炎症因子介导腔梗进展-Inflammation-Mediated Damage in Progressing Lacunar Infarctions
Inflammation-Mediated Damage in Progressing
Lacunar Infarctions
A Potential Therapeutic Target
Mar Castellanos,MD;JoséCastillo,MD,PhD;María M.García,MD,PhD;Rogelio Leira,MD,PhD;
Joaquín Serena,MD,PhD;Angel Chamorro,MD,PhD;Antoni Dávalos,MD,PhD
Background and Purpose —The mechanisms underlying neurological deterioration in patients with lacunar infarction are not completely understood.In this study,we sought to investigate the role of proinflammatory molecules in the early worsening and outcome of acute lacunar stroke.
Methods —We performed a secondary analysis of 113consecutive patients with lacunar infarction included within the first 24hours of the onset of symptoms in a previous study aimed at investigating clinical and biochemical factors of early neurological deterioration (END).END was defined as a fall of ?1points in the motor items of Canadian Stroke Scale between inclusion and 48hours.Poor outcome at 3months was considered death or Barthel Index ?85.Interleukin-6(IL-6),tumor necrosis factor-?(TNF-?),and intercellular adhesion molecule-1(ICAM-1)were determined by enzyme-linked immunoabsorbent assay in blood samples obtained on admission.
Results —END was recorded in 27patients (23.9%);poor outcome was noted in 26(23%).Median (quartiles)concentrations in plasma of TNF-?[16.5pg/mL (13.7and 21.2pg/mL)versus 7.5pg/mL (6.2and 9.0pg/mL)],IL-6[28.8pg/mL (22.5and 35.7pg/mL)versus 11.5pg/mL (8.5and 16.2pg/mL)],and ICAM-1[285pg/mL (219and 315pg/mL)versus 158pg/mL (137and 187pg/mL)]were significantly higher in patients who had END than in those with nonprogressing strokes (P ?0.001).Significant differences were also observed between patients with poor and good outcome at 3months.Logistic regression analysis after adjustment for potential confounders showed that TNF-??14pg/mL and ICAM-1?208pg/mL were independently associated with both END (OR,511;95%CI,17to 4937;P ?0.001;and OR,315;95%CI,17to 5748;P ?0.001,respectively)and poor outcome at 3months (OR,3.0;95%CI,1.0to 8.5;P ?0.042;and OR,4.2;95%CI,1.3to 13.6;P ?0.015,respectively).
Conclusions —High concentrations of inflammatory markers in blood are associated with END and poor functional outcome in lacunar infarctions.These findings suggest that inflammation contributes to brain injury in lacunar stroke.(Stroke .2002;33:982-987.)
Key Words:cytokines Ⅲinflammation Ⅲlacunar infarction Ⅲstroke outcome
A
pproximately 30%of all ischemic stroke patients have lacunar infarctions,and between 25%and 35%of them suffer neurological deterioration within the first few hours of the onset of symptoms and have a worse prognosis.1–8Although some clinical factors have been associated with progressing lacunar stroke,4–7the mechanisms involved in this progression have not been clearly established.Clinical and experimental research over the last few years has shown that inflammatory mechanisms participate in stroke-induced brain damage.9–11Increased levels of cytokines such as interleukin (IL)-1,tumor necrosis factor-?(TNF-?),and IL-6,12–15as well as adhesion molecules such as intercellular adhesion molecule-1(ICAM-1),16–18have been observed
after experimental brain ischemia.Clinical studies have reported increased levels of proinflammatory cytokines 19–22and adhesion molecules 23–25in the peripheral blood and cerebrospinal fluid (CSF)of patients with ischemic stroke.High IL-6concentrations in CSF and plasma have been associated with larger infarct size,neurological deterioration,and poor outcome independently of the stroke subtype.19,22,26–29
However,although accumulating evidence suggests that inflammatory-mediated damage plays a role in brain ische-mia,it remains unclear whether inflammation also intervenes in lacunar stroke progression and outcome.In this study,we sought to investigate the potential association between high
Received October 18,2001;final revision received December 12,2001;accepted December 12,2001.
From the Section of Neurology (M.C.,J.S.,A.D.)and Unit of Biostatistics (M.M.G.),Hospital Universitari Doctor Josep Trueta,Girona,Spain;Service of Neurology,Hospital Clínico Universitario (J.C.,R.L.),Santiago de Compostela,Spain;and Service of Neurology,Hospital Clinic Universitari (A.C.),Barcelona,Spain.
Partial results of this investigation were presented at the 26th International Stroke Conference,Fort Lauderdale,Fla,February 14–16,2001.
Correspondence to Dr Antoni Dávalos,Sección de Neurología,Hospital Universitari Doctor Josep Trueta,17007Girona,Spain.E-mail adavalose@meditex.es
?2002American Heart Association,Inc.Stroke is available at https://www.wendangku.net/doc/4817841560.html,
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concentrations of proinflammatory molecules in blood and the poor prognosis of lacunar infarctions.
