摘要
Alpha-黑素细胞刺激素(alpha-melanocyte-stimulating hormone,α-MSH)是由其前体——阿黑皮素原(proopiomelanoeortin)裂解产生,其通过与黑皮素受体(melanocortin receptor,MCR)结合而发挥作用。α-MSH具有很强的抗炎、免疫调节作用。α-MSH具有独特的抗炎特点:它可直接作用于脑细胞,抑制脑局部促炎症细胞因子的产生,保护神经元功能;通过下行神经通路抑制细菌内毒素诱导的外周循环中促炎症细胞因子生成;又可直接作用于外周组织细胞,抑制促炎症细胞因子的产生及活性。α-MSH抑制多种类型的人体细胞产生细胞因子和其他的炎症介质,包括NO和前列腺素等。α-MSH不是完全消除炎症介质的产生,而是适度地抑制其生成量,可以减轻炎症反应程度但却不损害宿主的防御能力。α-MSH的抗炎作用在某种程度上是通过抑制核因子NF-κB完成的。但是α-MSH作为抗炎免疫调节剂,本身也存在缺点,其对MC1-R和MC3-R有较高的选择性,对MC4-R和MC5-R的亲和力很低。我室研制的新型α-MSH类似物显示出对MC1-R和MC5-R的选择性,能减少一定的副作用。
急性肺损伤(acute lung injury,ALI)/急性呼吸窘迫综合征(acute respiratory distresssyndrome,ARDS)是一种常见危重症,病死率极高,严重威胁重症患者的生命并影响其生存质量。ALI/ARDS是在严重感染、休克、创伤及烧伤等非心源性疾病过程中,肺毛细血管内皮细胞和肺泡上皮细胞损伤造成弥漫性肺间质及肺泡水肿,导致的急性低氧性呼吸功能不全或衰竭。以肺容积减少、肺顺应性降低、严重的通气/血流比例失调为病理生理特征,临床上表现为进行性低氧血症和呼吸窘迫,肺部影像学上表现为非均一性的渗出性病变。流行病学调查显示ALI/ARDS是临床常见危重症。尽管ARDS已经研究了近40年,临床重症监护在期间取得了长足的进步。然而ARDS的死亡率仍高达40%～60%。人们对于ALI/ARDS发病机理的研究从未间断,当务之急是建立趋于完善的模拟临床的动物模型。越来越多的研究发现不同原因所致ALI/ARDS的发病原理及病理过程可能会有很大的不同,因而对ALI/ARDS致病动物模型的选用至关重要。目前认为“两次打击理论”更能反映体内的实际发病情况。此理论认为严重多发骨折等创伤作为第1次打击使机体处于中等状态的全身炎症反应综合征,此时如果遭受感染因素或不恰当复苏、手术打击、再次致伤因素等第二次打击,放大了已存在的炎症状态而发生过度的全身炎症反应综合征,会继发急性肺损伤/急性呼吸窘迫综合征以及多器官功能障碍综合征。失血性休克与内毒素血症都是临床多发病,特别是对于战伤,更具有重要的实际意义。因此,本研究选择了先失血性休克,1h后再气道内直接滴入LPS的方式来建立大鼠ALI模型,这样可以造成直接的肺损伤为主的ALI模型。
近年来,许多研究人员对α-MSH在各种脏器炎症中的作用进行了大量的研究并给予了充分的肯定。但是,新型α-MSH类似物在ALI/ARDS中是否有保护作用仍未可知。因此,本课题采用大鼠的二次打击ALI模型研究我室的新型α-MSH类似物对大鼠急性肺损伤的保护作用,并试图探讨一些新的作用机制,同时以α-MSH作为对照。首先是建立大鼠失血性休克+LPS二次打击模型,即采用自制的装置从大鼠颈动脉放血,在15 min内使血压降至40 mmHg,并维持此血压1h。之后,在2h内将全部失血回输至体内,并补充适当的生理盐水以恢复到最初的压力水平。休息1h后,再从气管内滴入LPS进行二次打击,完成ALI模型的制作并维持6h。另有动物除了给予LPS外,还同时给予α-MSH或α-MSH类似物,观察其保护作用。这样可将动物分为四组,即假手术(sham)组,LPS组以及LPS+α-MSH组和LPS+α-MSH类似物组。实验结束后,采用放血法处死大鼠,分别收集血浆、肺泡灌洗液(BALF)及肺组织待检。本实验采用HE染色观察了各组肺组织的病理改变情况;采用ELISA分别检测了BALF中的TNF-α、IL-1β、巨噬细胞移动抑制因子(MIF)及IL-10的浓度;采用化学法测定了BALF和肺组织中LDH、MDA、MPO、总蛋白含量和SOD的活性;采用免疫组化(Immunohistochemistry)方法观察了肺组织的P-选择素(P-selectin)的表达情况;用Western Blot检测了肺组织中血管紧张素转换酶2(ACE2)水平变化;以Real-time PCR方法检测了纤溶酶原激活物抑制剂-1(PAI-1)、细胞因子诱导中性粒细胞化学趋化因子-1(CINC-1)、Clara细胞蛋白(CC16)、血红素加氧酶-1(HO-1)等的表达。结果显示:与sham组比较,LPS组肺组织损伤严重,出现肺泡壁增厚,炎细胞浸润并伴有轻度水肿等病理改变,α-MSH类似物和α-MSH能明显改善这种情况。BALF中TNF-α、IL-1β、MIF、总蛋白含量和LDH代表了肺内炎症状况,前三者为促炎因子,LDH与总蛋白含量相互配合常用来表示肺组织的损伤程度。MDA和SOD反应了肺内的氧化应激水平。肺组织中MPO是用来反映中性粒细胞浸润的一个比较灵敏的指标。在二次打击后,这几项指标显著增高(P＜0.05),而抗炎因子IL-10则无明显降低(P＞0.05),由于其作用的复杂性,其在ALI中的作用还有待于进一步研究。P-选择素在中性粒细胞黏附血管壁的过程中起着很重要的作用,免疫组化结果表明,在给予LPS后,P-选择素表达量增加,同时给予α-MSH类似物或α-MSH则能抑制其表达。大量研究证实,纤溶系统参与了ALI的发生过程,其中PAI-1最为关键。ALI的一个显著特征就是大量的中性粒细胞在肺内被扣押,而CINC-1是大鼠体内最重要的中性粒细胞趋化因子,类似于人体内的IL-8。HO-1和CC16是两个肺内有着重要作用的抗炎因子。Real-time PCR结果显示,二次打击后肺组织内PAI-1、CINC-1和HO-1 mRNA水平显著上调,CC16则下调,α-MSH类似物和α-MSH均能抑制前三者的上调和抑制CC16的下调(P＜0.05)。
