Conselho Nacional de Desenvolvimento Científico e Tecnológico / O desenvolvimento de fibrose pulmonar (FP) induzida por bleomicina tem sido associado com as características genéticas e estresse oxidativo. Nosso objetivo foi investigar a influência do equilíbrio redox sobre a resistência a fibrose pulmonar induzida por bleomicina em diferentes linhagens de camundongos. Uma única dose de bleomicina (0,1 U/camundongo) ou salina (50 mL) foi administrada por via intratraqueal (i.t.) em camundongos C57BL/6, DBA/2 e camundongos BALB/c. Vinte e um dias após a administração de bleomicina, a taxa de mortalidade foi acima de 50% em camundongos C57BL/6 e 20% em DBA/2, enquanto não foi observada em BALB/c. Houve um aumento na elastância (p<0.001), &#916;P2 (p<0.05), &#916;Ptot (p<0.01) e DE,l (p<0.05) em camundongos C57BL/6. O volume dos septos aumentaram em camundongos C57BL/6 (p<0.05) e DBA/2 (p<0.001). Os níveis de INF-&#947; foram reduzidas em camundongos C57BL/6 (p<0.01). Níveis OH-prolina foram aumentados em camundongos C57BL/6 e DBA/2 (p<0.05). Atividade e expressão de SOD foram reduzidas em camundongos C57BL/6 e DBA/2 (p<0.001 e p<0.001, respectivamente), enquanto que a atividade de CAT reduziu em todas as linhagens (C57BL/6: p<0.05; DBA/2: p<0.01, BALB/c: p<0.01). A atividade da GPx e expressão GPx 1/2 diminuiram em camundongos C57BL/6 (p<0.001). Nós concluímos que a resistência da FP pode também estar relacionada com a atividade e expressão de SOD em camundongos BALB/c / The development of bleomycin-induced pulmonary fibrosis (PF) has been associated with differences in genetic background and oxidative stress status. Our aim was to investigate the cross-talk between the redox profile, lung architecture and function in PF in different mouse strains. A single dose of either bleomycin (0.1 U/mouse) or saline (50 &#956;L) was by intratracheal (i.t.) administration in C57BL/6, DBA/2 and BALB/c mice. Twenty-one days after bleomycin, the mortality rate was over 50% in C57BL/6 and 20% in DBA/2 mice and PF was not observed in BALB/c. There was an increase in Est (p<0.001), &#916;P2 (p<0.05), &#916;Ptot (p<0.01) and &#916;E (p<0.05) in C57BL/6 mice. Septa volume increase in C57BL/6 (p<0.05) and DBA/2 (p<0.001). The levels of INF-&#947; were reduced by in C57BL/6 mice (p <0.01). OH-proline levels were increased in C57BL/6 and DBA/2 mice (p<0.05). SOD activity and expression was reduced in C57BL/6 and DBA/2 mice (p<0.001 and p<0.001 respectively), whereas CAT was reduced in all strains 21 days following bleomycin when compared to saline groups (C57BL/6: p<0.05; DBA/2: p<0.01, BALB/c: p<0.01). GPx activity and GPx1/2 expression decreased in C57BL/6 (p<0.001). We conclude that the PF resistance may also be related to the activity and expression of SOD in BALB/c

Conselho Nacional de Desenvolvimento Científico e Tecnológico / O desenvolvimento de fibrose pulmonar (FP) induzida por bleomicina tem sido associado com as características genéticas e estresse oxidativo. Nosso objetivo foi investigar a influência do equilíbrio redox sobre a resistência a fibrose pulmonar induzida por bleomicina em diferentes linhagens de camundongos. Uma única dose de bleomicina (0,1 U/camundongo) ou salina (50 mL) foi administrada por via intratraqueal (i.t.) em camundongos C57BL/6, DBA/2 e camundongos BALB/c. Vinte e um dias após a administração de bleomicina, a taxa de mortalidade foi acima de 50% em camundongos C57BL/6 e 20% em DBA/2, enquanto não foi observada em BALB/c. Houve um aumento na elastância (p<0.001), &#916;P2 (p<0.05), &#916;Ptot (p<0.01) e DE,l (p<0.05) em camundongos C57BL/6. O volume dos septos aumentaram em camundongos C57BL/6 (p<0.05) e DBA/2 (p<0.001). Os níveis de INF-&#947; foram reduzidas em camundongos C57BL/6 (p<0.01). Níveis OH-prolina foram aumentados em camundongos C57BL/6 e DBA/2 (p<0.05). Atividade e expressão de SOD foram reduzidas em camundongos C57BL/6 e DBA/2 (p<0.001 e p<0.001, respectivamente), enquanto que a atividade de CAT reduziu em todas as linhagens (C57BL/6: p<0.05; DBA/2: p<0.01, BALB/c: p<0.01). A atividade da GPx e expressão GPx 1/2 diminuiram em camundongos C57BL/6 (p<0.001). Nós concluímos que a resistência da FP pode também estar relacionada com a atividade e expressão de SOD em camundongos BALB/c / The development of bleomycin-induced pulmonary fibrosis (PF) has been associated with differences in genetic background and oxidative stress status. Our aim was to investigate the cross-talk between the redox profile, lung architecture and function in PF in different mouse strains. A single dose of either bleomycin (0.1 U/mouse) or saline (50 &#956;L) was by intratracheal (i.t.) administration in C57BL/6, DBA/2 and BALB/c mice. Twenty-one days after bleomycin, the mortality rate was over 50% in C57BL/6 and 20% in DBA/2 mice and PF was not observed in BALB/c. There was an increase in Est (p<0.001), &#916;P2 (p<0.05), &#916;Ptot (p<0.01) and &#916;E (p<0.05) in C57BL/6 mice. Septa volume increase in C57BL/6 (p<0.05) and DBA/2 (p<0.001). The levels of INF-&#947; were reduced by in C57BL/6 mice (p <0.01). OH-proline levels were increased in C57BL/6 and DBA/2 mice (p<0.05). SOD activity and expression was reduced in C57BL/6 and DBA/2 mice (p<0.001 and p<0.001 respectively), whereas CAT was reduced in all strains 21 days following bleomycin when compared to saline groups (C57BL/6: p<0.05; DBA/2: p<0.01, BALB/c: p<0.01). GPx activity and GPx1/2 expression decreased in C57BL/6 (p<0.001). We conclude that the PF resistance may also be related to the activity and expression of SOD in BALB/c

