Koj Sabina, Niedziela Tomasz, Rossowska Joanna, Schmitt Jean-Louis, Lehn Jean-Marie, Nicolau Claude, Kieda Claudine
Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland.
ISIS-University of Strasbourg, Strasbourg, France.
J Cell Mol Med. 2025 Jan;29(2):e70343. doi: 10.1111/jcmm.70343.
The hypoxic microenvironment is crucial for tumour cell growth and invasiveness. Tumour tissue results from adaptation to reduced oxygen availability. Hypoxia first activates pro-angiogenic signals for alleviation. Pathologic, tumour angiogenesis maintains hypoxia, impairing treatment outcomes. Vessel normalisation requires physioxia. Oxygen delivery by red blood cell (RBC) carrying haemoglobin (Hb) is enhanced by myo-inositol trispyrophosphate (ITPP), an effector of oxygen transport by RBCs. Altering glycolytic activity, it lowers intracellular pH and increases oxygen release from Hb. P NMR tracking of 2,3-diphosphoglycerate (2,3-DPG), allosteric effector of Hb and non-penetrating anion in RBCs, reports on erythrocytes internal environment. P resonances of 2,3-DPG are pH-sensitive, their positions indicate the oxygenation state of RBCs and interactions with effectors such as ITPP. Here we show in vitro and in vivo, that modifying Hb activity through band-3 anion transporter, ITPP enhances oxygen release and controls RBC internal pH. Its blood availability validates applicability of ITPP-based strategies.
缺氧微环境对肿瘤细胞的生长和侵袭至关重要。肿瘤组织是对氧气供应减少的适应性结果。缺氧首先激活促血管生成信号以缓解缺氧状态。病理性的肿瘤血管生成会维持缺氧状态，从而影响治疗效果。血管正常化需要生理性氧环境。携带血红蛋白（Hb）的红细胞（RBC）通过肌醇三磷酸（ITPP）增强氧气输送，ITPP是红细胞氧气运输的一种效应物。它通过改变糖酵解活性来降低细胞内pH值并增加血红蛋白释放氧气。对红细胞内作为血红蛋白变构效应物和非穿透性阴离子的2,3-二磷酸甘油酸（2,3-DPG）进行磷核磁共振跟踪，可反映红细胞的内部环境。2,3-DPG的磷共振对pH敏感，其位置表明红细胞的氧合状态以及与ITPP等效应物的相互作用。在这里，我们在体外和体内均表明，通过带3阴离子转运体改变血红蛋白活性，ITPP可增强氧气释放并控制红细胞内部pH值。其在血液中的可用性验证了基于ITPP的策略的适用性。