本课题的创新点在于:①研究了我室自主设计的新型α-MSH类似物对急性肺损伤的保护作用,各种实验结果表明:α-MSH类似物与α-MSH都能有效地抑制促炎因子TNF-α、IL-1β、粘附分子P-选择素、趋化因子CINC-1以及纤溶系统中的关键因子PAI-1上调,以及能显著地促进抗炎因子HO-1的活性,显示了其抗炎特性。②对α-MSH这种神经内分泌肽调节炎症的作用机制有新的探讨,揭示出α-MSH在趋化因子,粘附分子及纤溶系统方面以前不为人所知的抗炎机制。ALI中最关键的因素是中性粒细胞的浸润,而P-选择素在中性粒细胞穿越内皮细胞的过程中起着重要的作用,介导了中性粒细胞于肺微循环内皮细胞的起始粘附,而α-MSH类似物能有效地抑制这一过程。PAI-1是体内纤溶系统中最重要的抑制物,对于稳定体内正常的血流起着很重要的作用。肺纤溶活性异常是急性和慢性炎症性肿损伤的共同表现。α-MSH能够有效地抑制PAI-1的上调,促进血液循环正常化,缓解肿部炎症。CINC-1是大鼠体内最重要的中性粒细胞趋化因子,而α-MSH也能有效地阻止其上调,这对于抑制中性粒细胞向肺部迁徙和穿越起着不可估量的作用。本课题还研究了与肺部关系密切的两个抗炎因子:HO-1和CC16。α-MSH可以促进CC16的上调和HO-1的下调,这对于判定ALI的病情也具有一定的帮助。③本研究还改进了动物模型的制作。以往的2次打击模型,死亡率高,稳定性和重复性很难令人满意,加之动物个体之间有很大的差异,用这样的模型很难得出令人信服的结论。本研究采用自动调整血压的装置代替注射器抽取,这样更宜于使血压保持稳定,减少大鼠的死亡率,采用定压和定容相结合的办法,来弥补仅基于一项指标的动物模型的不足。实验证明这是一种很好的控制动物失血休克的方法。采用这一方法能最大程度地减少动物的个体差异。既能使血压稳定在某一水平又能保证一定的失血量,更加真实地模拟了休克过程。
Alpha-melanocyte stimulating hormone (α-MSH), an endogenous neuropeptide, is derived from a larger precursor molecule pro-opiomelanocortin (POMC). POMC is a 29-kDa polypeptide that yields the biologically active peptides adrenocorticotropin (ACTH), endorphins (α,β,γ) and melanotropins (α-,β-, andγ-MSH).α-MSH was originally isolated and characterized from the intermediate lobe of the pituitary and it was first recognized by its effect on skin melanophores in lower vertebrates. Although necessary for its influence on pigmentation,α-MSH mediates other biologic functions. It has antipyretic, anti-inflammatory and antimicrobial effects. It is also involved in the control of food intake and body weight.α-MSH is produced by pituitary cells and astrocytes, as well as the cells of skin and other peripheral tissues. Studies revealed that endogenousα-MSH level increases in various clinical and experimental pathologic conditions such as rheumatoid arthritis, myocardial infarction, endotoxemia and HIV infection. Moreover, endotoxin injection to normal subjects causes a marked increase in plasma peptide concentration. In addition to plasmaα-MSH that reaches the tissues, local peptide production at inflammatory sites also increases. These observations suggest that increase inα-MSH concentration during inflammation is a compensatory mechanism and if the peptide is not sufficient to counteract the action of inflammatory mediators, the disease becomes more severe.