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The geometry of an organ’s vascular system determines the blood flow distribution to tissues for exchange of gas and nutrients by determining its vascular resistance. The importance of vascular geometry is evident in the placenta, where insufficient fetoplacental vascularity elevates vascular resistance thereby impairing perfusion, leading to one of the most common and severe pregnancy complications, intrauterine growth restriction (IUGR). The mouse is becoming a widely used model for human placental development due to the increasing availability of mouse models thought to have a placental defect. Vascular geometry can now be imaged and quantified using micro-computed tomography (micro-CT) and results used to estimate resistance to blood flow. This thesis first describes the implementation of contrast agent perfusion and micro-CT imaging of the mouse fetoplacental vasculature throughout late gestation. Application of a vascular segmentation technique is then described and evaluated for quantification of the arterial fetoplacental tree. Normal fetoplacental vascular development in late gestation is described for two common mouse strains, CD1 and C57Bl6 (B6). In B6 placentas, both late gestational capillary growth and thinning of the interhaemal membrane were blunted relative to CD1. Analysis of CD1 and B6 tree geometry revealed a constant number of arterial segments throughout late gestation in both strains but expansion of arterial diameters in B6 only, resulting in decreased B6 arterial resistance and shear stress in late gestation. Strain dependence shows the importance of genetics in fetoplacental vascular development. Quantification of the arterial tree in a mouse model of maternal pre-pregnancy exposure to chemicals commonly found in cigarettes revealed an increase in vascular tortuousity and a reduced number of arteriole sized vessels. This led to an increase in vascular resistance and a predicted decrease in blood flow, which could contribute to the observed reduction in fetal weights. In future studies, the methods described herein can be used in phenotyping numerous mouse models which currently are suspected to have a placental vascular defect.

The geometry of an organ’s vascular system determines the blood flow distribution to tissues for exchange of gas and nutrients by determining its vascular resistance. The importance of vascular geometry is evident in the placenta, where insufficient fetoplacental vascularity elevates vascular resistance thereby impairing perfusion, leading to one of the most common and severe pregnancy complications, intrauterine growth restriction (IUGR). The mouse is becoming a widely used model for human placental development due to the increasing availability of mouse models thought to have a placental defect. Vascular geometry can now be imaged and quantified using micro-computed tomography (micro-CT) and results used to estimate resistance to blood flow. This thesis first describes the implementation of contrast agent perfusion and micro-CT imaging of the mouse fetoplacental vasculature throughout late gestation. Application of a vascular segmentation technique is then described and evaluated for quantification of the arterial fetoplacental tree. Normal fetoplacental vascular development in late gestation is described for two common mouse strains, CD1 and C57Bl6 (B6). In B6 placentas, both late gestational capillary growth and thinning of the interhaemal membrane were blunted relative to CD1. Analysis of CD1 and B6 tree geometry revealed a constant number of arterial segments throughout late gestation in both strains but expansion of arterial diameters in B6 only, resulting in decreased B6 arterial resistance and shear stress in late gestation. Strain dependence shows the importance of genetics in fetoplacental vascular development. Quantification of the arterial tree in a mouse model of maternal pre-pregnancy exposure to chemicals commonly found in cigarettes revealed an increase in vascular tortuousity and a reduced number of arteriole sized vessels. This led to an increase in vascular resistance and a predicted decrease in blood flow, which could contribute to the observed reduction in fetal weights. In future studies, the methods described herein can be used in phenotyping numerous mouse models which currently are suspected to have a placental vascular defect.