Onclinx Cécile, Dogne Sophie, Jadin Laurence, Andris Fabienne, Grandfils Christian, Jouret François, Mullier François, Flamion Bruno
Molecular Physiology Research Unit, NARILIS, University of Namur, Belgium.
Laboratoire d'Immunobiologie, Institut de Biologie et de Médecine Moléculaire, Université Libre de Bruxelles, Belgium.
Haematologica. 2015 Aug;100(8):1023-30. doi: 10.3324/haematol.2015.123828. Epub 2015 May 1.
Hyaluronan is a major component of the extracellular matrix and glycocalyx. Its main somatic degrading enzymes are hyaluronidases 1 and 2, neither of which is active in the bloodstream. We generated hyaluronidase 2-deficient mice. These animals suffer from chronic, mild anemia and thrombocytopenia, in parallel with a 10-fold increase in plasma hyaluronan concentration. In this study we explored the mechanism of these hematologic anomalies. The decreased erythrocyte and platelet counts were attributed to peripheral consumption. The erythrocyte half-life was reduced from 25 to 8 days without signs of premature aging. Hyaluronidase 2-deficient platelets were functional. Major intrinsic defects in erythrocyte membrane or stability, as well as detrimental effects of high hyaluronan levels on erythrocytes, were ruled out in vitro. Normal erythrocytes transfused into hyaluronidase 2-deficient mice were quickly destroyed but neither splenectomy nor anti-C5 administration prevented chronic hemolysis. Schistocytes were present in blood smears from hyaluronidase 2-deficient mice at a level of 1% to 6%, while virtually absent in control mice. Hyaluronidase 2-deficient mice had increased markers of endothelial damage and microvascular fibrin deposition, without renal failure, accumulation of ultra-large multimers of von Willebrand factor, deficiency of A Disintegrin And Metalloproteinase with ThromboSpondin type 1 motifs, member 13 (ADAMTS13), or hypertension. There was no sign of structural damage in hepatic or splenic sinusoids, or in any other microvessels. We conclude that hyaluronidase 2 deficiency induces chronic thrombotic microangiopathy with hemolytic anemia in mice. The link between this uncommon condition and hyaluronidase 2 remains to be explored in humans.
透明质酸是细胞外基质和糖萼的主要成分。其主要的体内降解酶是透明质酸酶1和透明质酸酶2，二者在血液中均无活性。我们培育出了透明质酸酶2缺陷型小鼠。这些动物患有慢性轻度贫血和血小板减少症，同时血浆透明质酸浓度增加了10倍。在本研究中，我们探究了这些血液学异常的机制。红细胞和血小板计数减少归因于外周消耗。红细胞半衰期从25天缩短至8天，且无早衰迹象。透明质酸酶2缺陷型血小板功能正常。体外排除了红细胞膜或稳定性的主要内在缺陷以及高透明质酸水平对红细胞的有害影响。输入透明质酸酶2缺陷型小鼠体内的正常红细胞很快被破坏，但脾切除术和给予抗C5均不能预防慢性溶血。透明质酸酶2缺陷型小鼠的血涂片中有1%至6%的裂红细胞，而对照小鼠几乎没有。透明质酸酶2缺陷型小鼠的内皮损伤和微血管纤维蛋白沉积标志物增加，但没有肾衰竭、血管性血友病因子超大聚合物的积累、含Ⅰ型血小板反应蛋白基序的解聚素和金属蛋白酶13（ADAMTS13）缺乏或高血压。肝或脾血窦以及任何其他微血管均无结构损伤迹象。我们得出结论，透明质酸酶2缺陷在小鼠中诱发了伴有溶血性贫血的慢性血栓性微血管病。这种罕见病症与透明质酸酶2之间的联系在人类中仍有待探索。
