation with treatment resistance --- p.5 / Chapter 1.1.3 --- Aim of the study --- p.6 / Chapter Chapter 2: --- The drug sensitivity in HepG2 cells and A431 cells / Chapter 2.1 --- Introduction --- p.8 / Chapter 2.1.1 --- Treatment of cancer --- p.8 / Chapter 2.1.2 --- Drug resistance --- p.9 / Chapter 2.2 --- Materials and Methods --- p.10 / Chapter 2.2.1 --- Cell culture --- p.10 / Chapter 2.2.2 --- Drugs --- p.10 / Chapter 2.2.3 --- MTT assay --- p.11 / Chapter 2.3 --- Results --- p.12 / Chapter 2.3.1 --- The drugs to which G10HR and G20HR cells were more resistant --- p.12 / Chapter 2.3.2 --- "The drugs of which GP, G10HR and G20HR cells have similar response" --- p.12 / Chapter 2.3.3 --- The drugs to which A10HR and A20HR cells were more resistant --- p.17 / Chapter 2.3.4 --- The drugs to which A10HR and/or A20HR cells were more sensitive --- p.17 / Chapter 2.3.5 --- "The drugs which AP, A10HR and A20HR cells have similar response" --- p.18 / Chapter 2.4 --- Discussion --- p.24 / Chapter 2.4.1 --- Camptothecin and 10-hydroxy camptothecin --- p.27 / Chapter 2.4.2 --- Etoposide --- p.30 / Chapter 2.4.3 --- Hydrogen peroxide --- p.32 / Chapter 2.4.4 --- Interferons --- p.32 / Chapter 2.4.4.1 --- Interferon alpha --- p.33 / Chapter 2.4.4.2 --- Interferon gamma --- p.34 / Chapter 2.4.5 --- Methotrexate --- p.35 / Chapter 2.4.6 --- Vincristine --- p.36 / Chapter Chapter 3: --- The resistance mechanism of doxorubicin in A431 cells / Chapter 3.1 --- Introduction --- p.38 / Chapter 3.1.1 --- Chemotherapeutic resistance --- p.38 / Chapter 3.1.2 --- Tumor hypoxia --- p.39 / Chapter 3.1.3 --- Structure and function of doxorubicin --- p.39 / Chapter 3.1.4 --- Clinical use of doxorubicin --- p.40 / Chapter 3.1.5 --- Mechanisms of doxorubicin resistance --- p.41 / Chapter 3.1.6 --- Structure and function of P-glycoprotein --- p.42 / Chapter 3.1.7 --- Drug resistance contributed by P-glycoprotein and the solution --- p.43 / Chapter 3.1.8 --- Epigenetic modulation of mdr1 --- p.45 / Chapter 3.2 --- Materials and Methods --- p.47 / Chapter 3.2.1 --- Cell culture --- p.47 / Chapter 3.2.2 --- MTT assay --- p.47 / Chapter 3.2.3 --- Reverse transcription polymerase chain reaction (RT-PCR) --- p.47 / Chapter 3.2.4 --- Western blot analysis --- p.48 / Chapter 3.2.5 --- Doxorubicin efflux assay --- p.50 / Chapter 3.2.6 --- Drug sensitivity of A431 cells treated with verapamil --- p.50 / Chapter 3.2.7 --- Treatment with DNA methyltransferase inhibitor --- p.51 / Chapter 3.2.8 --- Drug sensitivity of A431 cells treated with 5-Aza-dC --- p.51 / Chapter 3.2.9 --- Methylation-specific PCR (MSP) --- p.51 / Chapter 3.2.10 --- Bisulfite genomic DNA sequencing --- p.52 / Chapter 3.3 --- Results --- p.54 / Chapter 3.3.1 --- Drug sensitivity of A431 cells to doxorubicin --- p.54 / Chapter 3.3.2 --- Expression profile of mdrl and P-glycoprotein in A431 cells --- p.54 / Chapter 3.3.3 --- Dox efflux-pump activity in A431 cells --- p.57 / Chapter 3.3.4 --- Drug sensitivity of A431 cells in the presence of verapamil --- p.59 / Chapter 3.3.5 --- Expression profile of mdrl in A431 cells in the presence of 5- Aza-dC --- p.59 / Chapter 3.3.6 --- Drug sensitivity of A431 cells in the presence of 5-Aza-dC --- p.62 / Chapter 3.3.7 --- Methylation status of mdrl promoter region --- p.64 / Chapter 3.3.8 --- Bisulfite genomic DNA sequencing of the mdrl promoter --- p.64 / Chapter 3.4 --- Discussion --- p.67 / Chapter Chapter 4: --- The resistance mechanism of cisplatin in HepG2 cells / Chapter 4.1 --- Introduction --- p.70 / Chapter 4.1.1 --- Tumor hypoxia and chemotherapeutic resistance --- p.70 / Chapter 4.1.2 --- Cisplatin and its action mechanism --- p.71 / Chapter 4.1.3 --- Mechanisms of cisplatin resistance --- p.74 / Chapter 4.1.4 --- Mismatch repair genes --- p.79 / Chapter 4.1.5 --- Epigenome and drug resistance in cancer --- p.80 / Chapter 4.2 --- Materials and Methods --- p.84 / Chapter 4.2.1 --- Cell culture --- p.84 / Chapter 4.2.2 --- MTT assay --- p.84 / Chapter 4.2.3 --- Reverse transcription polymerase chain