本文選題：人中性粒細(xì)胞多肽 + P2Y6��； 參考：《廣州醫(yī)科大學(xué)》2014年碩士論文

【摘要】：背景 急性呼吸窘迫綜合征（Acuterespiratorydistresssyndrome,ARDS）是由心源性以外的各種肺內(nèi)、外致病因素導(dǎo)致的急性、進(jìn)行性呼吸衰竭，由于缺乏特異有效的治療方法，其病死率仍然高達(dá)36%－44%。保護(hù)性機(jī)械輔助通氣是ARDS目前的主要支持治療手段，也是目前唯一能降低ARDS死亡率的治療手段，有效的藥物治療手段仍然缺乏，而即使是保護(hù)性機(jī)械通氣也無(wú)法避免機(jī)械通氣相關(guān)性肺損傷的發(fā)生，ARDS的死亡率仍居高不下。肺泡上皮及微血管內(nèi)皮通透構(gòu)成呼吸膜結(jié)構(gòu)，任何因素導(dǎo)致的肺泡上皮及肺微血管內(nèi)皮的損傷都將導(dǎo)致肺泡結(jié)構(gòu)的破壞，造成肺氣體交換功能障礙。ARDS的發(fā)病機(jī)制研究對(duì)探索有效的藥物治療手段降低ARDS死亡率至關(guān)重要。肺泡上皮和肺微血管內(nèi)皮通透性增高及肺泡內(nèi)大量中性粒浸潤(rùn)是ARDS急性期的特征性病理表現(xiàn)。活化的中性粒細(xì)胞在肺泡浸潤(rùn)并釋放大量炎癥介質(zhì)和蛋白酶類進(jìn)一步加重肺損傷，并趨化巨噬細(xì)胞細(xì)胞及其他炎癥細(xì)胞的浸潤(rùn)，造成持續(xù)的肺泡損傷。人中性粒細(xì)胞多肽(HNPs)是中性粒含量最多的蛋白，占中性粒細(xì)胞總蛋白5%以上，初級(jí)顆粒蛋白含量的50%以上。研究表明高濃度的HNPs對(duì)肺部損傷的誘導(dǎo)及進(jìn)展具有重要作用。嘌呤受體P2Y家族是一類促代謝型受體，由細(xì)胞外核苷酸激活并通過(guò)G-蛋白偶聯(lián)受體生成細(xì)胞內(nèi)第二信使。P2Y6是P2Y家族成員之一，可介導(dǎo)HNPs誘導(dǎo)IL-8生成，在炎癥誘導(dǎo)及免疫調(diào)節(jié)中具有重要作用。本研究以HNPs刺激原代小氣道上皮細(xì)胞(SAECs)及肺微血管內(nèi)皮細(xì)胞(HPMVECs)，探討HNPs介導(dǎo)SAECs及HPMVECs損傷的相關(guān)機(jī)制及P2Y6在其中的作用。 目的 研究HNPs對(duì)人肺小氣道上皮細(xì)胞及肺微血管內(nèi)皮細(xì)胞通透性的影響。 方法 體外培養(yǎng)人原代小氣道上皮細(xì)胞及肺微血管內(nèi)皮細(xì)胞，以不同濃度的HNPs對(duì)細(xì)胞進(jìn)行刺激，研究細(xì)胞通透性改變。 結(jié)果 1.20μg/ml及50μg/ml HNPs8h刺激可誘導(dǎo)HPMVECs通透性升高，50μg/ml8h刺激可誘導(dǎo)SAECs通透性升高 2. HNPs誘導(dǎo)的HPMVECs及SAECs通透性增加由P2Y6介導(dǎo)，可被MRS2578部分阻斷。 3. HPMVECs對(duì)HNPs敏感性高于SAECs，可能與P2Y6在HPMVCs表達(dá)明顯高于SAECs所致。 結(jié)論 HNPs可通過(guò)P2Y6介導(dǎo)SAECs及HPMVECs通透性增加。 背景 膿毒血癥是感染造成的全身性損傷性炎癥反應(yīng)，膿毒血癥病因復(fù)雜，以肺部感染最為常見(jiàn)，，其中又以革蘭陰性菌為主，由于病原菌陽(yáng)性診斷率低造成膿毒血癥早期診斷及治療困難。另一方面，膿毒癥患者病情異質(zhì)性大，老年患者居多，病人常有不同的基礎(chǔ)疾病，進(jìn)一步加重膿毒癥治療困難。膿毒血癥依病情輕重可分為膿毒血癥，重癥膿毒血癥及膿毒癥休克。目前，膿毒癥發(fā)病率仍以每年5~10%的速度上升，隨病情進(jìn)展患者的死亡率明顯升高，膿毒癥患者整體死亡率為30~50%，是目前ICU面臨的難題。感染誘導(dǎo)全身性炎癥反應(yīng)并造成一系列不同程度的組織器官損傷，如器官功能障礙，凝血與抗凝失衡，全身組織灌注不足與缺血缺氧等，患者最終往往不是死于感染，而是死于感染誘導(dǎo)的全身性損傷性炎癥。感染及其控制程度，全身性炎癥及其導(dǎo)致的組織器官功能障礙，基礎(chǔ)疾病，并發(fā)疾病，疾病進(jìn)展等都不同程度影響患者預(yù)后。衡量患者基礎(chǔ)病情，針對(duì)疾病的本質(zhì)監(jiān)測(cè)病情進(jìn)展，篩選膿毒血癥預(yù)后早期敏感因素，并及時(shí)有效糾正預(yù)后影響對(duì)膿毒血癥患者具重要意義。 目的 對(duì)重癥膿毒血癥患者的預(yù)后進(jìn)行多因素分析，并分析相對(duì)最敏感因素的早期預(yù)測(cè)指標(biāo)，為膿毒血癥早期干預(yù)提供理論依據(jù)。 