重组人生长激素对烧伤大鼠肠粘膜屏障及肠源性感染影响的研究
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摘要
目的
严重烧伤、创伤、休克、感染和大手术等多种病理因素,均可导致肠粘膜屏障功能障碍、肠道菌群生态失调和机体免疫功能受损,使肠道细菌和内毒素不断移位侵入宿主,诱生肿瘤坏死因子(TNF)等众多炎性介质释放,继而触发机体过度的炎症反应、高分解代谢和器官损害。移位的细菌和内毒素及其诱生的炎性介质又反作用于肠道加重其损伤,促进肠道细菌和内毒素移位而成恶性循环。临床上肠源性感染不但与早期暴发性脓毒症、持续的高代谢反应和脓毒性休克的发生、发展密切相关,而且在多器官功能障碍综合征(MODS)的发病机理中起关键作用。肠道是外科应激的一个中心器官,进一步探索防治肠源性感染的有效措施,特别是在严重创伤应激后如何维护或尽快恢复肠道的正常屏障是急需研究的重要课题。生长激素(GH)除具有促进蛋白质合成、加快创伤愈合、改善免疫功能、降低应激反应等作用外,还能够促进肠粘膜细胞增殖、抑制细胞凋亡、维护肠粘膜屏障功能。初步研究显示,GH能够减轻严重创伤应激后肠道细菌/内毒素移位及其并发症,能够改善其预后。然而,针对严重创伤应激后普遍存在的肠道损伤,以防治肠源性感染为主要目的的关于GH有效性的研究尚少,而且研究对象、处理因素各异,甚至出现GH增加危重病人死亡率的报道。
本研究采用能够引起肠源性感染的烧伤后免疫抑制大鼠模型,分别观察、探讨重组人生长激素(rhGH)早期大剂量应用对大鼠肠粘膜屏障、肠粘膜细胞凋亡、肠道细菌/内毒素移位和脓毒症及其预后的影响。
方法
共用成年雄性Wistar大鼠168只,随机分为对照组、烧伤组和GH组。后两
ObjectiveSevere burn, trauma, shock ,infection, major operation and other pathological factors can all lead to intestinal mucosal barrier dysfunction,intestinal flora ecosystem imbalance and the immune dysfunction which may induce bacteria/endotoxin translocation and release of inflammatory mediators such as tumor necrosis factor(TNF).Then excessive systemic inflammatory reactions, hypermetabolism and visceral damage can be triggered out. Translocated bacteria/endotion and inflammatory mediators made the intestinal damage even worse. It might be suggested that the infection subsequent to bacterial translocation from gut play an important role in the pathogenesis of early sepsis, hypermetabolism, septic shock and MODS.Intestine is an central organ involving surgical stress. It's deeply in need and very impotant to explore effective methods to preserve normal intestinal mucosal barrier and prevent gut derived infection caused by trausmatic stress. Besides accelerating wound healing, improving immune function, decreasing stress response,growth hormone(GH)can also promote postbum intestinal mucosal epithelial proliferation and inhibit injury epithelial apoptosis, thus preserve postburn intestinal mucosal barrier function.The current study was performed to explore the role of great dose of recombinant human growth hormone(rhGH)presenting in early postbum stage in maintaining gut barrier, inhibiting mucosal epithelial apoptosis,bacterial/endotoxin translocation,sepsis as well as the prognosis.
Methods168 grown male Wistar rats were randomly divided into three groups, i. e. control,scalding and GH groups.The rats in scalding and GH groups were inflicted with 25% TBSA III degree scalding on the back and immediately followed by intraperitoneal injection of dexamethasone (80 mg/kg) .The scalded rats were administered with normal saline and GH(1.33l>kg*1?d'1)since 2 postburn hours(PBHs),respectively in the last two groups. The following four aspects were invetisgated.1. The protective effect of rhGH on intestinal mucosal barrier in severely scalded rats. rhGh was given for 4 days.The changes of the apoptosis rate,the intestinal mucosal proliferative index(PI) and epithelial ultrastructure and the intestinal mucosal pathomorphology of distal end of ileal mucosal tissue were observed on 30 and 96 PBHs.2. The influence of rhGH on the apoptosis of intestinal mucosal cells in severely scalded rats. rhGHwas given single time at 2PBHs. The changes of intestinal mucosal pathomorphology of distal end of ileal mucosal tissue ,the apoptosis rate of mucosal cells,the expression of apoptosis related protein Fas,FasL,Bcl-2,Bax at 4,8,12,24 PBHs were observed by pathology, TUNEL and immunohistochemistry.3. The influence of rhGH on the intestinal bacteria/endotoxin translocation in severely scalded rats. The scalded rats were administered rhGH at 2 PBHs. The changes of the intestinal bacteria/endotoxin translocation rate, the endotoxin levels in portal and cava vein, the level of TNF a in cava venous serum and the hepatic functions were observed on 8 and 24 PBHs.4. The influence of rhGH on gut derived sepsis and prognosis in severely scalded rats. rhGH was given for three days. The changes of abcess in liver,spleen,kidneys, lung, portal and cava venous, the viable bacterial counts in tissues,the patholigical and functional changes of main organs were obsevered in 4,7,10 postburn days(PBDs). The changes of weight and survivor rate were determined.
