Irradiation-induced expression of hyaluronan (HA) synthase 2 and hyaluronidase 2 genes in rat lung tissue accompanies active turnover of HA and induction of types I and III collagen gene expression
Irradiation-induced expression of hyaluronan (HA) synthase 2 and hyaluronidase 2 genes in rat lung tissue accompanies active turnover of HA and induction of types I and III collagen gene expression
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DOI：
10.1165/ajrcmb.23.3.4102
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发表时间：
2000-09-01
影响因子：
6.4
通讯作者：
Heldin, P
中科院分区：
文献类型：
--
作者：
Li, YJ;Rahmanian, M;Heldin, P
透明质酸（HA）是一种线性糖胺聚糖，聚集在损伤肺的肺泡中，并抑制空气和血液之间的气体交换。在本研究中，我们研究了放射线诱发的大鼠肺纤维化早期HA局部转换的分子机制。大鼠右肺下部单次照射戈伊，照射后6周支气管肺泡灌洗液中HA明显增多，照射后10周HA基本恢复正常。这是平行的HA受体对肺泡巨噬细胞（AM）的瞬时下调; 4和6周后照射的结合[H-3]HA到AM减少到约50%的非照射对照大鼠的AM，恢复到几乎正常的水平，在10周后照射。大鼠HA合酶（HAS）亚型的表达分析（rHAS 1、rHAS 2和rHAS 3）和大鼠透明质酸酶北方印迹法检测rHYAL 1和rHYAL 2在照射后4、6和10 wk表达上调，而rHYAL 2在照射后6和10 wk表达逐渐下降; rHAS 1检测不到，而rHAS 3和rHYAL 1微弱检测到。虽然转化生长因子-β 1刺激正常肺成纤维细胞产生HA，但它抑制溶酶体中的HYAL活性和释放到培养基中的HYAL活性。另一个有趣的观察结果是，HA片段，这可能是由HYAL的作用，诱导I型和III型胶原基因的表达。我们的研究结果表明，rHAS 2和rHYAL 2参与肺损伤早期HA的转换，rHAS 2和rHYAL 2以及HA片段可能在肺纤维化的发病机制中发挥重要作用。
Hyaluronan (HA) is a linear glycosaminoglycan that accumulates in the interstitium of injured lung and inhibits gas exchange between air and blood. In the present study we investigated the molecular mechanisms behind the local turnover of HA during the early phase of irradiation-evoked lung fibrosis in rats. Irradiation with a single dose of 30 Gy to the lower part of the right lung of rats induced an accumulation of HA in bronchoalveolar lavage fluid 6 wk after irradiation, followed by return to almost normal levels at 10 wk after irradiation. This was parallelled with a transient downregulation of HA receptors on alveolar macrophages (AMs); 4 and 6 wk after irradiation the binding of [H-3]HA to AMs was decreased to about 50% of that of AMs from nonirradiated control rats, returning to almost normal level at 10 wk after irradiation. Analysis of the expression of rat HA synthase (HAS) isoforms (rHAS1, rHAS2, and rHAS3) and rat hyaluronidases (rHYAL1 and rHYAL2) by Northern blotting revealed an upregulation of rHAS2 messenger RNA at 4, 6, and 10 wk after irradiation, but a progressive decrease in the constitutive expression of rHYAL2 at 6 and 10 wk after irradiation; rHAS1 was undetectable, whereas rHAS3 and rHYAL1 were faintly detectable. Although transforming growth factor-beta 1 stimulated HA production by normal lung fibroblasts, it inhibited HYAL activity in lysosomes and HYAL activity released into the culture media. Another interesting observation was that HA fragments, which likely result from the action of HYAL, induced expression of types I and III collagen genes. Our results indicate that rHAS2 and rHYAL2 are involved in the turnover of HA during the early phase of lung injury and that rHAS2 and rHYAL2 as well as HA fragments may play important roles in the pathogenesis of lung fibrosis.