Insulin-Like Growth Factor 1 Regulates Acute Inflammatory Lung Injury Mediated by Influenza Virus Infection
Insulin-Like Growth Factor 1 Regulates Acute Inflammatory Lung Injury Mediated by Influenza Virus Infection
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DOI：
10.3389/fmicb.2019.02541
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发表时间：
2019-11-26
影响因子：
5.2
通讯作者：
Zhang, Chuanfu
中科院分区：
文献类型：
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作者：
Li, Guiping;Zhou, Lijuan;Zhang, Chuanfu
急性炎症性肺损伤是甲型流感病毒（IAV）感染导致死亡的重要原因。胰岛素样生长因子1（IGF 1）在免疫系统的炎症调节中发挥重要作用。为了研究IGF 1在IAV介导的急性炎性肺损伤中的作用，在A549细胞中检测IAV A/波多黎各/8/1934（H1N1;缩写为PR 8）感染后IGF 1和炎性细胞因子的表达。建立PR 8感染BALB/c小鼠模型。分别于感染后第3、5、7、9天取小鼠肺组织，检测IGF 1 mRNA和蛋白表达的变化。将小鼠分为四组：（1）PBS（磷酸盐缓冲盐水的缩写）;（2）PR 8 + PBS;（3）PR 8 + IGF 1;和（4）PR 8 + PPP（苦鬼臼脂素的缩写，IGF 1受体抑制剂）。每日监测小鼠体重和存活率，并记录小鼠临床症状。在感染后第5天，处死小鼠以获得血清和肺组织。采用酶联免疫吸附试验检测血清中炎性细胞因子的表达;苏木精-伊红染色观察肺损伤;实时定量PCR检测肺内病毒增殖情况; Western blot检测磷脂酰肌醇-3-激酶/蛋白激酶B（PI 3 K/AKT）和丝裂原活化蛋白激酶（MAPK）信号通路中主要分子的蛋白表达。结果发现，IGF 1的表达上调A549细胞和BALB/c小鼠感染PR 8，而IGF 1调节炎症细胞因子的表达诱导PR 8感染。IGF 1的过表达加重了IAV介导的炎症反应，而IGF 1受体的抑制则减轻了这种炎症反应。IAV感染后，IGF 1受体的磷酸化激活了PI 3 K/AKT和MAPK信号通路，诱导了炎症反应。因此，IGF 1在IAV介导的急性炎症性肺损伤中发挥重要的免疫功能。IGF 1可以为人类提供一个应对流感爆发的治疗靶点，抑制IGF 1或IGF 1受体可能代表一种新的流感治疗方法。
The acute inflammatory lung injury is an important cause of death due to influenza A virus (IAV) infection. Insulin-like growth factor 1 (IGF1) played an important role in the regulation of inflammation in the immune system. To investigate the role of IGF1 in IAV-mediated acute inflammatory lung injury, the expression of IGF1 and inflammatory cytokines was tested after IAV A/Puerto Rico/8/1934 (H1N1; abbreviated as PR8) infection in A549 cells. Then, a BALB/c mouse model of PR8 infection was established. On days 3, 5, 7, and 9 post-infection, the mice lung tissue was collected to detect the expression changes in IGF1 mRNA and protein. The mice were divided into four groups: (1) PBS (abbreviation of phosphate buffered saline); (2) PR8 + PBS; (3) PR8 + IGF1; and (4) PR8 + PPP (abbreviation of picropodophyllin, the IGF1 receptor inhibitor). The body weight and survival rate of the mice were monitored daily, and the clinical symptoms of the mice were recorded. On day 5 post-infection, the mice were sacrificed to obtain the serum and lung tissues. The expression of inflammatory cytokines in the serum was detected by enzyme linked immunosorbent assay; lung injury was observed by hematoxylin-eosin staining; the viral proliferation in the lung was detected by real-time quantitative PCR; and the protein expression of the main molecules in the phosphatidylinositol-3-kinases/protein kinase B (PI3K/AKT) and mitogen-activated protein kinase (MAPK) signaling pathways was detected by Western blot. It was found that IGF1 expression is upregulated in A549 cells and BALB/c mice infected with PR8, whereas IGF1 regulated the expression of inflammatory cytokines induced by PR8 infection. Overexpression of IGF1 aggravated the IAV-mediated inflammatory response, whereas the inhibition of IGF1 receptor reduced such inflammatory response. The phosphorylation of IGF1 receptor triggered the PI3K/AKT and MAPK signaling pathways to induce an inflammatory response after IAV infection. Therefore, IGF1 plays an important immune function in IAV-mediated acute inflammatory lung injury. IGF1 may provide a therapeutic target for humans in response to an influenza outbreak, and inhibition of IGF1 or IGF1 receptor may represent a novel approach to influenza treatment.