Results1. The protective effect of rhGH on intestinal mucosal barrier function ins everely scalded rats. ?The morphological changes in ileal mucosa: 30 PBHs,the scalded group: the intestinal mucosa began to atrophy,some of villi denuded.epithelial cells degenerated,necrotic and denuded. The lamina propria was edema and infiltrated with inflammatory cells.The GH group: the intestinal mucosal structure maintain intact with slight atrophy and submucosal edema in the villi tip. 96 PBHs,the injury of intestinal mucosa of scalded group began to recover,but was still severer than that of control group while the mucosa of GH group was proliferated. ?The ultrastructural changes of intestinal mucosa. 30 PBHs, the scalded group: By transmission electron microscope(TEM) examination,ileal mucosal lacteals were dilated and villi were denuded. By TEM examination,intercellular spaces between epithelial cells were dilated,microvilli were necrotic and denuded,mitochondria were swollen with cracked cristae. The GH group: mucosal epithelia and its cell junction were near those in control group. 96 PBHs, the injury of intestinal mucosa of scalded group began to recover,but the cell junction was still abnormal while it was normal in GH group. (3) The changes of PI and apoptosis rate: The PI in GH and scalding groups at 30 PBHs was evidently higher than that in control group (P<0.05~0.01).But the PI exhibited on obvious difference between scalding and GH groups.While the PI in GH group at 96 PBHs was obviously higher than that in both scalding and control groups(P< 0.01). The intestinal mucosal epithelial apoptotic rate in scalding group was significantly higher than that in control group(P< 0.01),while that in GH group was evidently lower than that in scalding and control group(P<0.05~0.01).2. The influence of rhGH on the apoptosis of intestinal mucosal cells in severely scalded rats. ?The morphological changes of intestinal mucosa: 4 PBHs,scalded group: the mucosa began to be injured and from bad to worse,mucosal membrane became thinner,some villi were atrophic,the cells in the tip of villi degenerated,necrotic and denuded. There were hemorrhage,edema in lamina propria. The lacteal dilated
and filtrated by inflammatory cells. GH group: the mucosal structure was intact with only lamina propria congestive and edema. (2)The changes of apoptosis: 4 PBHs, scalded group: apoptosis positive cells increase significantly(p<0.01), and distributed from tip to base of villi. The apoptosis was markedly severe in submucosa and lamina propria. The phenomenon was most severe at 12 PBHs. It was obviously less in GH group than in scalded group(p<0.05~0.01). ?The changes of expressions of Fas,FasL,Bcl-2,Bax. Distributed from tip to base of villi,the Fas positive cells began to increase 4 PBHs.and got its highest at 8-12 PBHs. It remained markedly higher than control group 24 PBHs (pO.Ol). The Fas positive cells were also increased in GH group, less than in scalded group and was significantly difference 24 PBHs (p<0.05). The expression changes of FasL was similar to Fas. The expresion of Bax increased and Bcl-2 reduced more significant in scald group than GH group(p<0.01 or/?<0.05).3. The influence of rhGH on the intestinal bacteria/endotoxin translocation in severely scalded rats. ?The changes of bacterial translocation. 23 of 4 kinds of normal intestinal bacteria were determined. The intestinal bacteria/endotoxin translocation rate and viable bacterial counts in tissues were evidently lower in GH group than in scalding group ( PO.05 ), while had no significant difference with control group( p>0.05 ). ?The endotoxin levels in portal and cava veins were also evidently lower in GH group than in scalding group (PO.01 ). ?The levels of TNF a in cava vein and were markedly lower in GH group than in scalding group ( P<0.05-0.01 ). ? The indices of hepatic functions such as alanine aminotransferase(ALT) and aspartate aminotransferase(AST) in scalded group were obviously higher than those in control group(p<0.01). ALT of GH group was hihger than that of control group 24 PBHs(/?<0.01),but lower than that of scalded group. AST of GH group was also higher than that of control group and significantly lower than that of scalded group(p<0.01-0.05).4. The influence of rhGH on gut-derived sepsis and the prognosis in severely