Subjects and Methods
We performed a secondary analysis of 113consecutive patients (mean age,69.7?9.3years;57%male)with lacunar infarction included within the first 24hours of the onset of symptoms in a previous study aimed at investigating clinical and biochemical factors of early neurological deterioration (END)in lacunar stroke.30The control group included 43healthy subjects (60.4%male;age,55?17years)without neurological disorders or inflammatory dis-eases.Patients with inflammatory or infectious diseases,cancer,hematological diseases,and severe renal and liver failure,as well as those who were under treatment with antiinflammatory drugs,were excluded.The study was approved by the ethics committees of both hospitals,and informed consent was obtained from patients or their relatives.A detailed description of the protocol has been published elsewhere.30In summary,it included a medical history with record-ing of potential stroke risk factors,clinical examination,blood and coagulation tests,12-lead ECG,chest radiography,arterial supraaor-tic trunk examination,and transcranial Doppler.Cranial CT was carried out at admission,and CT or MRI was repeated between the third and seventh days of the onset of symptoms.The second neuroimaging study was taken as the gold standard for the identifi-cation of lacunar infarction.Evaluation of all CT scans and MRI was carried out by the same neuroradiologist who was blinded to the clinical and biochemical results.Topographic classification of lacu-nar infarctions was assessed according to our previously defined criteria.30Lacunar stroke was diagnosed when the patient had 1of the clinical lacunar syndromes 1,31lasting ?24hours,no evidence of cortical dysfunction,and a normal or deep focal infarction with a diameter ?15mm in an appropriate location visualized by CT scan and/or MRI.
Stroke severity was quantified by an experienced neurologist using the Canadian Stroke Scale (CSS)32at admission and 48hours after inclusion.The CSS measures level of consciousness (alert ?3,drowsy ?1.5);speech (normal ?1,expressive deficit ?0.5,receptive deficit ?0);orientation (oriented ?1,disoriented or not applica-ble ?0);facial paresis (none ?0.5,present ?0);and weakness in arm,hand,and leg (none ?1.5,mild ?1,significant ?0.5,total ?0,scored individually for each item),with a total score ranging from 1.5(maximum deficit)to 10(absence of deficit).A fall of ?1points in the motor items of the CSS between admission and 48hours was considered neurological deterioration.In accordance with the diag-nostic criteria for lacunar stroke,only changes in the motor items of CSS were considered.The Barthel Index was used to evaluate the functional condition of patients at 3months.Poor outcome was defined as death or a Barthel Index score of ?85,which is the level at which patients report that they need help performing day-to-day activities,with a sensitivity of 95%and specificity of ?80%.33
Laboratory Tests
On admission,blood samples were collected in tubes with potassium edetate,centrifuged at 3000g for 5minutes,and immediately frozen and stored at ?80°C.Plasma IL-6,TNF-?,and ICAM-1levels were measured with commercially available quantitative sandwich enzyme-linked immunoabsorbent assay kits (Quantikine;R&D Sys-tems).These determinations were blinded to clinical and radiological data.Plasma glutamate and GABA levels were quantified by high-performance liquid chromatography as previously described.30
Statistical Analysis
Proportions between groups were compared by use of the ?2test.Given that proinflammatory molecules were not normally distrib-uted,they were expressed as median (quartiles)and compared between 2groups by the Mann-Whitney test.The Kruskal-Wallis test was used to compare the inflammatory molecule concentrations of 5groups of patients with different degrees of improvement or worsening in CSS score between admission and 48hours (absolute
differences:group 1,?2;group 2,1.5and 1.0;group 3,0.5,0,and ?0.5;group 4,?1.0and ?1.5;and group 5,?2.0).
Spearman ’s correlation coefficient was used to analyze the asso-ciation between inflammatory molecules and baseline continuous variables,including age,time from onset to inclusion,CSS score,systolic and diastolic blood pressures,body temperature,hematolog-ical and biochemical parameters,and glutamate and GABA concentrations.
Logistic regression analysis was used to determine the importance of the inflammatory markers in END and poor outcome of lacunar stroke.The first models were fitted to assess the adjusted odds ratios (ORs)of END and poor outcome for the proinflammatory molecules.Those clinical variables that reached a value of P ?0.15in the bivariate analysis were included as covariates.The parallel kinetic of release between TNF-?and IL-6probably determines the high correlation that exists between these 2molecules.This high corre-lation did not permit us to perform the analysis including TNF-?,IL-6,and ICAM-1in the same model.Because TNF-?seems to act
TABLE 1.Baseline Clinical Characteristics and Biochemical Parameters
Male sex,n (%)64(56.6)Age,y
69.7?9.2Mean time from stroke onset to blood sampling,h 10.3?6.9History of stroke risk factors,n (%)Arterial hypertension 61(54)Cigarette smoking 27(23.9)Alcohol intake (?40g/d)27(23.9)Atrial fibrillation 13(11.5)Diabetes mellitus
35(31)Prior stroke or transient ischemic attack 33(29.2)Aspirin intake before stroke 15(13.3)Clinical characteristics CSS on admission
7.8?1.2Lacunar syndrome on admission,n (%)Pure motor hemiparesis 59(52.2)Pure sensory stroke 12(10.6)Ataxic hemiparesis 5(4.4)Dysarthria or clumsy hand 4(3.5)Sensory-motor stroke 33(29.2)Suspected cause,n (%)Large-artery atherosclerosis 15(13.3)Cardioembolism 23(20.4)Small-vessel disease 72(63.7)Undetermined*
3(2.7)Biochemistry and vital signs at admission Plasma glucose,mg/dL 156?47Plasma fibrinogen,mg/dL 399?92Hematocrit,%
39.0?5.8Leucocyte count,103/mm 38.3?1.9Platelet count,105
/mm
3
204?79Systolic blood pressure,mm Hg 178?26Diastolic blood pressure,mm Hg 92?14Body temperature,°C
36.7?0.7
Continuous variables are expressed as mean ?SD.
*Coexistence of 2potential causes of stroke:atrial fibrillation and severe ipsilateral carotid or middle cerebral artery stenosis.
