Transforming growth factor-α deficiency reduces pulmonary fibrosis in transgenic mice
Transforming growth factor-α deficiency reduces pulmonary fibrosis in transgenic mice
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DOI：
10.1165/ajrcmb.20.5.3526
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发表时间：
1999-05-01
影响因子：
6.4
通讯作者：
Clark, JG
中科院分区：
文献类型：
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作者：
Madtes, DK;Elston, AL;Clark, JG
尽管有证据表明转化生长因子-α（TGF-α）参与急性肺损伤的发病机制，但TGF-α对纤维增生反应的作用尚不清楚。为了确定肺纤维化的发展是否依赖于TGF-α，我们用博莱霉素诱导TGF-α零突变转基因小鼠和野生型小鼠的肺损伤。肺羟脯氨酸含量分别为1.3，1.2和1.6倍，在野生型小鼠比TGF-α缺陷动物在第10，21和28天，单次气管内注射博莱霉素后。在博莱霉素治疗后第7天和第10天，野生基因型小鼠的肺总RNA含量是TGF-α缺陷动物的1.5倍。博莱霉素处理后，两种基因型小鼠的肺总DNA含量和核标记指数无显著差异。野生基因型小鼠在博来霉素治疗后第7天和第14天的肺纤维化评分显著高于TGF-α缺陷型小鼠。TGF-α缺陷小鼠和野生基因型小鼠在博莱霉素给药后的肺部炎症评分无显著差异。为了确定博来霉素诱导损伤后表皮生长因子（EGF）家族其他成员的表达是否增加，我们测定了肺EGF和肝素结合表皮生长因子（HB-EGF）mRNA水平。稳态HB-EGF mRNA水平分别为321%和478%的控制值在博莱霉素治疗的肺在第7和10天，但没有显着差异TGF-α缺陷和野生型小鼠。EGF mRNA在正常或博莱霉素治疗的两种基因型小鼠的肺中均未检测到。这些结果表明，TGF-α显着有助于博莱霉素诱导的损伤后肺纤维化的发病机制，并在其他EGF家族成员的代偿性增加不发生在TGF-α缺陷的小鼠。
Despite evidence that implicates transforming growth factor-alpha (TGF-alpha) in the pathogenesis of acute lung injury, the contribution of TGF-alpha to the fibroproliferative response is unknown. To determine whether the development of pulmonary fibrosis depends on TGF-alpha, we induced lung injury with bleomycin in TGF-alpha null-mutation transgenic mice and wild-type mice. Lung hydroxyproline content was 1.3, 1.2, and 1.6 times greater in wild-genotype mice than in TGF-alpha-deficient animals at Days 10, 21, and 28, respectively, after a single intratracheal injection of bleomycin. At Days 7 and 10 after bleomycin treatment, lung total RNA content was 1.5 times greater in wild-genotype mice than in TGF-alpha-deficient animals. There was no significant difference between mice of the two genotypes in lung total DNA content or nuclear labeling indices after bleomycin administration. Wild-genotype mice had significantly higher lung fibrosis scores at Days 7 and 14 after bleomycin treatment than did TGF-alpha-deficient animals. There was no significant difference between TGF-alpha-deficient mice and wild-genotype mice in lung inflammation scores after bleomycin administration. To determine whether expression of other members of the epidermal growth factor (EGF) family is increased after bleomycin-induced injury, we measured lung EGF and heparin-binding-epidermal growth factor (HB-EGF) mRNA levels. Steady-state HB-EGF mRNA levels were 321% and 478% of control values in bleomycin-treated lungs at Days 7 and 10, respectively, but were not significantly different in TGF-alpha-deficient and in wild-genotype mice. EGF mRNA was not detected in normal or bleomycin-treated lungs of mice of either genotype. These results show that TGF-alpha contributes significantly to the pathogenesis of pulmonary fibrosis after bleomycin-induced injury, and that compensatory increases in other EGF family members do not occur in TGF-alpha-deficient mice.