一氧化氮在大鼠肝脏缺血预处理中的作用

为探讨ＮＯ是否参与缺血预处理对肝脏的保护作用，本实验将动物分成四组：①正常对照组，不作肝门阻断；②再灌对照组：肝脏进行６０分钟的肝门阻断及３０分钟的再灌注；③预处理组：６０分钟的肝门阻断前先进行５分钟的肝脏缺血及５分钟的再灌注；④预处理加Ｌ－ＮＮＡ（Ｐ＋Ｌ）组：在预处理前先经门静脉注射Ｌ－ＮＮＡ。各组均在３０分钟再灌注完成时取肝组织标本及血标本检查ＡＴＰ、肝功能、脂质过氧化产物。结果显示：经过６０分钟的缺血及３０分钟的再灌注后，再灌对照组肝功能明显受损、ＡＴＰ浓度下降、脂质过氧化产物增加。预处理则能明显改善肝功能、增加ＡＴＰ储备和减少脂质过氧化。Ｐ＋Ｌ组则与再灌对照组无显著差异。结果表明：ＮＯ合成抑制剂Ｌ－ＮＮＡ能阻断缺血预处理对肝脏缺血再灌注损伤的保护作用，说明ＮＯ参与大鼠肝脏缺血预处理     

缺血预适应对老年大鼠缺血-再灌注心肌的影响

目的探讨缺血预适应（ischemic preconditioning,IPC）对老年大鼠缺血-再灌注损伤（I/R）后心肌的影响。方法取Wistar大鼠56只,其中21~23月龄（老年鼠）和4~5月龄（青年鼠）各28只,建立离体心脏Langendorff灌注模型,按随机数字表法分为7组（每组8只）：青年对照组、青年I/R组、青年IPC组、老年对照组、老年I/R组、老年IPC组、老年强化IPC组。对照组采用全心灌流90 min,不做任何处理;I/R组采用心脏平衡灌流30min后,缺血30 min,再复灌30     

Effects of Ozone Oxidative Preconditioning on Liver Regeneration after Partial Hepatectomy in Rats

ABSTRACT

Aim: Similar protective effect of ischemic and ozone oxidative preconditioning (OzoneOP) in hepatic ischemia–reperfusion (I/R) injury was demonstrated, providing evidences that both preconditioning settings shared similar biochemical mechanisms of protection. We investigated the effects of OzoneOP on liver regeneration after 70% partial hepatectomy (PHx) in rats. Methods: Rats were divided into three groups: PHx, I/R + PHx, and OzoneOP + I/R + PHx groups. Ozone (intraperitoneal, 1.2 mg/kg) was given to rats subjected to I/R and 70% hepatectomy daily five times before operation. At 24 hr and 48 hr after resection, samples were collected for the measurement of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6). Moreover, liver regeneration rate, proliferating cell nuclear antigen (PCNA) labeling index, mitotic index, and histopathological examination were evaluated. Results: OzoneOP reduced liver injury determined by liver histology and serum transaminases. There was a rise in serum TNF-α and IL-6 levels in the I/R + PHx group whereas OzoneOP significantly decreased the rise in the level of TNF-α but not IL-6 on the 24 hr and 48 hr of reperfusion. Moreover, liver regeneration in OzoneOP + PHx group, as assessed by the regenerated liver weight, mitotic, and PCNA-labeling index, was significantly improved when compared to I/R + PHx group. Conclusion: These results suggest that OzoneOP ameliorates the hepatic injury associated with I/R and has a stimulatory effect on liver cell regeneration that may make it valuable as a hepatoprotective modality.     

