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Perkowski S Scherpereel A Murciano JC Arguiri E Solomides CC Albelda SM Muzykantov V Christofidou-Solomidou M 《American journal of physiology. Lung cellular and molecular physiology》2006,291(5):L1050-L1058
The objective of this study was to quantitatively assess changes in cell adhesion molecule (CAM) expression on the pulmonary endothelial surface during hyperoxia and to assess the functional significance of those changes on cellular trafficking and development of oxygen-induced lung injury. Mice were placed in >95% O(2) for 0-72 h, and pulmonary injury and neutrophil (PMN) sequestration were assessed. Specific pulmonary CAM expression was quantified with a dual-radiolabeled MAb technique. To test the role of CAMs in PMN trafficking during hyperoxia, blocking MAbs to murine P-selectin, ICAM-1, or platelet-endothelial cell adhesion molecule-1 (PECAM-1) were injected in wild-type mice. Mice genetically deficient in these CAMs and PMN-depleted mice were also evaluated. PMN sequestration occurred within 8 h of hyperoxia, although alveolar emigration occurred later (between 48 and 72 h), coincident with rapid escalation of the lung injury. Hyperoxia significantly increased pulmonary uptake of radiolabeled antibodies to P-selectin, ICAM-1, and PECAM-1, reflecting an increase in their level on pulmonary endothelium and possibly sequestered blood cells. Although both anti-PECAM-1 and anti-ICAM-1 antibodies suppressed PMN alveolar influx in wild-type mice, only mice genetically deficient in PECAM-1 showed PMN influx suppression. Neither CAM blockade, nor genetic deficiency, nor PMN depletion attenuated lung injury. We conclude that early pulmonary PMN retention during hyperoxia is not temporally associated with an increase in endothelial CAMs; however, subsequent PMN emigration into the alveolar space may be supported by PECAM-1 and ICAM-1. Blocking PMN recruitment did not prevent lung injury, supporting dissociation between PMN infiltration and lung injury during hyperoxia in mice. 相似文献
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Christofidou-Solomidou M Scherpereel A Wiewrodt R Ng K Sweitzer T Arguiri E Shuvaev V Solomides CC Albelda SM Muzykantov VR 《American journal of physiology. Lung cellular and molecular physiology》2003,285(2):L283-L292
Targeted delivery of drugs to vascular endothelium promises more effective and specific therapies in many disease conditions, including acute lung injury (ALI). This study evaluates the therapeutic effect of drug targeting to PECAM (platelet/endothelial cell adhesion molecule-1) in vivo in the context of pulmonary oxidative stress. Endothelial injury by reactive oxygen species (e.g., H2O2) is involved in many disease conditions, including ALI/acute respiratory distress syndrome and ischemia-reperfusion. To optimize delivery of antioxidant therapeutics, we conjugated catalase with PECAM antibodies and tested properties of anti-PECAM/catalase conjugates in cell culture and mice. Anti-PECAM/catalase, but not an IgG/catalase counterpart, bound specifically to PECAM-expressing cells, augmented their H2O2-degrading capacity, and protected them against H2O2 toxicity. Anti-PECAM/catalase, but not IgG/catalase, rapidly accumulated in the lungs after intravenous injection in mice, where it was confined to the pulmonary endothelium. To test its protective effect, we employed a murine model of oxidative lung injury induced by glucose oxidase coupled with thrombomodulin antibody (anti-TM/GOX). After intravenous injection in mice, anti-TM/GOX binds to pulmonary endothelium and produces H2O2, which causes lung injury and 100% lethality within 7 h. Coinjection of anti-PECAM/catalase protected against anti-TM/GOX-induced pulmonary oxidative stress, injury, and lethality, whereas polyethylene glycol catalase or IgG/catalase conjugates afforded only marginal protective effects. This result validates vascular immunotargeting as a prospective strategy for therapeutic interventions aimed at immediate protective effects, e.g., for augmentation of antioxidant defense in the pulmonary endothelium and treatment of ALI. 相似文献
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Greve G Alechine E Pasantes JJ Hodler C Rietschel W Robinson TJ Schempp W 《PloS one》2011,6(12):e29311
Background
We have previously demonstrated that the Y-specific ampliconic fertility genes DAZ (deleted in azoospermia) and CDY (chromodomain protein Y) varied with respect to copy number and position among chimpanzees (Pan troglodytes). In comparison, seven Y-chromosomal lineages of the bonobo (Pan paniscus), the chimpanzee''s closest living relative, showed no variation. We extend our earlier comparative investigation to include an analysis of the intraspecific variation of these genes in gorillas (Gorilla gorilla) and orangutans (Pongo pygmaeus), and examine the resulting patterns in the light of the species'' markedly different social and mating behaviors.Methodology/Principal Findings
Fluorescence in situ hybridization analysis (FISH) of DAZ and CDY in 12 Y-chromosomal lineages of western lowland gorilla (G. gorilla gorilla) and a single lineage of the eastern lowland gorilla (G. beringei graueri) showed no variation among lineages. Similar findings were noted for the 10 Y-chromosomal lineages examined in the Bornean orangutan (Pongo pygmaeus), and 11 Y-chromosomal lineages of the Sumatran orangutan (P. abelii). We validated the contrasting DAZ and CDY patterns using quantitative real-time polymerase chain reaction (qPCR) in chimpanzee and bonobo.Conclusion/Significance
High intraspecific variation in copy number and position of the DAZ and CDY genes is seen only in the chimpanzee. We hypothesize that this is best explained by sperm competition that results in the variant DAZ and CDY haplotypes detected in this species. In contrast, bonobos, gorillas and orangutans—species that are not subject to sperm competition—showed no intraspecific variation in DAZ and CDY suggesting that monoandry in gorillas, and preferential female mate choice in bonobos and orangutans, probably permitted the fixation of a single Y variant in each taxon. These data support the notion that the evolutionary history of a primate Y chromosome is not simply encrypted in its DNA sequences, but is also shaped by the social and behavioral circumstances under which the specific species has evolved. 相似文献16.