scalded rats. (Din scalded group,organic abcess, swelled mesenteric lymph nodes, atrophic intestinal wall as well as ulcer and hemorrhage in intestinal mucosa could be observed. The incidence of abcess in GH group was significantly lower than that in scalded group(p<0.05). ?The changes of respiratory rate,weight and survivor rate: 7 PBDs,the changes of respiratory rate(p<0.01) and weight loss(p<0.05) in GH group were both lower than those in scalded group. The 10 days survivor rate in GH group(9/12) was higher than that in scalded group(5/12). ?Viable bacterial counts: 10 PBDs,78 of 7 kinds normal intestinal bacteria were determined which mostly located in mesenteric lymph nodes(MLN), lung and liver. The level of bacterial count in GH group was significantly lower than that in scalded group(p<0.01). ? Pathological changes: 10 PBDs,the pathological changes in GH group was obviously slighter than that in scalded group. ?The changes of the induces of hepatic and renal functions in vein cava:10 PBDs,ALT and creatinine(Cr) in GH group were significantly lower than that in scalded group(P<0.01) while had no difference with control group(p>0.05). AST and blood urea nitrogen(BUN) in the two groups were both higher than those in control group,however,they were lower in GH group than in scalded group(p<0.01-0.05). Conclusions1. rhGH could promote postburn intestinal mucosa epithelial proliferation in slow-action manner and inhibit injury epithelial apoptosis with rapid and obvious effects.As a result,the intestinal mucosal epithelial injury could be meliorated by rhGH by means of its inhibiting roles and the normal morphological structure of intestinal nucosa was maintained intact.2. rhGH could modulate the expression of apoptosis related protein such as Fas,FasL,Bcl-2,Bax. Which would inhibit the apoptosos of inntestinal mucosal cells and decrease the damage of intestinal mucosa as well as preserver its barrier function.3. rhGH could effectively reduce the intestinal bacteria/endotoxin translocation and decrease the release of inflammatory mediators as well as protect the hepatic functions.
严重烧伤、创伤、休克、感染和大手术等多种病理因素,均可导致肠粘膜屏障功能障碍、肠道菌群生态失调和机体免疫功能受损,使肠道细菌和内毒素不断移位侵入宿主,诱生肿瘤坏死因子(TNF)等众多炎性介质释放,继而触发机体过度的炎症反应、高分解代谢和器官损害。移位的细菌和内毒素及其诱生的炎性介质又反作用于肠道加重其损伤,促进肠道细菌和内毒素移位而成恶性循环。临床上肠源性感染不但与早期暴发性脓毒症、持续的高代谢反应和脓毒性休克的发生、发展密切相关,而且在多器官功能障碍综合征(MODS)的发病机理中起关键作用。肠道是外科应激的一个中心器官,进一步探索防治肠源性感染的有效措施,特别是在严重创伤应激后如何维护或尽快恢复肠道的正常屏障是急需研究的重要课题。生长激素(GH)除具有促进蛋白质合成、加快创伤愈合、改善免疫功能、降低应激反应等作用外,还能够促进肠粘膜细胞增殖、抑制细胞凋亡、维护肠粘膜屏障功能。初步研究显示,GH能够减轻严重创伤应激后肠道细菌/内毒素移位及其并发症,能够改善其预后。然而,针对严重创伤应激后普遍存在的肠道损伤,以防治肠源性感染为主要目的的关于GH有效性的研究尚少,而且研究对象、处理因素各异,甚至出现GH增加危重病人死亡率的报道。
本研究采用能够引起肠源性感染的烧伤后免疫抑制大鼠模型,分别观察、探讨重组人生长激素(rhGH)早期大剂量应用对大鼠肠粘膜屏障、肠粘膜细胞凋亡、肠道细菌/内毒素移位和脓毒症及其预后的影响。
方法
共用成年雄性Wistar大鼠168只,随机分为对照组、烧伤组和GH组。后两
ObjectiveSevere burn, trauma, shock ,infection, major operation and other pathological factors can all lead to intestinal mucosal barrier dysfunction,intestinal flora ecosystem imbalance and the immune dysfunction which may induce bacteria/endotoxin translocation and release of inflammatory mediators such as tumor necrosis factor(TNF).Then excessive systemic inflammatory reactions, hypermetabolism and visceral damage can be triggered out. Translocated bacteria/endotion and inflammatory mediators made the intestinal damage even worse. It might be suggested that the infection subsequent to bacterial translocation from gut play an important role in the pathogenesis of early sepsis, hypermetabolism, septic shock and MODS.Intestine is an central organ involving surgical stress. It's deeply in need and very impotant to explore effective methods to preserve normal intestinal mucosal barrier and prevent gut derived infection caused by trausmatic stress. Besides accelerating wound healing, improving immune function, decreasing stress response,growth hormone(GH)can also promote postbum intestinal mucosal epithelial proliferation and inhibit injury epithelial apoptosis, thus preserve postburn intestinal mucosal barrier function.The current study was performed to explore the role of great dose of recombinant human growth hormone(rhGH)presenting in early postbum stage in maintaining gut barrier, inhibiting mucosal epithelial apoptosis,bacterial/endotoxin translocation,sepsis as well as the prognosis.