方法 收集廣州醫(yī)科大學(xué)附屬第一醫(yī)院重癥醫(yī)學(xué)科2012-10-17至2013-8-8膿毒血癥患者臨床資料，納入膿毒血癥患者53例，根據(jù)患者ICU住院期間是否存在凝血功能障礙將病人分為A,B兩組，根據(jù)膿毒血癥嚴(yán)重程度將病人分為膿毒血癥，重癥膿毒血癥，膿毒血癥休克，根據(jù)APACHEII評(píng)分將病人分為低危(APACHEII＜10)，中危(APACHEII≥10)，高危(APACHEII≥20)。入組后記錄患者年齡，性別，等基本臨床資料，并進(jìn)行APACHEII評(píng)分及。24h內(nèi)采取血液標(biāo)本，血漿IL-6，IL-8；血乳酸，血清降鈣素原(PCT)為臨床檢查項(xiàng)目。根據(jù)臨床檢查及表現(xiàn)分析ICU住院期間是否存在凝血功能障礙及凝血功能障礙是否得到糾正與重癥膿毒血癥患者的28天預(yù)后及各影響因素的敏感性分析，并分析患者預(yù)后相對(duì)最敏感因素的早期評(píng)估。 結(jié)果 年齡、性別是重癥膿毒血癥患者28天預(yù)后的混雜因素；膿毒血癥分級(jí)，APACHEII評(píng)分，ICU住院期間是否存在凝血功能障礙及凝血功能障礙是否得到糾正，患者ICU住院首次血乳酸，血清PCT，血漿IL-6，IL-8與患者預(yù)后明顯相關(guān)；是否存在凝血功能障礙及凝血功能障礙是否得到糾正，血乳酸水平是膿毒血癥患者預(yù)后的獨(dú)立影響因素；是否存在凝血功能障礙及凝血功能障礙是否得到糾正是重癥膿毒血癥患者的最敏感預(yù)后影響因素；血漿IL-6，IL-8濃度是膿毒血癥患者是否出現(xiàn)凝血功能障礙的早期預(yù)測(cè)因子。 結(jié)論 膿毒血癥患者病情異質(zhì)性大，預(yù)后影響因素復(fù)雜，血乳酸、是否出現(xiàn)凝血功能障礙及凝血功能障礙是否糾正是膿毒血癥患者預(yù)后的獨(dú)立影響因素。IL-6，IL-8水平與是否出現(xiàn)凝血功能障礙密切相關(guān)，可能成為凝血功能早期檢測(cè)指標(biāo)。本研究以膿毒血癥患者ICU住院期間是否出現(xiàn)凝血功能障礙及28天預(yù)后研究觀察目標(biāo)，以患者入組第一天各項(xiàng)指標(biāo)為監(jiān)測(cè)指標(biāo)，未對(duì)各項(xiàng)指標(biāo)進(jìn)行動(dòng)態(tài)觀察，IL-6，IL-8水平與患者從入組至出現(xiàn)凝血功能障礙的時(shí)間是否存在關(guān)系尚待進(jìn)一步研究。
[Abstract]:background
Acuterespiratorydistresssyndrome (ARDS) is an acute, progressive respiratory failure caused by a variety of pulmonary and external pathogenic factors other than cardiogenic. Due to the lack of specific and effective treatment, the mortality rate is still up to 36% - 44%. protective mechanical ventilation is the main support for the treatment of ARDS. It is also the only treatment that can reduce ARDS mortality, and effective drug treatment is still lacking, and even protective mechanical ventilation can not avoid the occurrence of mechanical ventilation related lung injury. The mortality of ARDS is still high. Alveolar epithelium and microvascular endothelium constitute the respiratory membrane structure, and any factor caused by the lung. The damage of alveolar epithelium and pulmonary microvascular endothelium will result in the destruction of the alveolar structure. The pathogenesis of.ARDS, which causes pulmonary gas exchange