MicroRNA-1和microRNA-21在缺血预处理、后处理及远端预处理中的表达变化

目的 通过离体缺血-再灌注心脏模型,观察缺血预处理(IPC)、缺血后处理(IPO)和肢体远端预处理(RIPC)后心脏microRNA1(miRNA-1)和microRNA21 (miRNA-21)的表达变化,以及它们所调控靶蛋白热休克蛋白70 (HSP70)和程序性细胞死亡4(PDCD4)表达变化,期望从miRNA调控水平揭示心脏的内源性保护机制.方法 取Sprague-Dawley (SD)大鼠心脏,建立离体Langendorff心肌缺血-再灌注模型,随机分为4组(每组12只),对照组、IPC组、IPO组和RIPC组.检测各组血流动力学指标,蛋白印迹法(Western blotting)检测PpDCD4、HSP70、B细胞淋巴瘤/白血病-2(Bc1-2)和Bc1-2相关X蛋白(Bax)含量,taqman探针法检测miRNA-1和miRNA-21含量,末端脱氧核苷酸转移酶介导的原位缺口标记法(TUNEL)检测心肌细胞凋亡,2,3,5-氯化三苯基四氮唑(TTC)法检测心肌梗死面积. 结果 IPC组心肌的miRNA-1和miRNA-21表达明显高于对照组,但RIPC组和IPO组心肌的miRNA-1表达较对照组明显降低( P＜0.05).IPC组、RIPC组和IPO组心肌中HSP70、PDCD4和Bax蛋白含量较对照组明显减少(P＜ 0.05),Bc1-2蛋白含量各组间差异无统计学意义.IPC组、RIPC组和IPO组左室心肌梗死面积/左室总面积以及心肌细胞凋亡率明显低于对照组(P＜ 0.05). 结论 miRNA-1和miRNA-21在缺血预处理、缺血后处理和远端预处理后,表达变化是不同的,同时各处理组中miRNA与其靶蛋白并不都是负性调节关系.     

缺血预处理对大鼠肝脏移植物再灌注早期NF-κB活性的影响及意义

目的 观察缺血预处理对大鼠肝脏移植后再灌注早期核转录因子-κB(NF-κB)活性和TNF-α、细胞间黏附分子-1(ICAM-1)表达的影响,探讨缺血预处理的保护机理.方法 建立大鼠肝脏移植模型,供肝在林格液中保存2 h,实验分假手术组、对照组和缺血预处理组(IP组)3组,IP组于供肝切取前夹闭第一肝门10 min,然后开放10 min.分别于移植再灌注后1、2、4及6 h抽血进行肝酶学检查,切取肝脏作NF-κB活性、TNF-α和ICAM-1表达的测定.结果 IP组肝功能得到有效改善.与假手术组比较,对照组及IP组再灌注后移植物的NF-κB活性明显增强,且在1、2 h达高峰,4 h后减弱,TNF-α和ICAM-1表达也随之增加;同对照组相比,IP组的NF-κB活性降低,并且在1、2 h差异具有统计学意义(P＜0.05),TNF-α和ICAM-1表达亦降低.结论 缺血预处理对于供肝的保护作用可能是通过抑制再灌注早期NF-κB的活性,减少了TNF-α和ICAM-1炎症介质的释放,从而减轻了移植物再灌注早期的炎症反应实现的.     

缺血预处理对大鼠移植肝脏缺血再灌注损伤的保护作用

目的　探讨缺血预处理 (ischemicpreconditioning ,IP)对大鼠移植肝脏缺血再灌注损伤的保护作用。 方法　采用SD大鼠原位肝移植动物模型 ,供肝冷保存时间 10 0min ,无肝期 2 5min。 64只SD大鼠随机均分成两组 :对照组 ,获取供肝前仅以肝素生理盐水经门静脉灌注 ;IP组 ,获取供肝前阻断肝门血供 10min ,再灌注 10min ,然后再以肝素生理盐水经门静脉灌注。每组受体的一半 (n =8)用于观察存活率 ,另一半 (n =8)用于移植肝脏再灌注 2h后取血及肝脏检测。结果　IP组的 1w存活率、胆汁分泌量、抗氧化酶活力、血清NO水平均明显高于对照组 (P<0 .0 5 ) ,血清ALT、AST、LDH、TNF及肝组织中的过氧化产物含量均明显低于对照组 (P<0 .0 5 ) ,组织的病理改变也轻于对照组。结论　IP能够提高血清NO水平 ,降低血清TNF含量 ,对大鼠移植肝脏的缺血再灌注损伤具有保护作用     

Cardiac Effect of Ischemic Preconditioning and Heparin Following Intestinal Ischemia and Reperfusion in Rats