Methods168 grown male Wistar rats were randomly divided into three groups, i. e. control,scalding and GH groups.The rats in scalding and GH groups were inflicted with 25% TBSA III degree scalding on the back and immediately followed by intraperitoneal injection of dexamethasone (80 mg/kg) .The scalded rats were administered with normal saline and GH(1.33l>kg*1?d'1)since 2 postburn hours(PBHs),respectively in the last two groups. The following four aspects were invetisgated.1. The protective effect of rhGH on intestinal mucosal barrier in severely scalded rats. rhGh was given for 4 days.The changes of the apoptosis rate,the intestinal mucosal proliferative index(PI) and epithelial ultrastructure and the intestinal mucosal pathomorphology of distal end of ileal mucosal tissue were observed on 30 and 96 PBHs.2. The influence of rhGH on the apoptosis of intestinal mucosal cells in severely scalded rats. rhGHwas given single time at 2PBHs. The changes of intestinal mucosal pathomorphology of distal end of ileal mucosal tissue ,the apoptosis rate of mucosal cells,the expression of apoptosis related protein Fas,FasL,Bcl-2,Bax at 4,8,12,24 PBHs were observed by pathology, TUNEL and immunohistochemistry.3. The influence of rhGH on the intestinal bacteria/endotoxin translocation in severely scalded rats. The scalded rats were administered rhGH at 2 PBHs. The changes of the intestinal bacteria/endotoxin translocation rate, the endotoxin levels in portal and cava vein, the level of TNF a in cava venous serum and the hepatic functions were observed on 8 and 24 PBHs.4. The influence of rhGH on gut derived sepsis and prognosis in severely scalded rats. rhGH was given for three days. The changes of abcess in liver,spleen,kidneys, lung, portal and cava venous, the viable bacterial counts in tissues,the patholigical and functional changes of main organs were obsevered in 4,7,10 postburn days(PBDs). The changes of weight and survivor rate were determined.
Results1. The protective effect of rhGH on intestinal mucosal barrier function ins everely scalded rats. ?The morphological changes in ileal mucosa: 30 PBHs,the scalded group: the intestinal mucosa began to atrophy,some of villi denuded.epithelial cells degenerated,necrotic and denuded. The lamina propria was edema and infiltrated with inflammatory cells.The GH group: the intestinal mucosal structure maintain intact with slight atrophy and submucosal edema in the villi tip. 96 PBHs,the injury of intestinal mucosa of scalded group began to recover,but was still severer than that of control group while the mucosa of GH group was proliferated. ?The ultrastructural changes of intestinal mucosa. 30 PBHs, the scalded group: By transmission electron microscope(TEM) examination,ileal mucosal lacteals were dilated and villi were denuded. By TEM examination,intercellular spaces between epithelial cells were dilated,microvilli were necrotic and denuded,mitochondria were swollen with cracked cristae. The GH group: mucosal epithelia and its cell junction were near those in control group. 96 PBHs, the injury of intestinal mucosa of scalded group began to recover,but the cell junction was still abnormal while it was normal in GH group. (3) The changes of PI and apoptosis rate: The PI in GH and scalding groups at 30 PBHs was evidently higher than that in control group (P<0.05~0.01).But the PI exhibited on obvious difference between scalding and GH groups.While the PI in GH group at 96 PBHs was obviously higher than that in both scalding and control groups(P< 0.01). The intestinal mucosal epithelial apoptotic rate in scalding group was significantly higher than that in control group(P< 0.01),while that in GH group was evidently lower than that in scalding and control group(P<0.05~0.01).2. The influence of rhGH on the apoptosis of intestinal mucosal cells in severely scalded rats. ?The morphological changes of intestinal mucosa: 4 PBHs,scalded group: the mucosa began to be injured and from bad to worse,mucosal membrane became thinner,some villi were atrophic,the cells in the tip of villi degenerated,necrotic and denuded. There were hemorrhage,edema in lamina propria. The lacteal dilated