dysfunction, is very important for the exploration of effective drug treatment to reduce the mortality of ARDS. The increased permeability of alveolar epithelium and pulmonary microvascular endothelium and a large number of neutrophils in the alveoli are acute phase of ARDS. Characteristic pathological manifestations. Activated neutrophils infiltrate in the alveoli and release a large number of inflammatory mediators and proteases to further aggravate the lung injury, and chemotaxis the infiltration of macrophage cells and other inflammatory cells, causing persistent alveolar damage. Human neutrophil polypeptide (HNPs) is the most neutrophilic protein, which accounts for neutrophils. More than 5% of the total protein and more than 50% of the primary particle protein content. The study showed that the high concentration of HNPs was important for the induction and progression of lung injury. The purine receptor P2Y family is a class of metabolic receptor, activated by extracellular nucleotides and second messenger of.P2Y6 by the G- protein coupling receptor, one of the members of the P2Y family, This study can mediate HNPs induced IL-8 formation, which plays an important role in inflammatory induction and immunomodulation. This study used HNPs to stimulate primary small airway epithelial cells (SAECs) and pulmonary microvascular endothelial cells (HPMVECs) to explore the mechanism of HNPs mediated SAECs and HPMVECs damage and the effect of P2Y6 in it.
objective
Objective to study the effects of HNPs on the permeability of human pulmonary small airway epithelial cells and pulmonary microvascular endothelial cells.
Method
Human primary small airway epithelial cells and pulmonary microvascular endothelial cells were cultured in vitro and stimulated with different concentrations of HNPs to study cell permeability changes.
Result
1.20 mu g/ml and 50 g/ml HNPs8h stimulation can induce HPMVECs permeability increase, and 50 g/ml8h stimulation can induce SAECs permeability increase.
2. the permeability of HPMVECs and SAECs induced by HNPs was mediated by P2Y6 and partially blocked by MRS2578.