Evguenia Bouairi Robert Neff Cory Evans Allison Gold Michael C Andresen David Mendelowitz 《Journal of applied physiology》2004,97(4):1431-1436
Heart rate increases during inspiration and slows during postinspiration; this respiratory sinus arrhythmia helps match pulmonary blood flow to lung inflation and maintain an appropriate diffusion gradient of oxygen in the lungs. This cardiorespiratory pattern is found in neonatal and adult humans, baboons, dogs, rabbits, and seals. Respiratory sinus arrhythmia occurs mainly due to inhibition of cardioinhibitory parasympathetic cardiac vagal neurons during inspiration. Surprisingly, however, a recent study in anesthetized rats paradoxically found an enhancement of cardiac vagal activity during inspiration, suggesting that rats have an inverted respiratory sinus arrhythmia (Rentero N, Cividjian A, Trevaks D, Pequignot JM, Quintin L, and McAllen RM. Am J Physiol Regul Integr Comp Physiol 283: R1327-R1334, 2002). To address this controversy, this study examined respiratory sinus arrhythmia in conscious freely moving rats and tested whether the commonly used experimental anesthetics urethane, pentobarbital sodium, or ketamine-xylazine alter respiratory sinus arrhythmia. Heart rate significantly increased 21 beats/min during inspiration in conscious rats, a pattern similar to the respiratory sinus arrhythmia that occurs in other species. However, anesthetics altered normal respiratory sinus arrhythmia. Ketamine-xylazine (87 mg/kg and 13 mg/kg) depressed and pentobarbital sodium (60 mg/kg) abolished normal respiratory sinus arrhythmia. Urethane (1 g/kg) inverted the cardiorespiratory pattern so that heart rate significantly decreased during inspiration. Our study demonstrates that heart rate normally increases during inspiration in conscious, freely moving rats, similar to the respiratory sinus arrhythmia pattern that occurs in other species but that this pattern is disrupted in the presence of general anesthetics, including inversion in the case of urethane. The presence and consequences of anesthetics need to be considered in studying the parasympathetic control of heart rate. 相似文献
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Human immunodeficiency virus type 1 cDNAs produced in the presence of APOBEC3G exhibit defects in plus-strand DNA transfer and integration 总被引:12,自引:10,他引:2
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Mbisa JL Barr R Thomas JA Vandegraaff N Dorweiler IJ Svarovskaia ES Brown WL Mansky LM Gorelick RJ Harris RS Engelman A Pathak VK 《Journal of virology》2007,81(13):7099-7110
Encapsidation of host restriction factor APOBEC3G (A3G) into vif-deficient human immunodeficiency virus type 1 (HIV-1) blocks virus replication at least partly by C-to-U deamination of viral minus-strand DNA, resulting in G-to-A hypermutation. A3G may also inhibit HIV-1 replication by reducing viral DNA synthesis and inducing viral DNA degradation. To gain further insight into the mechanisms of viral inhibition, we examined the metabolism of A3G-exposed viral DNA. We observed that an overall 35-fold decrease in viral infectivity was accompanied by a five- to sevenfold reduction in viral DNA synthesis. Wild-type A3G induced an additional fivefold decrease in the amount of viral DNA that was integrated into the host cell genome and similarly reduced the efficiency with which HIV-1 preintegration complexes (PICs) integrated into a target DNA in vitro. The A3G C-terminal catalytic domain was required for both of these antiviral activities. Southern blotting analysis of PICs showed that A3G reduced the efficiency and specificity of primer tRNA processing and removal, resulting in viral DNA ends that are inefficient substrates for integration and plus-strand DNA transfer. However, the decrease in plus-strand DNA transfer did not account for all of the observed decrease in viral DNA synthesis associated with A3G. These novel observations suggest that HIV-1 cDNA produced in the presence of A3G exhibits defects in primer tRNA processing, plus-strand DNA transfer, and integration. 相似文献
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