Low molecular weight hyaluronan from stretched lung enhances interleukin-8 expression
Low molecular weight hyaluronan from stretched lung enhances interleukin-8 expression
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DOI：
10.1165/rcmb.2002-0167oc
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发表时间：
2004-01-01
影响因子：
6.4
通讯作者：
Quinn, DA
中科院分区：
文献类型：
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作者：
Mascarenhas, MM;Day, RM;Quinn, DA
机械通气已被证明会导致呼吸机诱导的肺损伤（VILI），可能是由于过度膨胀或拉伸肺。低分子量（LMW）形式的透明质酸（HA）是细胞外基质的一种组分，已显示可诱导细胞因子产生。LMW HA由透明质酸合成酶3（HAS 3）产生。我们发现在VILI动物模型中HAS 3 mRNA表达上调，并且LMW HA积累。我们假设牵张诱导的导致VILI中细胞因子释放的LMW HA产生依赖于HAS 3 mRNA表达。我们用体外肺细胞拉伸来探讨这一假设。细胞牵张诱导成纤维细胞HAS 3 mRNA表达和低分子量HA. HAS 3的非特异性抑制剂（环己脲和地塞米松）、蛋白酪氨酸激酶的非特异性抑制剂（染料木黄酮）和Janus激酶2抑制剂（AG 490）阻断牵张诱导的HAS 3表达和LMW HA的合成。来自成纤维细胞的拉伸诱导的LMW HA引起静态和拉伸上皮细胞中白细胞介素-8产生的显著剂量依赖性增加。这些结果表明，从头合成的LMW HA诱导肺成纤维细胞通过拉伸通过酪氨酸激酶信号通路，并可能在增强诱导VILI的促炎细胞因子中发挥作用。
Mechanical ventilation has been shown to cause ventilator induced lung injury (VILI), probably by overdistending or stretching the lung. Hyaluronan (HA), a component of the extracellular matrix, in low molecular weight (LMW) forms has been shown to induce cytokine production. LMW HA is produced by hyaluronan synthase 3 (HAS 3). We found that HAS 3 mRNA expression was upregulated and that LMW HA accumulated in an animal model of VILI We hypothesized that stretch induced LMW HA production that causes cytokine release in VILI was dependent on HAS 3 mRNA expression. We explored this hypothesis with in vitro lung cell stretch. Cell stretch induced HAS 3 mRNA expression and LMW HA in fibroblasts. Nonspecific inhibitors of HAS 3 (cyclohexamide and dexamethasone), a nonspecific inhibitor of protein tyrosine kinases (genistein), and a janus kinase 2 inhibitor (AG490) blocked stretch-induced HAS 3 expression and synthesis of LMW HA. Stretch-induced LMW HA from fibroblasts caused a significant dose-dependent increase in interleukin-8 production both in static and stretched epithelial cells. These results indicated that de novo synthesis of LMW HA was induced in lung fibroblasts by stretch via tyrosine kinase signaling pathways, and may play a role in augmenting induction of proinflammatory cytokines in VILI.