Panfoli Isabella, Cassanello Michela, Bruschettini Matteo, Colella Marina, Cerone Roberto, Ravera Silvia, Calzia Daniela, Candiano Giovanni, Ramenghi Luca
Dipartimento di Farmacia, Laboratorio di Biochimica, Università di Genova, Genoa, Italy.
Neonatal Intensive Care Unit, Istituto Giannina Gaslini, Genova, Italy.
Med Hypotheses. 2016 May;90:53-6. doi: 10.1016/j.mehy.2016.03.007. Epub 2016 Mar 12.
Our preliminary data show high levels of adenosine in the blood of very low birth weight (VLBW) infants, positively correlating to their prematurity (i.e. body weight class). This prompted us to look for a mechanism promoting such impressive adenosine increase. We hypothesized a correlation with oxygen challenge. In fact, it is recognized that either oxygen lack or its excess contribute to the pathogenesis of the injuries of prematurity, such as retinopathy (ROP) and periventricular white matter lesions (PWMI). The optimal concentration of oxygen for resuscitation of VLBW infants is currently under revision. We propose that the elevated adenosine blood concentrations of VLBW infants recognizes two sources. The first could be its activity-dependent release from unmyelinated brain axons. Adenosine in this respect would be an end-product of the hypometabolic VLBW newborn unmyelinated axon intensely firing in response to the environmental stimuli consequent to premature birth. Adenosine would be eventually found in the blood due to blood-brain barrier immaturity. In fact, adenosine is the primary activity-dependent signal promoting differentiation of premyelinating oligodendrocyte progenitor cells (OPC) into myelinating cells in the Central Nervous System, while inhibiting their proliferation and inhibiting synaptic function. The second, would be the ecto-cellular ATP synthesized by the endothelial cell plasmalemma exposed to ambient oxygen concentrations due to premature breathing, especially in lung. ATP would be rapidly transformed into adenosine by the ectonucleotidase activities such as NTPDase I (CD39), and NT5E (CD73). An ectopic extra-mitochondrial aerobic ATP synthetic ability was reported in many cell plasma-membranes, among which endothelial cells. The potential implications of the cited hypotheses for the neonatology area would be great. The amount of oxygen administration for reviving of newborns would find a molecular basis for its assessment. VLBW infants may be regarded as those in which premature exposure to ambient oxygen concentrations and oxidative stress causes a premature functioning of the extra-mitochondrial oxidative phosphorylation primarily in axons and endothelium. Adenosine may become a biomarker of prematurity risk, whose implications further studies may assess.
我们的初步数据显示，极低出生体重（VLBW）婴儿血液中的腺苷水平很高，这与他们的早产情况（即体重类别）呈正相关。这促使我们寻找促进腺苷如此显著增加的机制。我们假设这与氧应激有关。事实上，人们认识到缺氧或氧过量均会导致早产相关损伤的发病机制，如视网膜病变（ROP）和脑室周围白质病变（PWMI）。目前正在重新审视用于VLBW婴儿复苏的最佳氧浓度。我们提出，VLBW婴儿血液中腺苷浓度升高有两个来源。第一个可能是其从无髓鞘脑轴突的活动依赖性释放。在这方面，腺苷将是代谢低下的VLBW新生儿无髓鞘轴突因早产导致的环境刺激而强烈放电的终产物。由于血脑屏障不成熟，腺苷最终会出现在血液中。事实上，腺苷是促进中枢神经系统中少突胶质前体细胞（OPC）分化为有髓鞘细胞的主要活动依赖性信号，同时抑制其增殖并抑制突触功能。第二个来源是由于早产呼吸，尤其是在肺部，内皮细胞质膜暴露于环境氧浓度下合成的细胞外ATP。ATP会通过诸如NTPDase I（CD39）和NT5E（CD73）等外核苷酸酶的活性迅速转化为腺苷。许多细胞质膜，包括内皮细胞，都报道了异位的线粒体外有氧ATP合成能力。上述假设对新生儿学领域的潜在影响将是巨大的。用于新生儿复苏的给氧量将找到评估其的分子基础。VLBW婴儿可被视为那些过早暴露于环境氧浓度和氧化应激下，主要在轴突和内皮中导致线粒体外氧化磷酸化过早发挥作用的婴儿。腺苷可能成为早产风险的生物标志物，其影响有待进一步研究评估。