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as the primary“trigger”of the inflammatory cascade,13a first analysis was carried out including only plasma TNF-?and ICAM-1 concentrations.Inflammatory markers were included as categorical variables because the cutoffs meant that there was a lack of linearity of the ORs(1?high,0?low).Cutoff values were calculated by the method described by Robert et al.34Because we previously found a relationship between neurotransmitter amino acids and the progres-sion of lacunar infarctions,30the odds of END for TNF-?and ICAM-1were further adjusted for plasma glutamate and GABA concentrations.
Results
The main characteristics of the studied population are sum-marized in Table 1.Plasma IL-6,TNF-?,and ICAM-1 concentrations were significantly higher in patients with lacunar infarctions than in the control group(Table2). Similar levels of proinflammatory molecules were found between groups classified by the suspected cause of lacunar stroke,lacunar syndromes,and the presence or absence of the main stroke risk factors such as hypertension,diabetes mellitus,atrial fibrillation,and prior stroke or transient ischemic attack(data not shown).However,significantly lower levels of IL-6[11.2pg/mL(7.2and13.8pg/mL)versus 15.8pg/mL(9.8and26.2pg/mL),P?0.01],TNF-?[7.6 pg/mL(6.5and9.4pg/mL)versus8.3pg/mL(6.4and16.2pg/mL),P?0.05],and ICAM-1[141pg/mL(129and166) versus169pg/mL(143and213pg/mL),P?0.01]were found in the15patients who were under aspirin treatment at stroke onset compared with those who did not take aspirin.
TNF-?[11.5pg/mL(7.8and16.2pg/mL)versus7.6pg/mL (6.2and13.3pg/mL),P?0.01]and ICAM-1[193pg/mL(153 and264pg/mL)versus162pg/mL(138and196pg/mL), P?0.01]but not IL-6concentrations were significantly higher in patients with lacunar infarctions located at the basal ganglia and brainstem than in those with normal CT/MRI or lacunar infarc-tions located at the white matter.
Plasma concentrations of the proinflammatory molecules did not correlate with age,time from stroke onset to inclu-sion,baseline CSS score,body temperature,systolic and diastolic blood pressures,hematocrit,platelet and leukocyte count,and fibrinogen and glucose levels(data not shown). However,significant correlations were found between gluta-mate and GABA levels and concentrations of IL-6(r?0.46 and r??0.47),TNF-?(r?0.39and r??0.42),and ICAM-1 (r?0.34and r??0.44)(all P?0.001).
END was recorded in27patients(23.9%),and poor outcome at3months was found in26(23%).Thirteen patients(48%)with END and13patients(15%)without END had poor outcome(P?0.001).As previously described, baseline clinical and radiological factors associated with subsequent END were history of hypertension,high leuko-cyte count,and basal ganglia or brainstem location of lacunar infarction,whereas prior treatment with aspirin prevented worsening.30Patients with poor outcome showed a signifi-cantly higher baseline stroke severity(mean?SD CSS score, 7.2?1.0versus8.0?1.2;P?0.003),systolic blood pressure (191?26versus174?25mm Hg,P?0.006),serum glucose (177?39versus150?48mg/dL,P?0.009),and body
tem-Figure1.Median values and quartiles(25%and75%)of plasma in?ammatory markers by early clinical course and outcome at3
months.*P?0.05;**P?0.001.
TABLE2.Median Concentrations of Inflammatory Markers in
Patients With Lacunar Infarctions and Control Subjects
Patients
(n?113)
Control Subjects
(n?43)P
IL-6,pg/mL13.9(9.2,23.8) 3.1(1.3,4.1)?0.001
TNF-?,pg/mL8.2(6.4,15.3)7.0(5.7,8.4)0.001
ICAM-1,pg/mL187(172,223)167(140,207)0.015
Numbers in parentheses are quartiles.
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perature (37.0?0.7°C versus 36.7?0.6°C,P ?0.013)com-pared with those with good outcome.
As shown in Figure 1,median plasma levels of IL-6,TNF-?,and ICAM-1on admission were significantly higher in patients with END than in patients who remained stable or improved during the first 48hours.The levels of the inflam-matory molecules were also significantly higher in those patients with poor outcome at 3months.Although the median values of these biochemical compounds were higher in those patients with any degree of END,we did not observe a graded relationship between concentrations of IL-6,TNF-?,and ICAM-1and the degree of change in the CSS score (Figure 2).
Logistic regression analysis showed that plasma TNF-??14pg/mL and ICAM-1?208pg/mL were significantly associated with neurological deterioration independently of the history of arterial hypertension,leukocyte count,and infarct location (Table 3).All patients taking aspirin at the onset of stroke had a subsequent nonprogressing course,so the model could not be adjusted for this particular factor.However,the results of the logistic model were not modified after the exclusion of patients under prior treatment with aspirin.The ORs of END for TNF-?and ICAM-1did not change after adjustment for plasma glutamate and GABA concentrations (Table 4).Plasma TNF-??14pg/mL (OR,3.0;95%CI,1.0to 8.5;P ?0.042),ICAM-1?208pg/mL (OR,4.2;95%CI,1.3to 13.6;P ?0.001),and baseline CSS score (OR,0.48;95%CI,0.29to 0.79;P ?0.004)were independently associated with poor outcome at 3months.
