High levels of hyaluronan in idiopathic pulmonary arterial hypertension
High levels of hyaluronan in idiopathic pulmonary arterial hypertension
复制标题
DOI：
10.1152/ajplung.90306.2008
复制
发表时间：
2008-11-01
影响因子：
4.9
通讯作者：
Dweik, Raed A.
中科院分区：
文献类型：
--
作者：
Aytekin, Metin;Comhair, Suzy A. A.;Dweik, Raed A.
Aytekin M，Comhair SA，de拉莫特C，Bandyopadhyay SK，Farver CF，Hascall VC，Erzurum SC，Dweik RA.特发性肺动脉高压患者的高水平透明质酸。美国生理学杂志肺细胞分子生理学295：L789-L799，2008年。首次发表于2008年9月5日; doi：10.1152/ajplung.90306.2008。透明质酸（HA）是ECM中发现的一种大的糖胺聚糖，在肺和血管生物学和疾病中具有重要作用。然而，其在特发性肺动脉高压（IPAH）中的作用尚不清楚。我们推测IPAH中HA代谢异常。我们测量了IPAH和健康个体的血浆HA水平。我们还评估了HA合成和HA酶和透明质酸酶在肺动脉平滑肌细胞（PASMCs）中的表达。与对照组相比，IPAH组血浆HA水平显著升高[HA（ng/ml，平均值+/-SD）：IPAH 325 +/-80，对照组28 +/-9; P +/-0.02]。在体外，与对照细胞相比，未刺激的IPAH PASMC产生高水平的HA [上清液中的HA（μ g/ml，平均值+/-SD）：IPAH 12 +/-2，对照6 +/-0.9; P +/-0.04]。HA水平在IPAH PASMC裂解物中也较高。HA增加具有生物学相关性，如组织染色和与对照PASMC相比单核细胞与IPAH的HA特异性结合增加所示[结合细胞数× 104（平均值+/-SD）：IPAH 9.5 +/-3，对照3.0 +/-1; P +/-0.01]。通过加入透明质酸酶消除这种结合。HA合成酶-2和透明质酸酶-2在对照和IPAH PASMCs中占优势。有趣的是，与对照组相比，IPAH中HA合成酶-2和透明质酸酶-2的表达降低了约2倍[HA合成酶-2（相对表达平均值+/-SE）：IPAH 4.3 +/-0.02，对照7.8 +/-0.1; P +/-0.0004;透明质酸酶-2（相对表达平均值+/-SE）：IPAH 4.2 +/-0.06，对照组7.6 +/-0.07; P +/-0.008]。因此，与对照组相比，IPAH患者具有更高的HA循环水平，并且来自IPAH肺的PASMC产生更多的HA。这与组织水平增加和炎性细胞结合增加相关，表明HA在IPAH的重塑和炎症中的作用。
Aytekin M, Comhair SA, de la Motte C, Bandyopadhyay SK, Farver CF, Hascall VC, Erzurum SC, Dweik RA. High levels of hyaluronan in idiopathic pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 295: L789- L799, 2008. First published September 5, 2008; doi:10.1152/ajplung.90306.2008.- Hyaluronan (HA), a large glycosaminoglycan found in the ECM, has major roles in lung and vascular biology and disease. However, its role in idiopathic pulmonary arterial hypertension (IPAH) is unknown. We hypothesized that HA metabolism is abnormal in IPAH. We measured the plasma levels of HA in IPAH and healthy individuals. We also evaluated HA synthesis and the expression of HA synthases and hyaluronidases in pulmonary artery smooth muscle cells (PASMCs) from explanted lungs. Plasma HA levels were markedly elevated in IPAH compared with controls [HA (ng/ml, mean +/- SD): IPAH 325 +/- 80, control 28 +/- 9; P +/- 0.02]. In vitro, unstimulated IPAH PASMCs produced high levels of HA compared with control cells [HA in supernatant (mu g/ml, mean +/- SD): IPAH 12 +/- 2, controls 6 +/- 0.9; P +/- 0.04]. HA levels were also higher in IPAH PASMC lysates. The increased HA was biologically relevant as shown by tissue staining and increased HA-specific binding of mononuclear cells to IPAH compared with control PASMCs [number of bound cells x 104 (mean +/- SD): IPAH 9.5 +/- 3, control 3.0 +/- 1; P +/- 0.01]. This binding was abrogated by the addition of hyaluronidase. HA synthase-2 and hyaluronidase-2 were predominant in control and IPAH PASMCs. Interestingly, the expressions of HA synthase-2 and hyaluronidase-2 were similar to 2-fold lower in IPAH compared with controls [HA synthase-2 (relative expression mean +/- SE): IPAH 4.3 +/- 0.02, control 7.8 +/- 0.1; P +/- 0.0004; hyaluronidase-2 (relative expression mean +/- SE): IPAH 4.2 +/- 0.06, control 7.6 +/- 0.07; P +/- 0.008]. Thus patients with IPAH have higher circulating levels of HA, and PASMCs derived from IPAH lungs produce more HA compared with controls. This is associated with increased tissue levels and increased binding of inflammatory cells suggesting a role for HA in remodeling and inflammation in IPAH.