reaction (RT-PCR) --- p.84 / Chapter 4.2.4 --- Oligonucleotide transfection --- p.85 / Chapter 4.2.5 --- Treatment with DNA methyltransferase inhibitor --- p.86 / Chapter 4.2.6 --- Drug sensitivity of HepG2 cells treated with 5-Aza-dC --- p.87 / Chapter 4.2.7 --- Treatment with histone deacetylase inhibitor --- p.87 / Chapter 4.2.8 --- Drug sensitivity of HepG2 cells treated with TSA --- p.87 / Chapter 4.3 --- Results --- p.89 / Chapter 4.3.1 --- Drug sensitivity of HepG2 cells to cisplatin --- p.89 / Chapter 4.3.2 --- Expression profile of the MMR genes in HepG2 cells --- p.89 / Chapter 4.3.3 --- Drug sensitivity of HepG2 cells to cisplatin after the knock- down of PMS2 --- p.91 / Chapter 4.3.4 --- Expression profile of MMR genes in the presence of 5-Aza-dC --- p.95 / Chapter 4.3.5 --- Drug sensitivity of HepG2 cells to cisplatin after the addition of 5-Aza-dC --- p.95 / Chapter 4.3.6 --- Expression profile of MMR genes in the presence of trichostatin A --- p.98 / Chapter 4.3.7 --- Sensitivity of HepG2 cells to cisplatin after the addition of trichostatin A --- p.98 / Chapter 4.4 --- Discussion --- p.101 / Chapter Chapter 5: --- The role of PMS2 in cisplatin-induced apoptosis / Chapter 5.1 --- Introduction --- p.105 / Chapter 5.1.1 --- Apoptosis --- p.105 / Chapter 5.1.2 --- Extrinsic pathway of apoptosis --- p.106 / Chapter 5.1.3 --- Intrinsic pathway of apoptosis --- p.106 / Chapter 5.1.4 --- Cisplatin-induced apoptosis --- p.107 / Chapter 5.1.5 --- MMR and apoptosis --- p.109 / Chapter 5.2 --- Materials and Methods --- p.111 / Chapter 5.2.1 --- Cell culture --- p.111 / Chapter 5.2.2 --- Flow cytometric analysis of apoptosis --- p.111 / Chapter 5.2.3 --- Oligonucleotide transfection --- p.111 / Chapter 5.2.4 --- Western blot analysis --- p.111 / Chapter 5.2.5 --- Drug and antibodies --- p.112 / Chapter 5.3 --- Results --- p.113 / Chapter 5.3.1 --- Cisplatin induced apoptosis --- p.113 / Chapter 5.3.2 --- Knockdown of PMS2 by siRNA --- p.113 / Chapter 5.3.3 --- Cisplatin-induced apoptosis involved caspases --- p.115 / Chapter 5.3.4 --- Protein expressions of anti-apoptotic genes --- p.119 / Chapter 5.3.5 --- Protein expressions of pro-apoptotic genes --- p.119 / Chapter 5.3.6 --- Protein expressions of apoptotic proteins after knockdown of PMS2 --- p.122 / Chapter 5.4 --- Discussion --- p.124 / Chapter Chapter 6: --- General discussion and conclusion / Chapter 6.1 --- Diverse sensitivity for hypoxia/reoxygenation treated cells to anticancer drugs --- p.128 / Chapter 6.2 --- Resistance mechanism of doxorubicin in A10HR and A20HR cells --- p.129 / Chapter 6.3 --- Resistance mechanism of cisplatin in G10HR and G20HR cells --- p.129 / Chapter 6.4 --- The role of PMS2 as a direct signaling molecule and the alteration of apoptotic proteins in cisplatin-induced apoptosis --- p.130 / Chapter 6.5 --- Future work --- p.131 / References --- p.132

Se evaluó el efecto del tiempo de exposición a las grandes alturas sobre la oxidación de proteínas y lípidos del tejido cerebral de cobayos nativos del nivel del mar trasladados a las grandes alturas (Morococha, 4540 m), y sacrificados los días 1, 3, 7 y 14 después de su arribo. Se determinó los niveles medios de cuerpos carbonílicos (CC), malondialdehído (MDA) e hidroperóxidos lipídicos (LOOH) como marcadores de la oxidación de proteínas y lípidos respectivamente; así como, las actividades de las enzimas antioxidantes superóxido dismutasa (SOD), catalasa (CAT) y glutation peroxidasa (GPx) y fosfolipasa A2 (FLA2) como mediadora de la peroxidación lipídica. Se encontró niveles de CC, LOOH y MDA incrementados al primer día; CC disminuyó por debajo del control al tercer día, LOOH mantuvo la tendencia a disminuir y MDA mantuvo sus niveles altos. Las actividades de las enzimas antioxidantes: GPx y CAT incrementaron desde el primer día; la actividad de SOD aumentó hasta el tercer día disminuyendo posteriormente; la actividad de FLA2 aumentó hasta el tercer día. Los resultados indican que la exposición por diferentes tiempos a las grandes alturas influye