To study the role of heparin and ischemic preconditioning (IPC) in cardiac injury after intestinal ischemia (I) and reperfusion (R), 54 rats underwent 60 minutes of I, which was produced by occlusion of the superior mesenteric artery, and/or 120 minutes of R. The IPC group had the I procedure stimulation for 5 minutes and R for 10 minutes. The control group was subjected to sham surgery only, and the other groups were injected with saline solution (SS; 0.1 mL) or heparin (100 IU/kg) via the inferior cava vein 5 minutes before I and 5 minutes before R and 55 minutes after the R begins in I-R groups. In all animals, cardiac samples were stained with hematoxylin and eosin for optical microscopy analysis, and other sample was processed for lipid peroxidation determination. In I-R groups, both heparin and IPC showed significant protection compared to the SS group; conversely, in animals subjected only to I, no protection was observed. Moreover, when heparin was associated with IPC, I-R protection was compromised and the ischemic injury increased. Data showed that IPC and heparin attenuated cardiac dysfunction caused by intestinal I and I-R, but when used in association did not show beneficial effects.     

Role of Ischemic Preconditioning in Liver Surgery and Hepatic Transplantation

Introduction  

The purpose of this review is to summarize intraoperative surgical strategies available to decrease ischemia–reperfusion injury associated with liver resection and liver transplantation.     

生长抑素对鼠大部肝切除术后肝再生的影响

目的　探讨生长抑素对肝切除术后肝再生的影响。　方法　 6 0只SD大鼠随机分为对照组及生长抑素组 ,按Higgins方法行 70 %肝切除术 ,术后给药并分批于术后 6、2 4、48、72、96h处死 ,作如下比较 :①残肝肝重 ;②增殖细胞核抗原 (PCNA)标记指数 ;③图像定量分析测量PCNA阳性产物面积。　结果　与对照组比较 ,生长抑素组残肝肝重在术后 48、72、 96h显著降低 (P <0 .0 5 ) ,PCNA标记指数、PCNA阳性产物面积在术后 2 4、48、72h显著降低 (P <0 .0 5 ) ,且以 2 4、 48h最为明显 (P <0 .0 1)。　结论　生长抑素能抑制肝再生 ,且肝再生程度越强 ,抑制效应越明显     

The Effect of Normothermic Recirculation is Mediated by Ischemic Preconditioning in NHBD Liver Transplantation

We have evaluated the involvement of hepatic preconditioning mediators (adenosine, adenosine A1 and A2 receptors) during normothermic recirculation (NR) in a model of liver transplantation from non-heart-beating donor (NHBD) pigs. Application of NR after 20 min of warm ischemia (WI) reversed the lethal injury associated with transplantation of NHBD livers (achieving 5-day survival and diminishing glutathione S-transferase (GST), aspartate aminotransferase (AST) and hyaluronic acid (HA)). Adenosine administration prior to WI simulated the effect of NR. Measuring adenosine, we found that during NR, hepatic adenosine levels increased and xanthine levels decreased. Then when we blocked A2 receptors the effect of NR was abolished, whereas the blocking of A1 receptors further protected the liver. Furthermore, A2 blocking improved hepatic perfusion during NR whereas A1 blocking reduced it. The study suggests that NR has a preconditioning effect by maintaining adequate adenosine and xanthine levels. During NR, adenosine protects the liver through A2 activation and damages it through A1 activation although simultaneous stimulation of both receptors exerts a clear beneficial effect. The possible relation of NR mechanism with other preconditioning mediators such as cAMP and nitric oxide synthesis are discussed.     

缺血预处理对肝缺血再灌注后氧自由基损伤的保护作用

目的 探讨缺血预处理(PC)对肝缺血再灌注损伤的保护作用机制。方法 将18只犬随机分为三组:非缺血对照组、缺血再灌注组和缺血预处理组。对各组肝上下腔静脉血进行谷丙转氨酶(ALT)、谷草转氨酶(AST)、乳酸脱氢酶(LDH)以及丙二醛(MDA)和超氧化物歧化酶(SOD)、过氧化氢酶(CAT)、谷胱甘肽过氧化酶(GSH-PX)活性及总抗氧化(TAX)能力测定。结果 全肝缺血再灌注后ALT、AST、LDH和MDA含量明显上升(P<0.01),SOD、CAT、GSH-PX活性及TAX能力明显下降(P<0.01,P<0.05);而缺血预处理组与缺血再灌注组比较,ALT、AST、LDH和MDA含量明显下降(P<0.01,P<0.05),SOD、CAT、GSH-PX活性及TAX能力明显上升(P<0.01,P<0.05)。结论 缺血预处理能增强肝组织自身抗氧化能力,减轻肝缺血灌注后氧自由基对肝脏的损伤。     