Discussion
This study demonstrates in a large series of patients with lacunar infarctions an independent association of high levels of inflammatory molecules in blood with END and poor outcome.The effect of these compounds on END was stronger because the outcome depends particularly on base-line stroke severity.The mechanisms involved in END of lacunar infarctions have not been clearly established,and it seems unlikely that those factors currently accepted as con-tributing to worsening in other stroke subtypes offer a full explanation in the case of lacunar stroke.Increase in infarct volume has been proposed as the main cause of neurological deterioration,6,35a fact that could be explained by a delayed propagation of neuronal death mediated by multiple
molec-Figure 2.Median values and quartiles of plasma in ?ammatory molecule levels by absolute difference in CSS score between admission and 48hours.A,IL-6concentrations (Kruskal-Wallis test,P ?0.001);B,TNF-?concentrations (Kruskal-Wallis test,P ?0.001);C,ICAM-1concentrations (Kruskal-Wallis test,
P ?0.001).Horizontal lines indicate cutoff values as selected by the method of Robert et al.34
TABLE 3.Adjusted ORs of END for Baseline Clinical,CT,and Biochemical Variables
Variable
OR (95%CI)P History of hypertension 79(4.2–1475)0.003Leukocyte count,103/mm 3 1.2(0.70–2.05)0.517Topography on CT*7.7(0.6–97)0.113TNF-??14pg/mL 511(17–14937)?0.001ICAM-1?208pg/mL
315(17–5748)
?0.001
Cutoff values of TNF-?and ICAM-1were calculated by the method of Robert et al.34(see Subjects and Methods).
*Infarct location in basal ganglia or brainstem.
TABLE 4.ORs of END for Inflammatory Markers After Adjustment for Serum Glutamate and GABA Concentrations
Variables OR (95%CI)
Model A Model B Model C TNF-??14pg/mL 39(4.6-336)
28(3.0-266)37(1.6-863)ICAM-1?208pg/mL 125(14.7-1067)76(8.1-712)
70(3.0-1594)Glutamate ?200?mol/L ???
11(2.1-59)
???
GABA ?240nmol/L
??????
184(11.7-2893)
Model A was not adjusted for neurotransmitters;model B was adjusted for serum glutamate concentrations;model C was adjusted for serum GABA concentrations.Cutoff values were calculated by the method of Robert et al 34(see Subjects and Methods).
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ular and cellular mechanisms such as excitotoxicity and inflammation.We have recently reported that excitotoxicity may play a role in the pathophysiology of progressing lacunar infarctions.30High plasma glutamate concentrations and low GABA levels on admission were significantly associated with subsequent neurological worsening.The present findings support the hypothesis that inflammation may also have an important role in the progression of lacunar infarctions.TNF-?promotes the expression of adhesion molecules such as ICAM-1on the endothelium,facilitating leukocyte adherence and migration from capillaries into the brain,microvessel occlusion,and subsequently a progressive reduc-tion in blood flow.13,36The accumulation of polymorphonu-clear neutrophil leukocytes in the ischemic area as a result of the inflammatory process has been proved in a few clinical observations with brain scintigraphy or brain SPECT with labeled leukocytes.37,38High levels of TNF-?have been detected as soon as 15hours in brain samples of stroke victims,peaking during days 2and 3,39and plasma determi-nations after acute stroke have demonstrated an early activa-tion of ICAM-1,which peaks within 24hours of cerebral ischemia.23,25These findings are in accordance with our results because we found increased TNF-?and ICAM-1levels within 24hours (mean,11hours)of the onset of lacunar stroke.High levels of adhesion molecules may reflect a prior condition of chronic endothelial activation secondary to risk factors for atherosclerosis 40such as hypertension,which was significantly more frequent in our patients who had END.In this study,however,high ICAM-1levels remained independently associated with subsequent END after controlling for the history of hypertension in the logistic analysis.
An interesting finding in this study is that inflammatory molecules contributed to END after adjustment for glutamate and GABA concentrations in blood and that the ORs for TNF-?and ICAM-1were even higher than that for glutamate concentrations (see Table 4).These results suggest that inflammation may have an additional and stronger role than excitotoxicity in END of lacunar infarctions.30On the other hand,inflammatory and excitatory mechanisms might coop-erate in the progression of lacunar stroke because we have found a significant correlation between glutamate or GABA concentration and inflammatory markers in blood.Further-more,as occurred with amino acid concentrations,30we have observed higher levels of inflammatory molecules in patients with lacunar infarctions located in basal ganglia and brain-stem than in those with white matter infarctions,so excito-toxicity and inflammation might represent sequential and interacting processes in the progression of lacunar stroke,particularly in brain areas with a high density of glutamater-gic neurons.41This hypothesis is supported by experimental data suggesting that cytokines influence glutamate receptor-mediated excitotoxicity.The addition of TNF-?to human brain cell cultures of embryonic neurons previously treated with glutamate resulted in an increase in neuronal loss,which was blocked with anti –TNF-?antibodies and with the addi-tion of NMDA-receptor antagonists.42Other experiments have shown that the infusion of a low dose of IL-1receptor antagonist causes a 71%reduction in the volume of infarction
induced by NMDA-receptor activation,43whereas the admin-istration of IL-10,which has been related to neuroprotective actions,results in a reduction in glutamate-induced neuronal death.44
One of the major questions in our study is whether increased inflammatory molecules in blood are the expression of brain ischemia or originate as a result of the acute-phase reaction or systemic causes.Several facts support the idea that plasma levels of IL-6,TNF-?,and ICAM-1within the first 24hours of acute stroke reflect the total release of these molecules in the ischemic brain tissue.Although in this work we have not performed CSF determinations,previous studies have shown a good correlation between CSF and plasma levels of inflammatory molecules.22,27As we previously reported in this series of patients,30END and non-END groups did not show differences with respect to cardiovascu-lar risk factors,stroke severity,pathophysiology,biochemical parameters,and vital signs evaluated at the moment in which blood samples were taken,so we cannot attribute the differ-ences in levels of inflammatory molecules to a different acute-phase response or a distinct prior comorbidity.Al-though potential asymptomatic infections were not excluded by appropriate serological investigations,fever and other medical conditions were similar in frequency in both groups.However,a possible participation of systemic causes or an acute-phase reaction in the serum levels of inflammatory molecules cannot be totally ruled out.
