先天性肠闭锁近端肠壁组织中FGF10和BMP4表达的研究
摘要
先天性肠闭锁是新生儿常见的胃肠道畸形,是引起新生儿肠梗阻的主要原因,目前,通过外科手术恢复肠道连续通畅是唯一有效治疗手段,但是相当数量小肠闭锁患儿术后存在较长时间肠动力功能紊乱,闭锁近端肠管自身病理组织学改变被认为可能与该症发生有关。国内外已有报道：闭锁近端肠壁神经病变有随着远离闭锁盲端而逐渐减轻的趋势,但观察到的肠壁神经病变范围和由此确定的闭锁近端肠管切除范围并不一致。近年国外大量动物研究显示成纤维细胞生长因子10(fibroblast growth factor 10, FGF10)与小鼠的胃肠道发育密切相关,FGF10基因缺陷的小鼠存在胃肠道畸形如十二指肠闭锁、结肠闭锁等。同时已研究证实骨形成蛋白4(bone morphogenetic proteins 4, BMP4)与肠神经系统的发育成熟有关。
目的
本研究观察了先天性肠闭锁近端肠壁不同部位的FGF10和BMP4的分布情况,探讨二者与先天性肠闭锁的关系,并讨论与部分肠闭锁患儿术后肠功能不良的关系,指导临床治疗。
材料与方法
2008年7月—2009年5月在郑州大学第三附属医院行手术治疗并经病理检查确诊的先天性肠闭锁患儿20例,其中Ⅰ型3例,Ⅱ型10例,Ⅲ型7例。术中留取肠闭锁处、闭锁处近端5cm、10cm处肠壁全层组织,分别行免疫组化和RT-PCR检测。本组男12例,女8例,年龄1-6天,均为足月儿,为单发闭锁,术中未发现其它肠道合并畸形。20例均为散发。免疫组化对照组取10例死亡足月儿,无胃肠道畸形,尸检时取材,男6例,女4例。RT-PCR对照组取肠套叠、肠切除肠吻合手术、剖腹探查肠造瘘术中正常肠管组织10例作为对照,患儿年龄5天-4月,均未发现其它肠道合并畸形,家族史阴性。
1应用免疫组化技术观察20例先天性肠闭锁手术切除标本的肠闭锁处、闭锁近端5cm和闭锁近端10cm FGF10、BMP4蛋白的表达,正常对照肠壁组织10例。
2应用RT-PCR技术观察20例先天性肠闭锁手术切除标本的肠闭锁处、闭锁近端5cm和闭锁近端10cmFGF10 mRNA、BMP4 mRNA的表达,相应对照正常肠壁组织10例。
3统计学处理：应用SPSS13.0进行数据分析。计量资料用均数士标准差(x±s)表示。各组样本均数比较采用单因素方差分析,两两比较采用LSD-t检验,以α=0.05为检验水准。
结果
1免疫组化结果：FGF10正常对照组(148.32±1.90)与肠闭锁处(123.41±2.59)、肠闭锁近端5cm处(137.51±2.13)相比有统计学意义(P<0.05),正常对照组(148.32±1.90)与肠闭锁近端10cm处(147.51±2.76)相比无统计学意义(P>0.05)；BMP4正常对照组(206.40±3.22)与肠闭锁处(138.57±2.81)、肠闭锁近端5cm处(171.01±2.84)相比有统计学意义(P<0.05),正常对照组(206.40±3.22)与肠闭锁近端10cm处,(204.48±2.18)相比无统计学意义(P>0.05)；
2RT-PCR结果：FGF10mRNA正常对照组(0.95±0.12)与肠闭锁处(0.56±0.08)、肠闭锁近端5cm处(0.59±0.09)相比有统计学意义(P<0.05),正常对照组(0.95±0.12)与肠闭锁近端10cm处(0.89±0.10)相比无统计学意义(P>0.05)；BMP4mRNA正常对照组(1.12±0.10)与肠闭锁处(0.67±0.09)、肠闭锁近端5cm处(0.78±0.11)相比有统计学意义(P<0.05),正常对照组(1.12±0.10)与肠闭锁近端10cm处(1.10±0.11)相比无统计学意义(P>0.05)。
结论
1 FGF10、BMP4蛋白及mRNA在先天性肠闭锁闭锁处、闭锁近端5cm的肠壁组织中表达较正常肠壁组织明显减少,这种异常分布与肠神经系统的发育异常有关。
2 FGF10、BMP4蛋白在先天性肠闭锁近端的肠壁组织中表达明显减少且性质稳定,可作为诊断先天性肠闭锁切除范围的一种新的判断指标。
3肠闭锁近端肠管10cm处的FGF10和BMP4的表达接近正常肠管,为了保证术后肠功能顺利恢复,肠管的切除范围应该超过10cm。
Congenital intestinal atresia (CIA), a common neonatal gastrointestinal tract malformation, is the main cause of neonatal intestinal obstruction. At present, the surgery is the only effective method to restore intestinal smooth, but a considerable amount of CIA postoperatives are suffering from a longer period of gastrointestinal motile disorders. Histopathological changes in proximal intestines of CIA are considered to be related to the occurrence of the disease.The trend has been reported at home and abroad that nerve pathological changes of CIA proximal segments are reducing gradually as moving away from the caecum of CIA segment, but the observed scope of intestinal nerve pathological changes is not consistent with the range of intestinal proximal resection. In recent years, a large number of animal studies abroad have shown that FGF10 is closely related to the development of the gastrointestinal tract of the mice. The mice with FGF10 gene defects have gastrointestinal malformations such as duodenal atresia, colon atresia and so on. Meanwhile, it has been proved that BMP4 is related to the development and maturation of intestinal nerve system. Object
By studying the distribution of FGF10 and BMP4 of the proximal intestinal wall in different parts of CIA, this research is to explore the relationship of CIA, FGF10 and BMP4 respectively and to discuss problems of children with intestinal dysfunction after the operations and guide the clinical treatment. Materials and Methods