Ischemic Postconditioning Modified Renal Oxidative Stress and Lipid Peroxidation Caused By Ischemic Reperfusion Injury in Rats

Several recent studies have shown that ischemic postconditioning (IPostC) protects hears from ischemic reperfusion insults in various animal models. However, the mechanism of IPostC remains unclear. In the present study, we investigated the hypothesis that PostC protected kidneys against ischemic reperfusion injury by modifying renal oxidative stress and lipid peroxidation. Rats underwent 45 minutes of renal pedicle ligature followed by reperfusion for 1, 3, 6, 12, or 24 hours. IPostC was performed using 6, 10 second cycles of reperfusion and 10 seconds of renal pedicle occlusion at the end of the ischemia. Our data showed that IPostC attenuated renal dysfunction, significantly increasing the activity of antioxidases, including superoxide dismutase (SOD), catalase (CAT), and glutathione perokidase (GSH-Px) in renal homogenates, and concentrations of GSH and SOD expression. The level of malondialdehyde (MDA) and the activity of myeloperoxidase (MPO) were significantly decreased in IPostC rats. These results indicated that the protective effects of IPosC may be related to modification of renal oxidative stress and lipid peroxidation caused by ischemic reperfusion injury in rats.     

低温对缺血预调心肌保护作用的影响

目的:为确定体外循环心脏直视手术时应用"缺血预调"(IPC)的可能性,分别在两部分实验中研究了(1)IPC对长时间低温缺血心肌的保护作用.(2)IPC期间心肌低温对IPC诱导心肌保护作用的影响.方法:建立离体灌注的大鼠工作心脏模型,稳定后施行不同的预调方案,进而缺血停搏.在预调处理前和缺血再灌注后两次测定工作心脏的主动脉流量(AF).在第一部分研究中,离体心脏在18℃低温条件下缺血60分钟,IPC方案为1b组:5分钟缺血+5分钟再灌注(5×1);1c组:5分钟缺血+5分钟再灌注,反复2次(5×2);1d组:5分钟缺血+5分钟再灌注,反复3次(5×3).1a组为对照组,缺血前不施行预调处理.在第二部分研究中,离体心脏在37℃条件下常温缺血15分钟,实验组(包括6组:Ⅱ,Ⅲ,Ⅳ,Ⅴ,Ⅵ和Ⅶ组)的预调方案均为5×1,但IPC期的心肌温度不同,其中:Ⅱ组为37℃,Ⅲ组32℃,Ⅳ组27℃,Ⅴ组22℃,Ⅳ组17℃,Ⅶ组12℃.Ⅰ组为对照组,缺血前不施行预调处理.结果:在第一系列研究中,对照组的主动脉流量(AF)仅恢复到缺血前的2.7%.预调各组的AF恢复程度显著提高,与对照组比较1b组为22%(P＜0.01),1c组为34%(P＜0.0,1d组为14,9%(P＜0.05).5×2的预调方案具有最强的心肌保护作用.在第二系列研究中,预调期温度高于22℃的各组AF恢复程度显著提高.其中Ⅱ组为76%,Ⅲ组70%,Ⅳ组71%,Ⅴ组62%.而对照组AF恢复不足20%(Ⅱ、Ⅲ、Ⅳ、Ⅴ组与对照组比较,P＜0.05),Ⅵ组和Ⅶ组的AF恢复值与对照组比较差异均不显著,表明IPC期心肌温度低于22℃时,无心肌保护作用.结论:无论在常温或低温(＞22℃)条件下进行缺血预调均有显著的心肌保护作用,IPC有可能应用于改进体外循环合并中度低温时心脏手术的心肌保护.     

Different Intervals of Ischemic Preconditioning on Small Bowel Ischemia-Reperfusion Injury in Rats

Purpose

The purpose of this study was to establish morphologically the best time of vascular occlusion to induce ischemic preconditioning (IPC) for rat small bowel undergoing ischemia and reperfusion injury.