A further point of interest is that prior treatment with aspirin was associated with lower levels of proinflammatory molecules in blood and with a lack of END in lacunar stroke.Some clinical studies have demonstrated that aspirin may reduce the severity and size of cerebral infarction,as well as the frequency of END.45,46Recently,a neuroprotective effect of aspirin has been proposed because low doses of aspirin,at the antiplatelet range,have been related to inhibition of glutamate release in both clinical and experimental conditions of focal cerebral ischemia.47,48Furthermore,high doses of aspirin may inhibit the activation of necrosis factor-?
B and,in turn,the inflammatory cytokines.49However,a confounder effect of aspirin in this study may be reasonably ruled out because the association between high levels of proinflamma-tory molecules and END or poor outcome remained after exclusion of patients taking aspirin.
Although our work has only partially evaluated the effects of the inflammatory cascade,the present findings suggest that inflammation contributes to the END and poor prognosis of lacunar infarctions.Further studies are needed to confirm these promising results,which open new therapeutic avenues in lacunar infarctions.
Acknowledgments
This study was partially supported by a grant from the Programa da Promoci ón Xeral da Investigaci ón do Plan Galego de IDT da Xunta de Galicia (PGIDT99PX120803B)and by the Fundaci óDoctor Josep Trueta.
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Inflammation-Mediated Damage in Progressing Lacunar Infarctions: A Potential
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急性心肌梗死患者中几种炎症因子与传统心肌损伤标志物的相关性研究_何晨
基础研究 中国分子心脏病学杂志 V o l u m e 10 N o .4 A u g u s t 2010 急性心肌梗死患者中几种炎症因子与传统心肌损伤标志物的相关性研究 何 晨 唐晓芳 袁晋青 陈纪林 杨跃进 陈珏 尤士杰 吴元 李健军 刘海波 吴永建 姚 民 秦学文 乔树宾 高润霖 【摘要】目的 选取多个炎症因子—基质金属蛋白酶抑制剂1（TIMP1）,基质金属蛋白酶9（MMP9），新蝶呤（Neopterin ），观察其在急性心肌梗死（AMI ），不稳定性心绞痛、稳定性心绞痛和正常人群中的不同表达水平以及与传统心肌损伤标志物之间的相互关系，以期探索其在AMI 发病进展过程中的作用和用于预测急性心梗风险的可行性。方法 从收住本院的患者中，入选AMI51例，不稳定性心绞痛48例，稳定性心绞痛54例，正常人44例。所有患者的确诊依据世界卫生组织诊断标准和中华医学会的相关指南。所有患者均接受冠脉造影检查，同时采集血标本。用ELISA 法分别测定4组患者的MMP9,TIMP1和Neopterin 浓度。所得数据使用SPSS 统计软件处理，以P<0.05作为有统计学意义的显著性差异。各个数据之间的相关采用单回归线性分析检验。结果 （1）基本临床资料：四组之间在年龄和高血脂，糖尿病发病率上无显著性差异，正常组男性，高血压和吸烟史相对其他组较少。稳定心绞痛和不稳定心绞痛高血压的发生率高于急性心梗。（2）传统的心肌损伤标志物和炎症因子检测结果：高敏C 反应蛋白，肌酸激酶，肌酸激酶同工酶和肌钙蛋白I ，急性心梗组皆高于其他3个组，有显著性差异。而其他三组之间并无显著性差异。（3）其他炎症因子检测结果：，MMP9、TIMP1、 MMP9/TIMP1以及 Neopterin 各个指标， AMI 组皆高于其他3组，有显著性差异。其他三个组相互之间并无显著性差异。(4) 入选病人的Hs-CRP 与Neopterin 和CK 呈良好的正相关性(P<0.05)，而MMP9/TIMP1与hs-CRP 及CK 皆无相关性。Neopterin 与CK 也无相关性。