20 cases of CIA have been studied who have been confirmed by pathological examination and surgical treatment from July 2008 to May 2009 at the Third Affiliated Hospital of Zhengzhou University, of which 3 cases are typeⅠ,10 cases typeⅡ,7 cases typeⅢ. The CIA segments, the proximal 5cm, and 10cm were retained and detected with the method of immunohistochemistry and RT-PCRJ. Children in this group include 12 males and 8 females, aged 1 to 6d, who were full-term children not found other intestinal malformation.20 cases were distributed. 10 cases in control group were dead full-term children with no gastrointestinal tract abnormalities of which six are males and four are females. In RT-PCR control group, 10 cases of normal intestinal tissue from children who took intussusception, intestinal resection and anastomosis, and enterostomy were chosen as control.Those children were aged 5 days to 4 months, who were not found other inestinal malformations and had negative family history.
1 20 cases of CIA segments, proximal 5cm and proximal 10cm were resected, and then FGF10 and BMP4 expressions were observed and compared with 10 cases of normal intestines by immunohistochemical technique.
2 20 cases of CIA segments, proximal 5cm and proximal 10cm were resected, and then FGF10 mRNA and BMP4 mRNA expressions were observed and compared with 16 cases of normal intestines by RT-PCR technique.
3 Statistical analysis:SPSS 16.0 for data analysis. Measurement data are indicated with the mean±and standard deviation (x±s). The mean of samples in each group was compared using single factor analysis of variance, pair comparisons using LSD-t test, the correlation between the factors using pearson correlation analysis, with a=0.05 as standard level and P<0.05 for significant difference. Results
1 Immunohistochemical results:the comparison of FGF10 between normal control group (148.32±1.90), CIA segments (123.41±2.59), and CIA proximal 5cm (137.51±2.13) respectively was statistically significant (P< 0.05) while the comparison of FGF10 between normal controls group (148.32±1.90) and CIA proximal 10cm (147.51±2.76) was not statistically significant (P> 0.05). the comparison of BMP4 between normal control group (206.40±3.22), CIA segments (138.57±2.81),and proximal 5cm (171.01±2.84) respectively was statistically significant (P<0.05), while the comparison of BMP4 between normal controls group (206.40±3.22) and CIA proximal 10cm (204.48±2.18) was not statistically significant (P>0.05).
2 Immunohistochemical results:the comparison of FGF10 mRNA between normal control group (0.95±0.12), CIA segments(0.56±0.08), and CIA proximal 5cm (0.59±0.09) respectively was statistically significant (P<0.05) while the comparison of FGF10 mRNA between normal controls group (0.95±0.12) and CIA proximal 10cm (0.89±0.10) was not statistically significant (P> 0.05). the comparison of BMP4 mRNA between normal control group (1.12±0.10), CIA segments (0.67±0.09), and proximal 5cm(0.78±0.11) respectively was statistically significant (P<0.05), while the comparison of BMP4 between normal controls group (1.12±0.10) and CIA proximal 10cm (1.10±0.11) was not statistically significant (P>0.05). Conclusions
1 The expressions of FGF 10 and BMP4 in CIA segments and proximal 5cm are significantly reduced compared with the normal intestine. This abnormal distribution is related to the abnormal development of nerve system.