Methods

After approval by the Ethics Committee, 36 EPM-1 young adult Wistar rats from 300-350 g were distributed into 6 groups: sham (S); ischemia and reperfusion (IR), with 50 minutes of cranial mesenteric artery occlusion and 30 minutes of reperfusion; IPC with 1 cycle of 2 minutes (IPC-2), 5 minutes (IPC-5), 10 minutes (IPC-10), or 15 minutes (IPC-15), followed by sustained IR. The animals anesthetized with ketamine (60 mg/kg) and xylazine (10 mg/kg) intramuscular (IM), were maintained on mattress heat, hydrated with saline (80 mL/kg), and injected with 100 IU heparin. Samples of jejunum were stained with hematoxylin and eosin (HE) and classified according to Park et al. Statistical analysis of results was performed using Kruskal-Wallis tests (P < .05).

Results

The histological evaluation showed no difference between IR and IPC15 rats (5.2 and 5, respectively; P = .84). Greater jejunal injury was observed with IPC15 (5) compared with other groups (IPC2 = 3, P = .03; IPC5 = 3.2, P = .05; IPC10 = 2.8, P = .02, respectively). There was no difference between groups IPC2 × IPC5 × IPC10.

Conclusion

Morphologically, IPC with short times promoted greater intestinal protection against the IR lesion in rats.     

Ischemic Preconditioning and Atenolol on Lung Injury After Intestinal Ischemia and Reperfusion in Rats

The aim of this study was evaluate the beta blocker atenolol (AT) and ischemic preconditioning (IPC) strategies for tissue protection against systemic effects of intestinal ischemia (I) and reperfusion (R) injury. Forty-two rats were pretreated with AT (1.5 mg · kg⁻¹), 0.9% saline solution (SS; 0.1 mL), or IPC and then subjected to prolonged occlusion of the superior mesenteric artery for 60 minutes leading to I followed or not by 120 minutes of R, according to the group. For IPC, 5 minutes of I prior to 10 minutes of R were established. After this process of I or I-R, the right lung of each animal was adequately prepared for staining with hematoxylin and eosin and subsequent histologic analysis for quantification of inflammatory infiltrate was done. The left lung was frozen and prepared for assessment of oxidative stress by the quantification of thiobarbituric acid-reactivity substances (TBARS). Histologic analysis showed an important inflammatory infiltrate in the I-R + SS (I-R + SS = 4.5), which was significantly (P < .05) reduced by IPC (I-R + IPC = 3.0) or AT (I-R + AT = 3.0). Likewise, the TBARS levels were decreased by both strategies (I-R + SS = 0.63; I-R + IPC = 0.23; I-R + AT = 0.38; P < .05). Our results showed that AT and IPC attenuate pulmonary lesions caused by intestinal I and R process.     

Is Ischemic Preconditioning a Useful Strategy in Steatotic Liver Transplantation?

This study examined the effect of preconditioning on steatotic livers for transplantation and attempted to identify the underlying protective mechanisms. Blood flow alterations, neutrophil accumulation, tumor necrosis factor alpha release and lipid peroxidation were observed in nonsteatotic livers after transplantation. Steatotic and nonsteatotic liver grafts were similar in their blood flow, neutrophil accumulation, and TNF release after transplantation. However, in the presence of steatosis, lipid peroxidation and hepatic injury increased. In addition, recipients of steatotic liver grafts were more vulnerable to lung damage associated with transplantation. The conversion of xanthine dehydrogenase to xanthine oxidase and the accumulation of xanthine during cold ischemia was greater in steatotic than in nonsteatotic liver grafts. The results obtained with xanthine oxidase inhibitors indicated that xanthine/xanthine oxidase could be responsible for the increased lipid peroxidation as well as the exacerbated liver and lung damage associated with transplantation of steatotic livers. Preconditioning reduced the xanthine accumulation and percentage of xanthine oxidase seen in steatotic liver grafts during cold ischemia, and conferred protection against liver and lung damage following transplantation. The benefits of preconditioning could be mediated by nitric oxide. These findings suggest that preconditioning could be a relevant new strategy to protect against the inherent risk of steatotic liver failure following transplantation.     

Delayed Ischemic Preconditioning Protects Against Liver Ischemia-Reperfusion Injury In Vivo

Objectives

Ischemic preconditioning (IP) affords resistance to liver ischemia-reperfusion (IR) injury, providing an early phase of protection. Development of delayed IP against IR injury was assessed using partial IR in rat liver.