结论 在AMI 患者,炎症因子MMP9、TIMP1、 Neopterin 均明显升高，除Neopterin 与Hs-CRP 有良好相关性以外，其他的炎症因子与传统的心肌损伤标志物并无相关性。 【关键词】 急性心梗 心梗标记物 炎症因子 Markers of In ? ammation Comparison with Traditional Myocardial Infarction Biomarker in Patients with Acute Myocardial Infarction qing, HA Chen,TANG Xiao-fang,YUAN Jin-qing,CHEN Ji-lin, YANG Yue-jin,CHEN Jue,YOUShi-jie,WU Yuan,LI Jianjun,LIU Hai-bo,WU Yong-jian,YAO Min,QIN Xue-wen,QIAO Shu-bin,GAO Run-lin.Center for Coronary Heart Disease, Fuwai Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100037, China. 【Abstract 】 Objective we selected several inflammation biomaker ,such as TIMP1,MMP9, Neopterin,and observed concentration levels in patients with acute myocardial infarction, unstable angina, stable angina and normal.Methods 197 patients were chosen, and was divided into 4 groups - acute myocardial infarction group(51 patients), unstable angina group (48 patients), stable angina(54 patients), and normal group(44 patients).All patients were to make a de ? nite diagnosis by WTO and Chinese Medical Association guideline. The blood plasma was collected and concentration was assayed by ELISA. Statistical analysis was performed using SAS software methods for small samples. A P value<0.05 was considered statistically signi ? cant. Result (1) Clinical characteristics: There were no signi ? cant differences in age and the prevalence of hyperlipemia and diabetes mellitus. In normal group, there were less men, hypertension and smoke history. (2)In AMI groups, there were a higher levels in Hs-CRP,CK,CK –MB and CTnI. There were no signi ? cant differences in traditional myocardial infarction biomarker between other three groups. (3)In AMI groups ,there were a higher levels in MMP9.TIMP1.MMP9/TIMP1 and neopterin. There were no signi ? cant differences in in ? ammation biomarker between other three groups.(4)There were a association between Hs-CRP and neopterin ,CK(P <0.05). Conclusion In AMI groups ,the in ? ammation biomakers(MMP9,TIMP1, neopterin) were signi ? cant elevated. There was an association between Hs-CRP and neopterin. There were no correlation between other in ? ammation biomarkers and traditional myocardial infarction biomarkers. 【Key words 】 Acute myocardial infarction; Myocardial infarction biomaker; Markers of in ? ammation 作者单位：100037 北京市，北京协和医学院 中国医学科学院 心血管病研究所 阜外心血管病医院 冠心病诊疗中心通讯作者：袁晋青 Email ：jqyuan29007@https://www.wendangku.net/doc/4817841560.html,
脓毒症患者血清炎症因子动态变化及其意义