directamente en el proceso de oxidación de proteínas y lípidos. La disminución de los niveles de CC podría deberse a la activación del sistema proteolítico, en especial de las proteasas dependientes de Ca+2 como las calpaínas o del sistema proteasomal, las cuales degradarían las proteínas dañadas por las EROs. La exposición a la altura influye además en la actividad de las enzimas antioxidantes, especialmente en GPx, que juega un rol importante en la detoxificación de LOOH, lo que explicaría la tendencia a disminuir al final del tiempo de estudio. / -- It was determined the effect of high-altitude exposition time (Morococha - 4540 m) on protein and lipid oxidation from brain of level-sea native guinea pig for different times (1,3,7 and 14 days). It was measured the level of carbonyl groups (CC), malondialdehyde (MDA) and lipids hydroperoxydes (LOOH) as protein and lipid oxidation markers respectively. Also, the activity of antioxidants enzymes superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and phospholipase A2 (PLA2) a mediator of lipid peroxidation were evaluated. The results showed an increase of the CC, LOOH and MDA levels during the first day; CC decreased below the control levels by the third day, LOOH level had a decrease trend in time and MDA kept its higher levels. The activity of both antioxidant enzymes GPx and CAT, increased since the first day. Moreover, the activity of SOD showed an increase up to third day followed by a decrease; the activity of PLA2 increased up to the third day. The dates recorded indicated that the expositions at altitudes for different times affect directly the oxidative process of both protein and lipid. The decrease on the CC level could be caused by the activation of the proteolytic system, especially the activation of calcium-dependent proteases as calpains or the proteasomal system which could degrade damaged proteins by EROs. The exposition of altitude might affect the activity of antioxidant enzymes, especially GPx, which could play an important role in the detoxification of LOOH. / Tesis

Little is known about the physiology or biochemistry of hypoxia (reduced levels of oxygen) tolerance during development in vertebrate embryos. In most species, relatively brief bouts of severe hypoxia are lethal or teratogenic. An exception to such hypoxia intolerance is the annual killifish Austrofundulus limnaeus, in which populations persist in hypoxic environments. This species inhabits seasonal ponds in Venezuela, surviving through the dry season in the form of diapausing embryos. Embedded in the pond sediment, embryos of A. limnaeus are routinely exposed to hypoxia and anoxia (lack of oxygen) as part of their normal development. Here, we exposed embryos to various levels of PO2 (21.2, 15.6, 10.8, 8.4, 6.1, 3.6, and 2.2 kPa) at two different temperatures (25°C and 30°C) to study the effects on developmental rate and heart rate. We also measured enzyme activity and quantified DNA content of individual embryos to compare differences among the varying levels of hypoxia and temperature. Hypoxia caused a significant decline in developmental rate and caused a stage-specific decline in heart rate. Higher temperature caused an increase in the developmental rate for those embryos incubated at PO2 of 6.1 kPa and greater. Temperature had a negative effect by hindering development below a PO2 of 6.1 kPa. Total embryonic DNA content was reduced at low partial pressures (15.6, 10.8, 8.4, 6.1, 3.6, and 2.2 kPa) of oxygen. Citrate synthase, lactate dehydrogenase, and phosphoenolpyruvate carboxykinase were all down-regulated indicating a complete lack of enzymatic metabolic compensation to combat reduced oxygen levels.

