中子及γ射线对肠免疫组织放射损伤效应及IL-2对肠上皮再生调控研究
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摘要
目的：中子辐射对肠道损伤较γ射线程度重、发生早、疗效差、难恢复，迄今机制未明，肠免疫组织参与其损伤修复过程，然关于中子对肠免疫组织损伤特点及IL-2对肠上皮损伤及修复作用及其机制尚未见报道。本文研究中子辐射后肠免疫组织病变特点及其对肠上皮再生调控作用，为其防治提供新思路。
方法：采用2.5～5.5Gy中子及5.5-12Gyγ射线照射350只BALB／C小鼠和IEC-6细胞(正常SD大鼠空肠隐窝上皮细胞)，并用IL-2(25×10~3～1×10~5U／L)及JAK_1阻断剂A77-1726于照前12h或照后即刻处理细胞，分别于照后6h，12h，1～5d，7d，14d，21d及28d活杀取材或15min，30min，1h，3h，6h，9h，12h，1～3d收集细胞，采用光镜、电镜、免疫组化、MTT、FACS、免疫印迹等方法对比研究中子及γ射线照后肠免疫组织损伤、恢复规律和IL-2对IEC-6再生作用及其机制。
结果：(1)肠免疫组织病理变化：中子组2.5Gy照后3d内，淋巴细胞发生凋亡、坏死，5d见再生，14～21d渐恢复，4.0和5.5Gy照后以坏死多见，未见明显恢复；γ射线组5.5Gy照后病变与中子2.5Gy组类似，但程度轻、再生早、凋亡多见，12Gy照后损伤程度介于中子4.0～5.5Gy组之间。(2)肠PP内T、B细胞及浆细胞变化：2.5Gy中子照后5d内，进行性减少，T／B比例升高，14d后恢复，其中T及浆细胞均呈量—效关系。(3)肠免疫因子变化：2.5Gy中子和5.5Gyγ射线照后5d内，IL-2，4及IgA均进行性减少，7～10d少量表达，14d后渐恢复，IFNγ，TGFβ_3，TNFα和IL-18于照后2d内进行性减少，3～7d增多，14d后恢复，均呈量—效关系。(4)IL-2对IEC-6作用及IL-2Rβ／JAK_1／STAT_5通路变化：中子4Gy照后3d内，IEC-6增殖活力降低，照后1d凋亡和坏死增多，以坏死为主，γ射线4～12Gy照后1d以凋亡多见；给予IL-2后1～3d，IEC-6增殖活力提高，凋亡减少，且呈量—效关系，同时IL-2R表达增加，JAK_1激酶和转录因子STAT_5活化增强；IEC-6经A77-1726、IL-2与8Gyγ线共处理后24h增殖活力降低，STAT_5活化减弱。
结论：(1)中子致肠免疫组织损伤重，恢复慢，损伤期凋亡与坏死并存，4.0和5.5Gy组以坏死为主，而γ射线照射以凋亡为主。(2)内源性IgA及肠上皮生长刺激因子IL-2、IL-4于中子损伤期减少，而生长抑制及凋亡诱导因子IFNγ，TGFβ，TNFα及IL-18于损伤期增多，进一步抑制肠上皮恢复。(3)4Gy中子照射抑制IEC-6增殖，以坏死损伤为重，而γ射线损伤以凋亡为主，IL-2可促进IEC-6增殖，抑其凋亡，活化JAK_1及STAT_5，A77-1726可抑制IL-2的促增殖及活化效应，IL-2可通过活化IL-2Rβ／JAK_1／STAT_5通路而介导其抗辐射效应。
Objective: Compared to y ray injury, Neutron radiation injury of intestine always occur more rapidly and severely, have less curative effect and recover more difficultly. Now characteristics of neutron injury on gut-associated lymphoid tissues and effects of IL-2 on reepithlialization of enteric epithelium after neutron radiation have not yet been reported. It is very important for prevention, diagnosis and treatment of neutron injury to research characteristics of pathological changes of gut-associated lymphoid tissues and regulation of which on reepithlialization of enteric epithelium after neutron injury.
Materials and methods: 350 BALB/C mice and IEC-6 (jejunum crypt epithelial cells of normal SD rats) was radiated by 2.5～5.5Gy neutron and 5.5～12Gy γ ray, and IEC-6 was treated by IL-2 (25 × 10~3～1×10~5U/L) and JAK, blocking agent (A77-1726) on 12h before radiation or immediately after radiation. The mice were sacrificed on 6h, 12h, 1～5d, 7d,14d, 21d and 28d after irradiation, IEC-6 were collected on 15min, 30min, 1h, 3h, 6h, 9h, 12h and 1～3d. Then the regularity of gut-associated lymphoid tissues injury and recovery and effects of IL-2 on reepithlialization of enteric epithelium could be studied with light microscope, electron microscope, histochemical stain, MTT colorimetry, FACS and immunoblot method and so on.