脓毒症患者血清炎症因子动态变化及其意义 发表时间：2017-10-27T16:51:04.180Z 来源：《医药前沿》2017年10月第29期作者：商嘉1 梁彦平2 赵连强3 李晓峰1（通讯作者）[导读] 脓毒症是重症病人主要死亡原因，早期诊断和有效治疗可有效降低病死率 [1]。 （1石河子大学医学院第三附属医院急诊ICU科新疆石河子 832000） （2石河子大学医学院第三附属医院急救中心新疆石河子 832000） （3石河子大学医学院第三附属医院急诊科新疆石河子 832000） 【摘要】目的：探讨炎症因子IL-1、IL-6、IL-10在脓毒症患者早期诊断及预后判断中的作用。方法：2016年2月-2017年1月收集54例脓毒症患者，30例同期健康体检者作为对照组。病例组按入院0、1、2、3、7天测血清IL-1、IL-6、IL-10、PCT并进行APACHEII、SOFA评分。对照组测入组时血清IL-1、IL-6、IL-10、PCT水平。分析炎症因子、PCT对脓毒症早期诊断及预后评估的价值。结果：脓毒症患者入院时，IL-1、IL-6、IL-10、PCT均高于对照组，且随治疗均呈下降趋势；脓毒症早期诊断各指标AUC比较，PCT＞IL-1＞IL-6＞IL-10；IL-1、PCT、APACHEⅡ评分、SOFA评分水平均高于生存组；各指标预测脓毒症病死率AUC比较，SOFA＞PCT＞APACHEⅡ＞IL-1＞IL-10＞IL-6。结论：IL-1、IL-6、IL-10是辅助脓毒症早期诊断的良好指标，IL-1与脓毒症预后有关，IL-6、IL-10与脓毒症预后无关。【关键词】脓毒症；炎症因子；降钙素原；危重症评分 【中图分类号】R631+.1 【文献标识码】A 【文章编号】2095-1752（2017）29-0197-03 脓毒症是重症病人主要死亡原因，早期诊断和有效治疗可有效降低病死率 [1]。PCT一度作为脓毒症诊断指标之一[2]，但PCT在病毒感染时不能有效鉴别脓毒症[3]。脓毒症公认的机制之一为机体促炎反应/抗炎反应的失衡。因此，我们拟通过观察炎症因子的动态变化，探讨其对脓毒症进行早期诊断及预后判断的意义。 1.资料与方法 1.1 分组、入选标准以及排除标准 收集2016年2月-2017年1月我院脓毒症患者54例，并收取同期健康体检者30例作为对照组。 入选标准[4]： 脓毒症：可疑或明确感染以及SOFA总分急性改变≥2。 排除标准：年龄小于18岁；入院24小时内死亡或自动出院；妊娠；肿瘤；使用免疫抑制剂的患者；不同意参加本研究的患者。 1.2 样本收集及验证因子水平的检测 病例组于入院0、1、2、3、7天采集全血，3000rpm，离心10min，取血清。采用电化学发光法检测IL-1、IL-6、IL-10、PCT检测，并进行APACHEⅡ评分及SOFA评分。 1.3 观察指标 各时间点IL-1、IL-6、IL-10、PCT水平及APACHEⅡ评分、SOFA评分；比较各指标对脓毒症早期诊断及预后的ROC曲线下面积。 1.4 统计学方法 数据采用SPSS19.0软件处理，计数资料采用χ2检验。符合正态分布的计量资料以（均数±标准差）表示，两组间比较采用t检验。偏态分布的计量资料以中位数（四分位间距）表示，两组间比较采用Mann-whitney检验。评价指标的诊断价值及预后价值采用ROC曲线，遵循约登指数最大为cut-off原则，计算此时诊断及预后的敏感度与特异性。P＜0.05为差异有统计学意义。 2.结果 2.1 一般资料 脓毒症组与健康组比较，性别、年龄均无明显差异（P＞0.05）。 2.2 脓毒症患者炎症因子、PCT、危重症评分动态变化 IL-1、IL-6、 IL-10、PCT水平及APACHEⅡ、SOFA评分随治疗均呈下降趋势，见表1。 2.3 炎症因子、PCT对脓毒症早期诊断价值 脓毒症患者入院时，IL-1、IL-6、IL-10、PCT均明显高于对照组，差异有统计学意义（P＜0.01）。见表1。
3、自由基与疾病
自由基与疾病【自由基是万病之源】 大家在日常生活中都非常了解，铁在空气中会生锈、钢在空气中会变绿色，银器在空气中会变黑，这就是氧化作用。大自然中氧化作用是破坏性，如铁生锈若不及时处理、保护，很快就会被腐蚀掉，而人的新陈代谢也是一种氧化，还原过程，自由基就是在这一过程中产生的，也如同人体生锈，如不及时预防处理也会构成对人体损害。 人体本身有一种能力称为“抗氧化能力”来清除多余的自由基，但人随年龄增大或患疾病时清除自由基的能力也随之降低。所以自由基开始对人的细胞攻击，诱发多种疾病，医学研究证明与自由基有关的疾病有100多种。 脑梗塞、脑出血、颅脑外伤、蛛网膜下腔出血、脑膜炎、脑水肿、老年性痴呆、帕金斯症、多发性硬化，甚至精神分裂症，都应当注意自由基的损伤。 氧自由基不但与衰老有关，而且还和许多衰老有关的疾病有关系，比如动脉硬化症、高血压、骨关节炎、白内障以及帕金森氏病等等。正常人体内有一套清除自由基的系统，即便如此，这个系统的力量会因人的年龄增长及体质改变而减弱，随着时间的推移，自由基会在细胞内不断积累。这会致使自由基的负面效应大大增强，从而引起多种疾病发病率的提高。 自由基与疾病的连锁反应 自由基与衰老有明显的关系，一些科学家认为自由基是引起衰老的主要原因。自由基能促使体内脂褐素生成，脂褐素在皮肤细胞中堆积即形成老年斑，在脑细胞中堆积，会引起记忆力减退或智力障碍，甚至出现老年痴呆症。自由基还可导致老年人皮肤松弛、皱纹增多、骨质再生能力减弱等，还会引起视网膜病变，诱发老年性视力障碍(如眼花、白内障)。而且，自由基还可引起器官组织细胞老化和死亡。老年人感觉与记忆力下降、动作迟钝及智力障碍的一个重要原因，就是由于过多的自由基导致了神经细胞数量大量减少。另外，自由基和脂质过氧化还与肺损伤、艾滋病、癌症、肾病、糖尿病的发生有密切关系，所以寻找消除自由基及抗氧化药物对于保护人类健康具有重大意义。 衰老与自由基1 自由基有两个来源：一是来自体外，如环境污染、紫外线照射、室内外废气、烟尘、细菌等等，它们会直接导致自由基的产生；二是来自体内，人体内也会自然形成自由基，它是人体代谢过程的正常产物，十分活跃又极不稳定，它们会附着于健康细胞之上，再慢慢瓦解健康细胞。 人体细胞遭受到自由基攻击,就好比铁暴露在空气中久了会生锈一样,这个过程叫做氧化。铁生锈了,就表示开始耗损,渐渐就会被腐蚀,人体衰老的过程就好像是铁被氧化的过程一样，实际上，生命衰老和病变的过程也就是氧化的速度超过还原的速度，而让我们体内细胞“生锈”的物质就是自由基。如果受损“生
炎症和氧化应激