Embryos of the annual killifish Austrofundulus limnaeus display a remarkable tolerance to anoxia during development, most notably during embryonic diapause. Little is known about the metabolic or enzymatic changes that accompany this state of anoxia tolerance. This study examined the metabolic changes associated with exposure to anoxia by measuring the activity of the enzyme phosphoenolpyruvate carboxykinase (PEPCK), and by profiling the concentration of 31 metabolites ranging from amino acids to citric cycle intermediates at 4 different developmental stages, diapause 2 (DII), 4 days post diapause (dpd), 12 and 22 dpd. Embryos of A. limnaeus showed stage specific changes in concentrations of several metabolites. The most notable changes in metabolite concentration in response to anoxia were the increases of lactate, alanine, GABA and succinate as well as a pronounced decrease in aspartate concentrations. However, a complete understanding of the mechanisms by which anoxia tolerance is achieved remains elusive. Further studies into the tissue specific responses of anoxia would enable greater resolution when attempting to explain changes in concentrations of metabolites both during development and in response to anoxic insult.

Very few vertebrates survive extended periods of time without oxygen. Entry into metabolic depression is central to surviving anoxia, which is supported by overall suppression of protein synthesis, yet requires increased expression of specific proteins. Studying the rapid and complex regulation of gene expression associated with survival of anoxia may uncover new mechanisms of cellular biology and transform our understanding of cells, as well as inform prevention and treatment of heart attack and stroke in humans. Small non-coding RNAs (sncRNAs) have emerged as regulators of gene expression that can be rapidly employed, can target individual genes or suites of genes, and are highly conserved across species. There are diverse types of sncRNAs, some coopted from degradation of longer RNAs in the cell. The sncRNA revolution has yielded a large body of literature revealing the roles of sncRNAs in a myriad of biological processes, from development to regulation of the cell cycle and apoptosis, to responding to stress, including freezing, dehydration, ischemia, and anoxia. Given the regulatory complexity required to survive anoxia, examining sncRNAs in the context of extreme anoxia tolerance has the potential to expand our understanding of the role that sncRNAs may play in basic cell biology, as well as in response to stresses such as anoxia. A comparative model including anoxia-tolerant and anoxia-sensitive phenotypes allows us to better identify sncRNAs that likely play a critical role in anoxia tolerance. Embryos of A. limnaeus are the most anoxia tolerant vertebrate known and are comprised of a range of anoxia-tolerance phenotypes. These characteristics create a unique opportunity for comparative study of the role of sncRNAs in anoxia tolerance in phenotypes with a common genomic background. The overall goals of this project were to: (1) describe the sncRNA transcriptome and changes in its expression in response to anoxia in the embryos of A. limnaeus and in other anoxia-tolerant vertebrates, and (2) to identify specific sncRNAs of interest based on these sequencing projects and to follow-up on their biogenesis, localization, and function in A. limnaeus embryos and a continuous cell line derived from A. limnaeus embryos. Chapter 2 focuses on the identity and expression of sncRNAs in embryos of A. limnaeus in 4 embryonic stages that differ in their anoxia tolerance and physiology. Chapter 3 explores sncRNA expression in brain tissue (the most oxygen-sensitive organ) in other anoxia-tolerant vertebrates: the crucian carp, western painted turtle, leopard frog, and epaulette shark. This allows us to assess the similarities and differences in sncRNA biology in species that evolved anoxia independently, and put the findings from A. limnaeus in an evolutionary context. Chapter 4 describes the establishment of the AL4 anoxia-tolerant cell line derived from A. limnaeus embryos, which allows for more detailed study of particular sncRNAs of interest in Chapter 5. Using whole embryos of A. limnaeus and the AL4 cell line, Chapter 5 describes the expression, localization, and possible biogenesis and mechanism of