2 FGF 10 and BMP4 in CIA proximal intestinal segments are significantly reduced. With its stable nature, both of them can be used as a new indicator of diagnosis of CIA.
3 The expression of FGF 10 and BMP4 in CIA proximal 10cm is close to the normal intestine. Therefore, in order to ensure a smooth postoperative recovery of intestinal function, the scope of intestinal resection should be more than 10cm..
目的
本研究观察了先天性肠闭锁近端肠壁不同部位的FGF10和BMP4的分布情况,探讨二者与先天性肠闭锁的关系,并讨论与部分肠闭锁患儿术后肠功能不良的关系,指导临床治疗。
材料与方法
2008年7月—2009年5月在郑州大学第三附属医院行手术治疗并经病理检查确诊的先天性肠闭锁患儿20例,其中Ⅰ型3例,Ⅱ型10例,Ⅲ型7例。术中留取肠闭锁处、闭锁处近端5cm、10cm处肠壁全层组织,分别行免疫组化和RT-PCR检测。本组男12例,女8例,年龄1-6天,均为足月儿,为单发闭锁,术中未发现其它肠道合并畸形。20例均为散发。免疫组化对照组取10例死亡足月儿,无胃肠道畸形,尸检时取材,男6例,女4例。RT-PCR对照组取肠套叠、肠切除肠吻合手术、剖腹探查肠造瘘术中正常肠管组织10例作为对照,患儿年龄5天-4月,均未发现其它肠道合并畸形,家族史阴性。
1应用免疫组化技术观察20例先天性肠闭锁手术切除标本的肠闭锁处、闭锁近端5cm和闭锁近端10cm FGF10、BMP4蛋白的表达,正常对照肠壁组织10例。
2应用RT-PCR技术观察20例先天性肠闭锁手术切除标本的肠闭锁处、闭锁近端5cm和闭锁近端10cmFGF10 mRNA、BMP4 mRNA的表达,相应对照正常肠壁组织10例。
3统计学处理：应用SPSS13.0进行数据分析。计量资料用均数士标准差(x±s)表示。各组样本均数比较采用单因素方差分析,两两比较采用LSD-t检验,以α=0.05为检验水准。
结果
1免疫组化结果：FGF10正常对照组(148.32±1.90)与肠闭锁处(123.41±2.59)、肠闭锁近端5cm处(137.51±2.13)相比有统计学意义(P<0.05),正常对照组(148.32±1.90)与肠闭锁近端10cm处(147.51±2.76)相比无统计学意义(P>0.05)；BMP4正常对照组(206.40±3.22)与肠闭锁处(138.57±2.81)、肠闭锁近端5cm处(171.01±2.84)相比有统计学意义(P<0.05),正常对照组(206.40±3.22)与肠闭锁近端10cm处,(204.48±2.18)相比无统计学意义(P>0.05)；
2RT-PCR结果：FGF10mRNA正常对照组(0.95±0.12)与肠闭锁处(0.56±0.08)、肠闭锁近端5cm处(0.59±0.09)相比有统计学意义(P<0.05),正常对照组(0.95±0.12)与肠闭锁近端10cm处(0.89±0.10)相比无统计学意义(P>0.05)；BMP4mRNA正常对照组(1.12±0.10)与肠闭锁处(0.67±0.09)、肠闭锁近端5cm处(0.78±0.11)相比有统计学意义(P<0.05),正常对照组(1.12±0.10)与肠闭锁近端10cm处(1.10±0.11)相比无统计学意义(P>0.05)。
结论
1 FGF10、BMP4蛋白及mRNA在先天性肠闭锁闭锁处、闭锁近端5cm的肠壁组织中表达较正常肠壁组织明显减少,这种异常分布与肠神经系统的发育异常有关。
2 FGF10、BMP4蛋白在先天性肠闭锁近端的肠壁组织中表达明显减少且性质稳定,可作为诊断先天性肠闭锁切除范围的一种新的判断指标。
3肠闭锁近端肠管10cm处的FGF10和BMP4的表达接近正常肠管,为了保证术后肠功能顺利恢复,肠管的切除范围应该超过10cm。
Congenital intestinal atresia (CIA), a common neonatal gastrointestinal tract malformation, is the main cause of neonatal intestinal obstruction. At present, the surgery is the only effective method to restore intestinal smooth, but a considerable amount of CIA postoperatives are suffering from a longer period of gastrointestinal motile disorders. Histopathological changes in proximal intestines of CIA are considered to be related to the occurrence of the disease.The trend has been reported at home and abroad that nerve pathological changes of CIA proximal segments are reducing gradually as moving away from the caecum of CIA segment, but the observed scope of intestinal nerve pathological changes is not consistent with the range of intestinal proximal resection. In recent years, a large number of animal studies abroad have shown that FGF10 is closely related to the development of the gastrointestinal tract of the mice. The mice with FGF10 gene defects have gastrointestinal malformations such as duodenal atresia, colon atresia and so on. Meanwhile, it has been proved that BMP4 is related to the development and maturation of intestinal nerve system. Object
By studying the distribution of FGF10 and BMP4 of the proximal intestinal wall in different parts of CIA, this research is to explore the relationship of CIA, FGF10 and BMP4 respectively and to discuss problems of children with intestinal dysfunction after the operations and guide the clinical treatment. Materials and Methods
