Regulation of hepatocyte growth factor secretion by fibroblasts in patients with acute lung injury
Regulation of hepatocyte growth factor secretion by fibroblasts in patients with acute lung injury
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DOI：
10.1152/ajplung.00096.2007
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发表时间：
2008-02-01
影响因子：
4.9
通讯作者：
Dehoux, Monique
中科院分区：
文献类型：
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作者：
Quesnel, Christophe;Marchand-Adam, Sylvain;Dehoux, Monique
急性呼吸窘迫综合征（ARDS）和急性肺损伤（ALI）的肺修复机制尚不清楚。肝细胞生长因子（HGF）和角质形成细胞生长因子（KGF）是参与肺泡上皮修复的关键因子，存在于ALI/ARDS患者的支气管肺泡灌洗液（BALF）中。BALF介质在其生产中的作用仍有待确定。我们评估了52例患者（27例有ALI/ARDS的通气患者，10例无ALI的通气患者和15例非通气对照患者）的BALF对肺成纤维细胞合成HGF和KGF的总体影响。在BALF存在下培养成纤维细胞。采用ELISA法测定HGF和KGF蛋白分泌，采用实时定量RT-PCR法评价mRNA表达。仅来自ALI/ARDS患者的BALF上调HGF和KGF mRNA表达和蛋白质合成（HGF和KGF分别为+271和+ 146%）。ALI/ARDS患者BALF诱导的HGF合成高于无ALI的机械通气患者（P < 0.05）。ALI/ARDS组HGF分泌与BALF中IL-1 β水平（rho = 0.62，P < 0.001）和IL-1 β/IL-1受体拮抗剂比值（rho = 0.54，P < 0.007）相关。抗IL-1 β抗体可部分（> 50%）抑制BALF诱导的HGF和PGE（2）分泌，而特异性环氧合酶-2（考克斯-2）抑制剂NS-398可完全抑制HGF和PGE（2）分泌，抗IL-1 β抗体和NS-398可逆转BALF诱导的考克斯-2上调。因此，IL-1 β是参与HGF分泌的主要BALF介质，其通过PGE（2）/考克斯-2依赖性机制介导。BALF介质可能参与ALI/ARDS时肺成纤维细胞产生HGF和KGF的过程。
The mechanisms of pulmonary repair in acute respiratory distress syndrome ARDS) and acute lung injury (ALI) are poorly known. Hepatocyte growth factor (HGF) and keratinocyte growth factor (KGF) are key factors involved in alveolar epithelial repair, present in the bronchoalveolar lavage fluid (BALF) from patients with ALI/ARDS. The role of BALF mediators in their production remains to be determined. We evaluated the overall effect of BALF from 52 patients ( 27 ventilated patients with ALI/ARDS, 10 ventilated patients without ALI, and 15 nonventilated control patients) on HGF and KGF synthesis by lung fibroblasts. Fibroblasts were cultured in the presence of BALF. HGF and KGF protein secretion was measured using ELISA, and mRNA expression was evaluated using quantitative real-time RT-PCR. Only BALF from ALI/ARDS patients upregulated both HGF and KGF mRNA expression and protein synthesis (+271 and + 146% for HGF and KGF, respectively). BALF-induced HGF synthesis from ALI/ARDS patients was higher than that from ventilated patients without ALI ( P < 0.05). HGF secretion was correlated with BALF IL-1 beta levels ( rho = 0.62, P < 0.001) and BALF IL-1 beta/IL-1 receptor antagonist ratio ( rho = 0.54, P < 0.007) in the ALI/ARDS group. An anti-IL-1 beta antibody partially (> 50%) inhibited the BALF-induced HGF and PGE(2) secretion, whereas NS-398, a specific cyclooxygenase-2 (COX-2) inhibitor, completely inhibited it. Anti-IL-1 beta antibodies as well as NS-398 reversed the COX-2 upregulation induced by BALF. Therefore, IL-1 beta is a main BALF mediator involved in HGF secretion, which is mediated through a PGE(2)/COX-2-dependent mechanism. BALF mediators may participate in vivo in the production of HGF and KGF by lung fibroblasts during ALI/ARDS.