action of mitochondria-derived sncRNAs, known as mitosRNAs. Chapter 6 summarizes the findings and discusses potential future directions. The work in this dissertation represents the first global survey of sncRNA expression in anoxia tolerant vertebrates. While many interesting patterns of expression were identified, the most interesting discovery is the expression of sncRNAs that are generated in the mitochondria, but have the potential to function in other compartments of the cell. This discovery could transform the way we view the role of the mitochondria in regulating gene expression in eukaryotic cells.

Thesis (Ph. D.)--West Virginia University, 2006. / Title from document title page. Document formatted into pages; contains vi, 156 p. : ill. (some col.). Includes abstract. Includes bibliographical references.

Se evaluó el efecto del tiempo de exposición a las grandes alturas sobre la oxidación de proteínas y lípidos del tejido cerebral de cobayos nativos del nivel del mar trasladados a las grandes alturas (Morococha, 4540 m), y sacrificados los días 1, 3, 7 y 14 después de su arribo. Se determinó los niveles medios de cuerpos carbonílicos (CC), malondialdehído (MDA) e hidroperóxidos lipídicos (LOOH) como marcadores de la oxidación de proteínas y lípidos respectivamente; así como, las actividades de las enzimas antioxidantes superóxido dismutasa (SOD), catalasa (CAT) y glutation peroxidasa (GPx) y fosfolipasa A2 (FLA2) como mediadora de la peroxidación lipídica. Se encontró niveles de CC, LOOH y MDA incrementados al primer día; CC disminuyó por debajo del control al tercer día, LOOH mantuvo la tendencia a disminuir y MDA mantuvo sus niveles altos. Las actividades de las enzimas antioxidantes: GPx y CAT incrementaron desde el primer día; la actividad de SOD aumentó hasta el tercer día disminuyendo posteriormente; la actividad de FLA2 aumentó hasta el tercer día. Los resultados indican que la exposición por diferentes tiempos a las grandes alturas influye directamente en el proceso de oxidación de proteínas y lípidos. La disminución de los niveles de CC podría deberse a la activación del sistema proteolítico, en especial de las proteasas dependientes de Ca+2 como las calpaínas o del sistema proteasomal, las cuales degradarían las proteínas dañadas por las EROs. La exposición a la altura influye además en la actividad de las enzimas antioxidantes, especialmente en GPx, que juega un rol importante en la detoxificación de LOOH, lo que explicaría la tendencia a disminuir al final del tiempo de estudio. / It was determined the effect of high-altitude exposition time (Morococha - 4540 m) on protein and lipid oxidation from brain of level-sea native guinea pig for different times (1,3,7 and 14 days). It was measured the level of carbonyl groups (CC), malondialdehyde (MDA) and lipids hydroperoxydes (LOOH) as protein and lipid oxidation markers respectively. Also, the activity of antioxidants enzymes superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and phospholipase A2 (PLA2) a mediator of lipid peroxidation were evaluated. The results showed an increase of the CC, LOOH and MDA levels during the first day; CC decreased below the control levels by the third day, LOOH level had a decrease trend in time and MDA kept its higher levels. The activity of both antioxidant enzymes GPx and CAT, increased since the first day. Moreover, the activity of SOD showed an increase up to third day followed by a decrease; the activity of PLA2 increased up to the third day. The dates recorded indicated that the expositions at altitudes for different times affect directly the oxidative process of both protein and lipid. The decrease on the CC level could be caused by the activation of the proteolytic system, especially the activation of calcium-dependent proteases as calpains or the proteasomal system which could degrade damaged proteins by EROs. The exposition of altitude might affect the activity of antioxidant enzymes, especially GPx, which could play an important role in the detoxification of LOOH.