20 cases of CIA have been studied who have been confirmed by pathological examination and surgical treatment from July 2008 to May 2009 at the Third Affiliated Hospital of Zhengzhou University, of which 3 cases are typeⅠ,10 cases typeⅡ,7 cases typeⅢ. The CIA segments, the proximal 5cm, and 10cm were retained and detected with the method of immunohistochemistry and RT-PCRJ. Children in this group include 12 males and 8 females, aged 1 to 6d, who were full-term children not found other intestinal malformation.20 cases were distributed. 10 cases in control group were dead full-term children with no gastrointestinal tract abnormalities of which six are males and four are females. In RT-PCR control group, 10 cases of normal intestinal tissue from children who took intussusception, intestinal resection and anastomosis, and enterostomy were chosen as control.Those children were aged 5 days to 4 months, who were not found other inestinal malformations and had negative family history.
1 20 cases of CIA segments, proximal 5cm and proximal 10cm were resected, and then FGF10 and BMP4 expressions were observed and compared with 10 cases of normal intestines by immunohistochemical technique.
2 20 cases of CIA segments, proximal 5cm and proximal 10cm were resected, and then FGF10 mRNA and BMP4 mRNA expressions were observed and compared with 16 cases of normal intestines by RT-PCR technique.
3 Statistical analysis:SPSS 16.0 for data analysis. Measurement data are indicated with the mean±and standard deviation (x±s). The mean of samples in each group was compared using single factor analysis of variance, pair comparisons using LSD-t test, the correlation between the factors using pearson correlation analysis, with a=0.05 as standard level and P<0.05 for significant difference. Results
1 Immunohistochemical results:the comparison of FGF10 between normal control group (148.32±1.90), CIA segments (123.41±2.59), and CIA proximal 5cm (137.51±2.13) respectively was statistically significant (P< 0.05) while the comparison of FGF10 between normal controls group (148.32±1.90) and CIA proximal 10cm (147.51±2.76) was not statistically significant (P> 0.05). the comparison of BMP4 between normal control group (206.40±3.22), CIA segments (138.57±2.81),and proximal 5cm (171.01±2.84) respectively was statistically significant (P<0.05), while the comparison of BMP4 between normal controls group (206.40±3.22) and CIA proximal 10cm (204.48±2.18) was not statistically significant (P>0.05).
2 Immunohistochemical results:the comparison of FGF10 mRNA between normal control group (0.95±0.12), CIA segments(0.56±0.08), and CIA proximal 5cm (0.59±0.09) respectively was statistically significant (P<0.05) while the comparison of FGF10 mRNA between normal controls group (0.95±0.12) and CIA proximal 10cm (0.89±0.10) was not statistically significant (P> 0.05). the comparison of BMP4 mRNA between normal control group (1.12±0.10), CIA segments (0.67±0.09), and proximal 5cm(0.78±0.11) respectively was statistically significant (P<0.05), while the comparison of BMP4 between normal controls group (1.12±0.10) and CIA proximal 10cm (1.10±0.11) was not statistically significant (P>0.05). Conclusions
1 The expressions of FGF 10 and BMP4 in CIA segments and proximal 5cm are significantly reduced compared with the normal intestine. This abnormal distribution is related to the abnormal development of nerve system.
2 FGF 10 and BMP4 in CIA proximal intestinal segments are significantly reduced. With its stable nature, both of them can be used as a new indicator of diagnosis of CIA.
3 The expression of FGF 10 and BMP4 in CIA proximal 10cm is close to the normal intestine. Therefore, in order to ensure a smooth postoperative recovery of intestinal function, the scope of intestinal resection should be more than 10cm..
引文
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