3. the sensitivity of HPMVECs to HNPs is higher than that of SAECs, which is probably higher than that of P2Y6 in HPMVCs expression.
conclusion
HNPs can increase the permeability of SAECs and HPMVECs through P2Y6.
background
Sepsis is a systemic inflammatory response caused by infection. The etiology of sepsis is complex and the most common in the lung infection, which is mainly Gram-negative bacteria. Because of the low diagnostic rate of pathogenic bacteria, the early diagnosis and treatment of sepsis are difficult. On the other hand, the patients with sepsis are with large heterogeneity and many elderly patients. There are often different basic diseases that further aggravate the difficulty of the treatment of sepsis. Sepsis can be divided into sepsis, severe sepsis and septic shock according to the severity of the disease. At present, the incidence of sepsis is still rising at the rate of 5~10% every year. The mortality of patients with progressing is significantly higher, and the overall mortality rate of sepsis is 30~50%, ICU is a difficult problem at present. Infection induces systemic inflammatory response and causes a series of different degrees of tissue and organ damage, such as organ dysfunction, coagulation and anticoagulant imbalance, deficiency of whole body tissue perfusion and ischemia and hypoxia, and the patients are often not dying from infection, but die from infection induced systemic inflammatory inflammation. Infection and The degree of control, systemic inflammation and its resulting tissue and organ dysfunction, basic disease, disease, and disease progression all affect the patient's prognosis in varying degrees. Measure the patient's basic condition, monitor the disease progression, screen the early sensitivity factors of the prognosis of sepsis, and correct the prognosis effect on sepsis in time and effectively. The patient is of great significance.
objective
The prognosis of patients with severe sepsis was analyzed by multifactor analysis, and the early prediction indexes of the relative most sensitive factors were analyzed to provide the theoretical basis for the early intervention of sepsis.
Method
The clinical data of patients with sepsis from 2012-10-17 to 2013-8-8, the First Affiliated Hospital of Guangzhou Medical University, were collected and included in 53 patients with sepsis. The patients were divided into A and B two according to the presence of coagulation dysfunction during the hospitalization of ICU, and the patients were divided into sepsis and severe sepsis according to the severity of sepsis. Septic shock was divided into low risk (APACHEII < 10), middle risk (APACHEII > 10), and high risk (APACHEII > 20). The age, sex, and other basic clinical data were recorded in the group, and the APACHEII score and the blood samples in.24h, the plasma IL-6, IL-8, blood lactic acid, and serum calcitonin (PCT) were the clinical examination items. Objective. On the basis of clinical examination and performance analysis, an analysis of the 28 day prognosis of patients with severe sepsis and the sensitivity analysis of the 28 day prognosis of patients with severe sepsis and the early evaluation of the relative most sensitive factors in patients with severe sepsis were analyzed.
Result
Age, sex was a confounding factor in the 28 day prognosis of severe sepsis; sepsis grading, APACHEII score, whether coagulation dysfunction and coagulation dysfunction were corrected during ICU hospitalization; patients with ICU first blood lactic acid, serum PCT, plasma IL-6, IL-8 were significantly related to the prognosis of patients; and the presence of coagulation function was found. Whether obstruction and coagulation dysfunction are corrected, blood lactic acid level is an independent prognostic factor in patients with sepsis; whether or not clotting dysfunction and coagulation dysfunction are corrected is the most sensitive prognostic factor in patients with severe sepsis; plasma IL-6, IL-8 concentration is a coagulant in patients with sepsis. Early predictors of blood dysfunction.
conclusion
Patients with sepsis have large heterogeneity and complex prognostic factors. Blood lactic acid, coagulation dysfunction and coagulation dysfunction are independent factors that affect the prognosis of patients with sepsis.IL-6. The level of IL-8 is closely related to the appearance of coagulation dysfunction. This study may be an early detection index of coagulation function. In patients with sepsis, whether coagulation dysfunction and 28 days of prognosis were observed during the hospitalization of patients with sepsis, the indexes of the first day of the patients were monitored as the monitoring indexes and no dynamic observation on the indexes was carried out. The relationship between the level of IL-6, IL-8 and the time of the patients from entering the group to the obstruction of coagulation function remains to be further studied.

【學(xué)位授予單位】：廣州醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R563.8

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