Birthweight, early passive respiratory system mechanics, and ventilator requirements as predictors of outcome in premature infants with respiratory failure.

Early respiratory mechanics have been reported to predict outcome in newborns with respiratory failure. However, it remains unknown whether measurements of pulmonary function add significantly to the predictive value of more readily available variables The present study was designed to answer this question. Passive respiratory system mechanics were measured by an airway occlusion technique in 104 ventilator-dependent premature infants between 6 and 48 hours of life and corrected for infant size. A ventilation index [FiO2 x mean airway pressure (MAP)] was calculated at the time of pulmonary function testing. Poor outcome was defined as death from respiratory failure or need for supplemental oxygen at 28 days. Stepwise logistic function regression examined whether ventilation index and respiratory mechanics added predictive power over and above birthweight. Five infants died, and 45 patients required supplemental oxygen at 28 days. Birthweight was a strong predictor and would have entered the logistic model first in any case. Ventilation index added significantly to the predictive model (P = 0.038). Respiratory system conductance (P = 0.15) and compliance (P = 0.93) entered on the third and last step, respectively. We conclude that in premature infants with respiratory failure, birthweight is a strong predictor of outcome. Early ventilator requirements but not respiratory system mechanics, add significantly to this predictive model.     

The docking protein FRS2α is a critical regulator of VEGF receptors signaling

Vascular endothelial growth factors (VEGFs) signal via their cognate receptor tyrosine kinases designated VEGFR1-3. We report that the docking protein fibroblast growth factor receptor substrate 2 (FRS2α) plays a critical role in cell signaling via these receptors. In vitro FRS2α regulates VEGF-A and VEGF-C–dependent activation of extracellular signal-regulated receptor kinase signaling and blood and lymphatic endothelial cells migration and proliferation. In vivo endothelial-specific deletion of FRS2α results in the profound impairment of postnatal vascular development and adult angiogenesis, lymphangiogenesis, and arteriogenesis. We conclude that FRS2α is a previously unidentified component of VEGF receptors signaling.Vascular endothelial growth factors (VEGFs) are key regulators of blood and lymphatic vessel development and homeostasis. The absence of VEGF-A during development results in a complete failure of blood vasculature formation (1), whereas VEGF-C knockout abolishes lymphangiogenesis (2). Both VEGF-A and VEGF-C play equally critical roles in postnatal formation and maintenance of various blood and lymphatic vessel beds (3–6). The two VEGFs signal via, respectively, the two receptor tyrosine kinases (RTK) VEGFR2 and VEGFR3 with the former primarily expressed in the arterial and venous vasculature and the latter in the lymphatic vasculature in adult tissues (7). The other VEGF receptor, VEGFR1, is thought to function largely as a “decoy” receptor in endothelial cells but can transmit signaling in mononuclear cells (7).All VEGF receptors share a number of structural similarities including an extracellular ligand binding domain, a single transmembrane region, and a cytoplasmic domain containing a tyrosine kinase domain with an insert region. Receptor activation requires ligand-induced dimerization that results in autophosphorylation of cytoplasmic tyrosines that serve as binding sites for various signaling proteins. In the case of VEGF-A receptor, VEGFR2 phosphorylation of Y¹⁰⁵⁴/Y¹⁰⁵⁹ is required for maximal VEGFR2 kinase activity that leads to phosphorylation of Y¹¹⁷⁵ (a phospholipase Cγ1 binding site also required for ERK activation) and Y⁹⁵¹ (a TSAd binding site leading to Src activation) among others (7). VEGF-C signals via VEGFR3 in a similar manner.In the course of studying fibroblast growth factor (FGF) signaling, we noticed that an endothelial knockdown or deletion of a scaffold protein FRS2α, known to be involved in FGF and neural growth factor (NGF) receptor signaling (8–10), also affects VEGF signaling. FRS2α is a docking protein that contains an N-terminal myristylation site, a PTB domain, and a large C-terminal tail that contains four binding sites for the SH2 domain of the adaptor protein Grb2 and two binding sites for the SH2 domain of the tyrosine phosphatase Shp2 (11). Tyrosine phosphorylation of FRS2α at these binding sites leads to activation of MAPK signaling (12).In this study, we found that FRS2α plays a central role in regulation of VEGF signaling in blood and lymphatic endothelial cells. Its deletion profoundly reduced VEGF signaling in vitro and in vivo and resulted in impairment of postnatal vascular development and adult angiogenesis, lymphangiogenesis, and arteriogenesis.     