The roles ofα-MSH were supported by the gene cloning of a family of specific receptors. To date five melanocortin receptors have been described (MC1R to MC5R). All of them belong to the heterodimeric guanine nucleotide-binding protein (G-protein) coupled family of receptors, characterized by the presence of seven transmembrane repeat spanning domains. Five melanocortin receptor subtypes (MC1-MC5) are recognized. MC1 is expressed in melanocytes, melanoma cells and cells involved in the immune/inflammatory response including monocytes, dendritic cells and lymphocytes. MC2, the ACTH receptor, is mainly expressed in the adrenal glands but also in white adipose tissue and in the skin. MC3 is expressed in the brain, placenta, gut and heart. MC4 occurs in various brain areas but has been recently recognized also in peripheral organs in the rat. The MC5 receptor, initially recognized in the brain, was subsequently found to be ubiquitous, but mainly in the periphery. Antipyretic and anti-inflammatory activities ofα-MSH have been traced to a "message sequence" contained within the COOH-terminal region, the tripeptide Lys-Pro-Val. Although the mechanism of the antimicrobial action is poorly understood, it is conceivable thatα-MSH could be useful in the treatment of various infectious conditions.
However,α-MSH has its limitation as a novel melanogenic drugs, such as higher selective to MC1R and MC3R but lower to MC4R and MC5R. Therefore, a novel alpha-melanocyte stimulating hormone analogue was developmented by our laboratory. This new peptide has been proved to be more selective to MC1R and MC5R. thanα-MSH, two key receptors which the peptide is depended on for its anti-inflammatory activity. Besides, the novel peptide is also an agonist to MC1R, MC3R, MC4R and MC5R. The result shows that our peptide has a good applicative prospect.
The ALI/ARDS may occur as a consequence of critical illness of diverse etiologies, including direct injury to lung, such as pneumonia, aspiration, toxic inhalation, near-drowning, or lung contusion, as well as indirect mechanisms, such as sepsis, burn, pancreatitis, gynecological insults (abruption of placenta, amniotic embolism, eclampsia), or massive blood transfusion. The mortality rate associated with ARDS has declined from 90% about twenty years ago to 30%～40% at present. However, it is still one of the major causes of pulmonary and nonpulmonary morbidity in patients after discharge. Animal studies that have attempted to mimic human ALI/ARDS have been useful and will likely continue to provide valuable observations regarding both the mechanisms underlying the pathogenesis, progression and resolution of this syndrome and ways in which its course can be modulated therapeutically. However, the lack of an animal model that unequivocally mimics key aspects of human ALI/ARDS has been limiting in mechanistic studies and in providing meaningful and rapid extrapolations to the clinical syndrome. Furthermore, there is uncertainty as to which of the many available animal models best reflects the human clinical syndrome. Animal models are usually monitored over a shorter term than the human syndrome, which requires hours or days to develop. A two-hit theory suggests that an initial insult, such as hemorrhage and resuscitation (H/R), primes the host for an exaggerated or abnormal response to a second insult, often infection. Hemorrhagic shock is the most important cause of early death after major trauma. There is increasing evidence that lipopolysaccharide (LPS) induces an inflammatory response in the lung. Therefore, in the present studies, a two-hit model of resuscitated hemorrhagic shock followed by intratracheal LPS in the rodent was used to evaluate the protective mechanisms ofα-MSH and our novel peptide to the lung.