Methods

The IP manuver (10 minutes of ischemia and up to 72 hours of reperfusion) was induced before 1 hour of ischemia and 20 hours of reperfusion. At the end of the reperfusion period, blood and liver samples were analyzed for serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), haptoglobin and tumor necrosis factor-α (TNF-α) levels, hepatic histology, protein carbonyl and glutathione (GSH) contents as well as nuclear factor-κB (NF-κB), and activating protein-1 (AP-1) DNA binding.

Results

The IP manuver significantly increased protein carbonyl/GSH ratios (275%), serum ALT (42%), and AST (58%); these changes normalized after 12 hours. Serum AST, ALT, and LDH levels were significantly increased by IR (4-, 5.6-, and 7.0-fold, respectively), with significant changes in liver histology, protein carbonyl/GSH ratio (481% enhancement), and serum TNF-α (6.1-fold increase). Delayed IP in IR animals reduced serum AST (66%), ALT (57%), and LDH (90%) and liver GSH depletion (89%), with normalization of protein carbonyl content, serum TNF-α levels, and liver histology. Enhanced AP-1/NF-κB DNA binding ratios and diminished haptoglobin expression induced by IR were normalized by IP.

Conclusion

These data support that delayed IP suppresses IR-induced liver injury, oxidative stress, and TNF-α response, which coincide with recovery of IR-altered signaling functions represented by normal AP-1/NF-κB DNA binding ratios and acute phase responses.     

Neuroprotective Effect of Epidural Electrical Stimulation against Ischemic Spinal Cord Injury in Rats: Electrical Preconditioning

Background: Electroconvulsion therapy is likely to serve as an effective preconditioning stimulus for inducing tolerance to ischemic brain injury. The current study examines whether electrical stimuli on the spinal cord is also capable of inducing tolerance to ischemic spinal cord injury by transient aortic occlusion.

Methods: Spinal cord ischemia was induced by occlusion of the descending thoracic aorta in combination with maintaining systemic hypotension (40 mmHg) during the procedure. Animals implanted with epidural electrodes were divided into four groups according to electrical stimulation and sham. Two groups consisted of rapid preconditioning (RE group, n = 8) and sham procedure (RC group, n = 8) 30 min before 9 min of spinal cord ischemia. In the two groups that underwent delayed preconditioning, rats were exposed to 9 min of aortic occlusion 24 h after either pretreatment with epidural electrical stimulation (DE group, n = 8) or sham (DC group, n = 8). In addition, rats were exposed to 6-11 min of spinal cord ischemia at 30 min or 24 h after epidural electrical stimulation or sham stimulation. The group P50 represents the duration of spinal cord ischemia associated with 50% probability of resultant paraplegia.

Results: Pretreatment with electrical stimulation in the DE group but not the RE group protected the spinal cord against ischemia, and this stimulation prolonged the P50 by approximately 15.0% in the DE group compared with the DC group.     

大鼠肝移植后肝再生的实验研究

目的：探讨部分肝移植术后移植肝的再生问题。方法：建立大鼠部分肝移植模型，实验分为肝切除组（PLR组）、全肝移植组（OLT组）和部分肝移植组（POLT组）3组，分别于术后不同时间段取外周血检测总胆红素和谷丙转氨酶水平；取肝组织行组织学检查及流式细胞仪检测移植肝的增殖活性。结果：移植术后1w，肝功能酶学指标增高，后逐步降低；组织学检查术后可见单核细胞浸润，特别在门静脉周围汇管区，肝实质可见点状坏死。术后1个月可见胆管增殖；PLR组和POLT组还可见二倍体和多倍体的肝细胞，中央小静脉、肝窦和叶间静脉轻度扩张。PLR组和POLT组肝细胞增生活跃，3组分别于术后1d、2d、4d达到增殖高峰。结论：部分移植肝和肝切除后肝脏具有同样的增殖活性，但增殖高峰POLT组及OLT组均要晚于肝切除后的肝脏，但移植组增殖周期长。这可能是由于手术操作及肝脏缺血再灌注损伤所致。而持续时间长可能与受体免疫系统产生的细胞因子和激素的调控相关。