and filtrated by inflammatory cells. GH group: the mucosal structure was intact with only lamina propria congestive and edema. (2)The changes of apoptosis: 4 PBHs, scalded group: apoptosis positive cells increase significantly(p<0.01), and distributed from tip to base of villi. The apoptosis was markedly severe in submucosa and lamina propria. The phenomenon was most severe at 12 PBHs. It was obviously less in GH group than in scalded group(p<0.05~0.01). ?The changes of expressions of Fas,FasL,Bcl-2,Bax. Distributed from tip to base of villi,the Fas positive cells began to increase 4 PBHs.and got its highest at 8-12 PBHs. It remained markedly higher than control group 24 PBHs (pO.Ol). The Fas positive cells were also increased in GH group, less than in scalded group and was significantly difference 24 PBHs (p<0.05). The expression changes of FasL was similar to Fas. The expresion of Bax increased and Bcl-2 reduced more significant in scald group than GH group(p<0.01 or/?<0.05).3. The influence of rhGH on the intestinal bacteria/endotoxin translocation in severely scalded rats. ?The changes of bacterial translocation. 23 of 4 kinds of normal intestinal bacteria were determined. The intestinal bacteria/endotoxin translocation rate and viable bacterial counts in tissues were evidently lower in GH group than in scalding group ( PO.05 ), while had no significant difference with control group( p>0.05 ). ?The endotoxin levels in portal and cava veins were also evidently lower in GH group than in scalding group (PO.01 ). ?The levels of TNF a in cava vein and were markedly lower in GH group than in scalding group ( P<0.05-0.01 ). ? The indices of hepatic functions such as alanine aminotransferase(ALT) and aspartate aminotransferase(AST) in scalded group were obviously higher than those in control group(p<0.01). ALT of GH group was hihger than that of control group 24 PBHs(/?<0.01),but lower than that of scalded group. AST of GH group was also higher than that of control group and significantly lower than that of scalded group(p<0.01-0.05).4. The influence of rhGH on gut-derived sepsis and the prognosis in severely
scalded rats. (Din scalded group,organic abcess, swelled mesenteric lymph nodes, atrophic intestinal wall as well as ulcer and hemorrhage in intestinal mucosa could be observed. The incidence of abcess in GH group was significantly lower than that in scalded group(p<0.05). ?The changes of respiratory rate,weight and survivor rate: 7 PBDs,the changes of respiratory rate(p<0.01) and weight loss(p<0.05) in GH group were both lower than those in scalded group. The 10 days survivor rate in GH group(9/12) was higher than that in scalded group(5/12). ?Viable bacterial counts: 10 PBDs,78 of 7 kinds normal intestinal bacteria were determined which mostly located in mesenteric lymph nodes(MLN), lung and liver. The level of bacterial count in GH group was significantly lower than that in scalded group(p<0.01). ? Pathological changes: 10 PBDs,the pathological changes in GH group was obviously slighter than that in scalded group. ?The changes of the induces of hepatic and renal functions in vein cava:10 PBDs,ALT and creatinine(Cr) in GH group were significantly lower than that in scalded group(P<0.01) while had no difference with control group(p>0.05). AST and blood urea nitrogen(BUN) in the two groups were both higher than those in control group,however,they were lower in GH group than in scalded group(p<0.01-0.05). Conclusions1. rhGH could promote postburn intestinal mucosa epithelial proliferation in slow-action manner and inhibit injury epithelial apoptosis with rapid and obvious effects.As a result,the intestinal mucosal epithelial injury could be meliorated by rhGH by means of its inhibiting roles and the normal morphological structure of intestinal nucosa was maintained intact.2. rhGH could modulate the expression of apoptosis related protein such as Fas,FasL,Bcl-2,Bax. Which would inhibit the apoptosos of inntestinal mucosal cells and decrease the damage of intestinal mucosa as well as preserver its barrier function.3. rhGH could effectively reduce the intestinal bacteria/endotoxin translocation and decrease the release of inflammatory mediators as well as protect the hepatic functions.
引文
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