Se ha estudiado el efecto del ketoprofeno, un antiprostaglandínico bloqueador de la enzima ciclooxigenasa, sobre la presión arterial pulmonar media (PAPm) en 10 terneros Jersey, machos, de 1 a 2 meses de edad, nacidos a nivel del mar y expuestos durante 3 días a una hipoxia ambiental de 3 320m. de altitud; los cuales fueron divididos en 2 grupos de 5 animales cada uno: Grupo Control que recibió placebo y Grupo Tratamiento al que se le suministró ketoprofeno, en dosis de 3mg/kg de peso vivo, por 5 días consecutivos, durante su estadía a nivel del mar. La PAPm se determinó mediante la técnica de cateterismo cardiaco a nivel del mar y al tercer día de su arribo a dicha altitud. Los valores promedio de la PAPm (mmHg) a nivel del mar fueron de 19,00 ± 0,94 para el Grupo Control y 21,00 ± 3,39 para el Grupo Tratamiento, y en la altura de 39,50 ± 6,00 para el Grupo Control y 31,25 ± 5,70 para el Grupo tratamiento. Al no existir diferencia por efecto del ketoprofeno, se analizaron ambos grupos en conjunto obteniéndose los siguientes resultados de la PAPm: A nivel del mar 20,00 ± 2,68 y al tercer día de exposición a la altura 35,28 ± 7,16. Estos resultados nos inducen a sugerir que el ketoprofeno no tuvo efecto significativo (p>0.05) sobre la PAPm en los terneros Jersey sometidos durante 3 días a la hipoxia de la altura; sin embargo sólo la exposición a dicha hipoxia incrementó significativamente (p≤0.05) la PAPm. / The effect of ketoprofen, an antiprostaglandin sustance that inhibits the enzyme ciclooxigenase, had been studied on the mean pulmonary arterial pressure (mPAP) in 10 Jersey, male calves, from 1 to 2 months old. They were born at sea level and exposed during 3 days to a environmental hypoxia of 3 320m. of altitude and were divided in 2 groups of 5 animals each: Control Group which received destiled water as placebo, and Treatment Group which received ketoprofen in dose of 3mg/kg body weight for 5 consecutive days during its permanence at sea level. The mPAP was determinated by cardiac cateterism at sea level and 3 days after arriving to altitude. The mean values of mPAP (mmHg) at sea level were: Control Group 19,00 ± 0,94 and Treatment Group 21,00 ± 3,39; whereas at the altitude were: Control Group 39,50 ± 6,00 and Treatment Group 31,25 ± 5,70. Since there was not significative effect due to ketoprofen, the two groups were joined and analysed together, obtaining the following values for mPAP: At sea level 20,00 ± 2,68 and at day 3 of exposition to altitude 35,28 ± 7,16. These results induce us to sugest that ketoprofen have not significative effect (p>0.05) on the mPAP in Jersey calves exposed during 3 days at altitude hypoxia, however just the effect of this hypoxia increased significatively (p≤0.05) the mPAP.