Melanocortins are potent modulators of inflammation. Administration of melanocortins is immunoprotective in models of systemic inflammation, peritonitis, myocardial ischemia, renal ischemia, allergic airway inflammation, experimental heart transplantation, and colonic inflammation. In many of these studies, administration of melanocortin peptides results in the suppression of cytokine production, inhibition of leukocyte infiltration, and preservation of tissue histology. But, according to our present comprehension, its protection on ALI has not been researched. In this paper, a two-hit model of ALI is used to test the anti-inflammatory activity of our novel alpha-melanocyte stimulating hormone analogue and traditionalα-MSH. In this model, characteristic hallmarks of ARDS such as lung edema and interstitial neutrophil infiltration were observed by the evaluation of total protein, TNF-α, IL-1β, MPO, SOD, MDA, P-selectin, PAI-1, CINC-1, CC16, HO-1 and ACE2 by means of histopathology, Real-Time PCR, ELISA, and immunohistochemistry. The data demonstrate that both our new peptide andα-MSH have good protective effect on ALI. For example, the alpha-melanocyte stimulating hormone analogue and traditionalα-MSH can significantly inhibit the upregulation of TNF-α, IL-1β, MPO, SOD and MDA. Besides, some new protective mechanisms of them have been explored, including the regulatory effects ofα-MSH and its noval analogue on the expression of P-selectin, PAI-1, CINC-1, CC16, HO-1 and ACE2. CINCs are known to be potent chemotactic factors for rat neutrophils, and to belong to the IL-8 superfamily. CINCs can induce a marked increase in neutrophils adherent to the venular endothelium, and enhance their transendothelial migration across the venular wall. It is well established that neutrophil-mediated tissue injury is a common mechanism underlying the development of organ dysfunction during acute lung injury including ARDS. Our data demonstrate that both the new peptide andα-MSH have significant inhibition to CINC-1. The accumulation of neutrophils in the lung tissue is initially mediated through increased adhesion of neutrophils to endothelial cells of the inflamed pulmonary microvasculature, and this process requires the upregulation of various adhesion molecules expressed on the surface of pulmonary microvessel endothelial cells as well as circulating neutrophils. Extensive research has demonstrated that activation of coagulation and inhibition of fibrinolysis are thought to underlie the events in ALI. Mechanisms that contribute to the changes in the homeostatic balance include both tissue factor expression and increased plasminogen activator inhibitor (PAI-1) synthesis or release. Similar experiments exposing PAI-1 knockout mice to bleomycin showed a decrease in fibrin deposition in the PAI-1 knockout mice, while controls showed PAI-1 to be increased by bleomycin. Clara cells act as stem cells in the repair of the bronchial epithelium, have a high xenobiotic biotransformation capacity and secrete several substances with important biological activities. One of the major proteins secreted by Clara cells is the 16 kDa Clara cell protein (CC16). Even though the exact in vivo function of the CC16 remains to be clarified, there is growing evidence that this protein plays a protective role against pulmonary inflammatory response. During several months of 2002, severe acute respiratory syndrome (SARS) caused by SARS-coronavirus (SARS-CoV) spread rapidly from China throughout the world, causing more than 800 deaths due to the development of acute respiratory distress syndrome (ARDS), which is the severe form of acute lung injury (ALI). Interestingly, a novel homologue of angiotensin-converting enzyme, termed angiotensin-converting enzyme 2 (ACE2), has been identified as a receptor for SARS-CoV. Angiotensin-converting enzyme and ACE2 share homology in their catalytic domain and provide different key functions in the renin-angiotensin system (RAS). Angiotensin-converting enzyme cleaves angiotensin I to generate angiotensin II, which is a key effector peptide of the system and exerts multiple biological functions, whereas ACE2 reduces angiotensin II levels. Importantly, recent studies using ACE2 knockout mice have demonstrated that ACE2 protects murine lungs from ARDS. Furthermore, SARS-CoV infections and the Spike protein of the SARS-CoV reduce ACE2 expression. Notably, injection of SARS-CoV Spike into mice worsens acute lung failure in vivo, which can be attenuated by blocking the renin-angiotensin pathway, suggesting its key role in ALI. Both the new peptide andα-MSH can significantly inhibit the upregulation of PAI-1 and P-selectin and downregulation of and CC16. However, failure to induce the downregulation of ACE2 after hemorrhagic shock and LPS hits underscores an incomplete understanding of the two-hit model. In general,α-MSH and its new analogue could attenuate the progression of the inflammation, thereby preventing the development of chronic lung disease.
There are three originality of this experiment: first, the novel alpha-melanocyte stimulating hormone analogue has been proved to be effective in the protection against acute lung injury. Second, some new mechanisms of this protection has been discovered, including inhibition of PAI-1, CINC-1 and P-selectin and the modulation of ACE2, HO-1 and CC16 byα-MSH. The third, the two-hit model has been improved to mimic hemorrhagic shock and endotoxemia better.
引文
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