The role of hypothalamic estrogen receptors in metabolic regulation

Estrogens regulate key features of metabolism, including food intake, body weight, energy expenditure, insulin sensitivity, leptin sensitivity, and body fat distribution. There are two ‘classical’ estrogen receptors (ERs): estrogen receptor alpha (ERS1) and estrogen receptor beta (ERS2). Human and murine data indicate ERS1 contributes to metabolic regulation more so than ESR2. For example, there are human inactivating mutations of ERS1 which recapitulate aspects of the metabolic syndrome in both men and women. Much of our understanding of the metabolic roles of ERS1 was initially uncovered in estrogen receptor α-null mice (ERS1^−/−); these mice display aspects of the metabolic syndrome, including increased body weight, increased visceral fat deposition and dysregulated glucose intolerance. Recent data further implicate ERS1 in specific tissues and neuronal populations as being critical for regulating food intake, energy expenditure, body fat distribution and adipose tissue function. This review will focus predominantly on the role of hypothalamic ERs and their critical role in regulating all aspects of energy homeostasis and metabolism.     

Caveolin-1下调细胞外调节蛋白激酶1/2抑制血管吻合口再狭窄

目的 探讨Caveolin-1对新西兰兔颈总动脉血管吻合口再狭窄的作用,以及与细胞外调节蛋白激酶(extracellular regulated protein kinases,ERK)的关系.方法 40只新西兰兔,随机分为正常对照组、手术组、空转染组和Caveolin-1转染组.行左侧颈总动脉血管端端吻合,并局部转染Caveolin-1质粒(转染组)或空质粒(空转染组).于术后第7天各组中分别取5只新西兰兔血管标本,用于Western blot和逆转录-聚合酶链反应(RT-PCR)检测蛋白和mRNA的表达;其余新西兰兔于术后28 d处死取颈总动脉,通过HE染色观察内膜增生情况,用Image-Pro Plus6.0软件测量内膜与中膜面积比值(IA/MA).结果 血管HE染色后测量内膜与中膜面积比值:Caveolin-1转染组的血管内膜/中膜面积比值较手术组降低约50％;与手术组比较,转染组Caveolin-1的mRNA和蛋白的表达明显升高,差异有统计学意义(t=36.59,P＜0.01);而在高表达Caveolin-1的血管吻合口上,ERK1/2的mRNA的表达以及蛋白质的活性都显著低于手术组(t值分别为:32.64和7.28,两者均P＜0.01).结论 Caveolin-1抑制吻合口再狭窄的作用可能与调节ERK1/2的活化有关.     

MK2 plays an important role for the increased vascular permeability that follows thermal injury

We previously reported Rho kinase is involved in vessel hyper-permeability caused by burns. Here we further explore the Rho kinase downstream signaling, it is found that its specific inhibitor Y27632 significantly diminishes the activation of JNK and p38 MAPKs but not ERK that induced by serum from burned rats (burn-serum). JNK activation was found involved in the expression of HUVEC adhesion molecules following thermal injury, although not in the process of stress fiber formation. Inhibition of various MAPKs by specific inhibitors showed that SB203580 (inhibitor of p38), but neither SP600125 (inhibitor of JNK) nor PD98059 (inhibitor of ERK), abolish activation of the p38 downstream kinase MK2. Demonstration of stress fibers by fluorescent-labeled phalloidin showed that inhibition of MK2, either by its specific inhibitor or by dominant negative adeno-viral-carried constructs, significantly reduced burn-serum-induced HUVEC stress-fiber formation, while inhibition of another downstream p38 MAPK kinase, PRAK, had no such effects. Transfection of dominant negative adeno-viral MK2 (Ad-MK2(A)) significantly inhibited thermal injury-induced blood vessel hyper-permeability in rats and, moreover, prolonged the survival of burned rats beyond 72 h following thermal injury. One of the mechanisms behind these phenomena is that Ad-MK2(A) causes a significant depression of burn-serum-induced HSP27-phosphorylation, while the adeno-viral transported dominant negative PRAK (Ad-PRAK(A)) does not block. Although the effect of blockade of MK2 through its adeno-viral approach requires further study and investigation of alternatives to know for sure, we may have found a new pathway behind thermal-injury-induced blood vessel hyper-permeability, namely: Rho kinase > p38 > MK2 > HSP27.