Results: (1) Pathological changes of gut-associated lymphoid tissues: lymphocytes occurred apoptosis and necrosis within 3d, regenerated on 5d, and recovered during 14～21d after 2.5Gy neutron radiation, most lymphocytes appeared necrosis after 4.0 and 5.5Gy neutron radiation and no recovery. Pathological changes of 5.5Gy y ray group were similar to those of 2.5Gy neutron group, but were more slight, earlier regeneration and much more apoptosis. Degree of injury of 12Gy y ray was between 4.0 and 5.5Gy neutron group. (2) Changes of T, B lymphocytes in intestinal PP and plasmocytes: decreased progressingly within 5d after 2.5Gy neutron radiation, T/B ratio increased, and recovered after 14d. T lymphocytes and plasmocytes appeard dose-effect
方法：采用2.5～5.5Gy中子及5.5-12Gyγ射线照射350只BALB／C小鼠和IEC-6细胞(正常SD大鼠空肠隐窝上皮细胞)，并用IL-2(25×10~3～1×10~5U／L)及JAK_1阻断剂A77-1726于照前12h或照后即刻处理细胞，分别于照后6h，12h，1～5d，7d，14d，21d及28d活杀取材或15min，30min，1h，3h，6h，9h，12h，1～3d收集细胞，采用光镜、电镜、免疫组化、MTT、FACS、免疫印迹等方法对比研究中子及γ射线照后肠免疫组织损伤、恢复规律和IL-2对IEC-6再生作用及其机制。
结果：(1)肠免疫组织病理变化：中子组2.5Gy照后3d内，淋巴细胞发生凋亡、坏死，5d见再生，14～21d渐恢复，4.0和5.5Gy照后以坏死多见，未见明显恢复；γ射线组5.5Gy照后病变与中子2.5Gy组类似，但程度轻、再生早、凋亡多见，12Gy照后损伤程度介于中子4.0～5.5Gy组之间。(2)肠PP内T、B细胞及浆细胞变化：2.5Gy中子照后5d内，进行性减少，T／B比例升高，14d后恢复，其中T及浆细胞均呈量—效关系。(3)肠免疫因子变化：2.5Gy中子和5.5Gyγ射线照后5d内，IL-2，4及IgA均进行性减少，7～10d少量表达，14d后渐恢复，IFNγ，TGFβ_3，TNFα和IL-18于照后2d内进行性减少，3～7d增多，14d后恢复，均呈量—效关系。(4)IL-2对IEC-6作用及IL-2Rβ／JAK_1／STAT_5通路变化：中子4Gy照后3d内，IEC-6增殖活力降低，照后1d凋亡和坏死增多，以坏死为主，γ射线4～12Gy照后1d以凋亡多见；给予IL-2后1～3d，IEC-6增殖活力提高，凋亡减少，且呈量—效关系，同时IL-2R表达增加，JAK_1激酶和转录因子STAT_5活化增强；IEC-6经A77-1726、IL-2与8Gyγ线共处理后24h增殖活力降低，STAT_5活化减弱。
结论：(1)中子致肠免疫组织损伤重，恢复慢，损伤期凋亡与坏死并存，4.0和5.5Gy组以坏死为主，而γ射线照射以凋亡为主。(2)内源性IgA及肠上皮生长刺激因子IL-2、IL-4于中子损伤期减少，而生长抑制及凋亡诱导因子IFNγ，TGFβ，TNFα及IL-18于损伤期增多，进一步抑制肠上皮恢复。(3)4Gy中子照射抑制IEC-6增殖，以坏死损伤为重，而γ射线损伤以凋亡为主，IL-2可促进IEC-6增殖，抑其凋亡，活化JAK_1及STAT_5，A77-1726可抑制IL-2的促增殖及活化效应，IL-2可通过活化IL-2Rβ／JAK_1／STAT_5通路而介导其抗辐射效应。
Objective: Compared to y ray injury, Neutron radiation injury of intestine always occur more rapidly and severely, have less curative effect and recover more difficultly. Now characteristics of neutron injury on gut-associated lymphoid tissues and effects of IL-2 on reepithlialization of enteric epithelium after neutron radiation have not yet been reported. It is very important for prevention, diagnosis and treatment of neutron injury to research characteristics of pathological changes of gut-associated lymphoid tissues and regulation of which on reepithlialization of enteric epithelium after neutron injury.
Materials and methods: 350 BALB/C mice and IEC-6 (jejunum crypt epithelial cells of normal SD rats) was radiated by 2.5～5.5Gy neutron and 5.5～12Gy γ ray, and IEC-6 was treated by IL-2 (25 × 10~3～1×10~5U/L) and JAK, blocking agent (A77-1726) on 12h before radiation or immediately after radiation. The mice were sacrificed on 6h, 12h, 1～5d, 7d,14d, 21d and 28d after irradiation, IEC-6 were collected on 15min, 30min, 1h, 3h, 6h, 9h, 12h and 1～3d. Then the regularity of gut-associated lymphoid tissues injury and recovery and effects of IL-2 on reepithlialization of enteric epithelium could be studied with light microscope, electron microscope, histochemical stain, MTT colorimetry, FACS and immunoblot method and so on.
Results: (1) Pathological changes of gut-associated lymphoid tissues: lymphocytes occurred apoptosis and necrosis within 3d, regenerated on 5d, and recovered during 14～21d after 2.5Gy neutron radiation, most lymphocytes appeared necrosis after 4.0 and 5.5Gy neutron radiation and no recovery. Pathological changes of 5.5Gy y ray group were similar to those of 2.5Gy neutron group, but were more slight, earlier regeneration and much more apoptosis. Degree of injury of 12Gy y ray was between 4.0 and 5.5Gy neutron group. (2) Changes of T, B lymphocytes in intestinal PP and plasmocytes: decreased progressingly within 5d after 2.5Gy neutron radiation, T/B ratio increased, and recovered after 14d. T lymphocytes and plasmocytes appeard dose-effect
引文
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