炎症和氧化应激 炎症可以引起氧化应激，氧化应激也可以引起炎症。首先我们要清楚一些概念。如：炎症、炎症细胞。 炎症细胞指炎症反应时参与炎症反应、浸润炎症组织局部的细胞。如巨噬细胞、淋巴细胞、中性粒细胞和嗜酸性粒细胞以及参与炎症反应的血小板和内皮细胞等。 一、炎症定义：炎症是机体对各种物理、化学、生物等有害刺激所产生的一种以防御为主的病理反应，是一种具有血管系统的活体组织对损伤因子的防御性反应。血管反应是炎症过程的中心环节。在炎症过程中，一方面损伤因子直接或间接造成组织和细胞的破坏，另一方面通过炎症充血和渗出反应，以稀释、杀伤和包围损伤因子。同时通过实质和间质细胞的再生使受损的组织得以修复和愈合。因此可以说炎症是损伤和抗损伤的统一过程。炎症以局部血管为中心，典型特征是红、肿、热、痛和功能障碍，炎症可参与清除异物和修补组织等。（一）根据持续时间不同分为急性和慢性。急性炎症以发红、肿胀、疼痛等为主要征候，即以血管系统的反应为主所构成的炎症。局部血管扩张，血液缓慢，血浆及中性白细胞等血液成分渗出到组织内，渗出主要是以静脉为中心，但象蛋白质等高分子物质的渗出仅仅用血管内外的压差和胶体渗透压的压差是不能予以说明的，这里能够增强血管透性的种种物质的作用受到重视。这种物质主要有：（1）组织胺、5-羟色胺等胺类物质可导致炎症刺激后所出现的即时反应。（2）以舒缓激肽（bradykinin）、赖氨酰舒缓激肽（kallidin）、甲硫氨酰-赖氨酰-舒缓激肽（methio－nyl－lysyl－bradykinin）为代表的多肽类。其共同的特征是可使血管透性亢进、平滑肌收缩、血管扩张，促进白细胞游走。（3）血纤维溶解酶（plasmin）、激肽释放酶（kallikrein）、球蛋白透性因子（globulin－PF）等蛋白酶（protease），其本身并不能成为血管透性的作用物质。但可使激肽原（kininoge）变为激肽（kinin）而发挥作用。然而上述这些物质作用于血管的那个部位以及作用机制多属不明。在组织学上可以看到发生急性炎症时出现的血管渗出反应和修复过程混杂在一起的反应。并可见有巨噬细胞、淋巴细胞、浆细胞的浸润和成纤维细胞的增生。 （二）从炎症的主要的组织变化可分类如下：（1）变质性炎症。（2）渗出性炎症（浆液性炎、纤维素性炎、化脓性炎、出血性炎、坏死性炎、卡他性炎）。（3）增生性炎症。（4）特异性炎症。 二、炎症的成因：（一）感染性：细菌毒素病毒等病原微生物感染，如呼吸道、消化道感染，创面感染等。严重的如胸腔内、腹腔内感染、胆道感染等。 （1）被病原体入侵所激活的中性粒细胞在吞噬活动时耗氧量增加，其摄入O2的70-90%在NADPH氧化酶和NADH氧化酶的催化下接受电子形成氧自由基，用于杀灭病原微生物。氧化应激引起高凝状态组织缺血激活补体系统，或产生多种具有趋化活性的物质，如C3片段、白三烯等，吸引、激活中性粒细胞。再灌注期组织重新获得O2供应，氧自由基爆发。 （2）病原体入侵机体后，机体处于应激状态，如《伤寒论》：“太阳之为病，脉浮、头项强痛而恶寒”脉浮，是由交感兴奋引起，儿茶酚胺增加释放，由于儿茶酚胺的自氧化，可以产生大量的氧自由基，氧化应激造成高凝状态使组织缺血，激活补体系统，或产生多种具有趋化活性的物质，如C3片段、白三烯等，吸引、激活中性粒细胞。再灌注期组织重新获
自由基与疾病
龙源期刊网 https://www.wendangku.net/doc/4817841560.html, 自由基与疾病 作者：吴国隆 来源：《现代养生》2006年第04期 自由基又称游离基，是化合物分子中的共价键，为人体代谢过程中形成的原子或原子团。人体的自由基是一种活性氧，活性氧是人体内极不安定的原子碎片，因为它本身缺少一个电子，它总想从正常细胞里拉出一个电子作为它的配偶。但是正常的细胞失去一个电子后，可能导致癌变。机体内常见的自由基有羟自由基、脂质自由基、氧化脂质自由基、过氧化脂质自由基…… 自由基的生物活性具有双重性。在生理情况下有增强白细胞对细菌的吞噬和抑制细菌增殖的功能，增强机体抗感染及免疫能力；在病理情况下，又能对组织产生不可逆的损伤，使组织细胞化学结构发生破坏性反应，因此是许多疾病的病理基础。可见自由基是个“两面派”。 一、自由基是缺血再灌注损伤的一个重要因素，涉及各主要器官组织，因组织缺血、缺氧时细胞内能量分解大于合成，三磷酸腺苷分解产物大量产生，在酶的催化下形成自由基。 二、自由基造成器官组织损伤是导致休克发生的基础。自由基可能增加毛细血管通透性，使大量血浆渗出，而有效循环血量减少。自由基使细胞屏障作用损害，加重休克。休克时缺血、缺氧造成细胞能量代谢障碍，可产生大量的自由基，故休克本身又是体内自由基增多的原因之一。 三、人体内中性粒细胞在吞噬过程中，可生成自由基，炎症区的吞噬细胞被细菌等激活后，其耗氧量急剧上升，高达正常的2～20倍，产生自由基而杀伤正常组织细胞。 四、人体在外界因素如毒物、辐射、感染等作用下，吞噬细胞被激活，释放出自由基，攻击细胞结构，诱发自身抗体。一些对自身抗体敏感的细胞，与受体结合的同时，也激活中性粒细胞生成自由基，促使自身组织破坏。在某些自身免疫病，如类风湿性关节炎除吞噬细胞产生大量的自由基外，还存在铁代谢异常，也可产生自由基。 五、自由基在体内攻击和破坏生物大分子，产生过氧化变性，引起细胞结构上功能破坏，产生组织损害和器官退行性变，导致老年病和衰老的发生。 六、①自由基是对脂质的过氧化作用和破坏细胞膜引起的，脑外伤时催化自由基反应导致脑水肿，还引起微循环障碍，加重脑细胞损伤；②当冠状动脉供血不足，心肌梗塞和心脏术后恢复供血，心脏功能并不象人们所期望的那样好转，而是继续恶化，其原因在于自由基的形成；③细菌感染后，内毒素激活中性白细胞产生自由基并释放炎性介质和前列腺素等物质，它们共同破坏肺血管内皮细胞和肺泡组织，最终发生成人呼吸窘迫综合征；④大剂量的肝毒性物
炎症和氧化应激
。 炎症和氧化应激 炎症可以引起氧化应激，氧化应激也可以引起炎症。首先我们要清楚一些概念。如：炎症、炎症细胞。 炎症细胞指炎症反应时参与炎症反应、浸润炎症组织局部的细胞。如巨噬细胞、淋巴细胞、中性粒细胞和嗜酸性粒细胞以及参与炎症反应的血小板和内皮细胞等。 一、炎症定义：炎症是机体对各种物理、化学、生物等有害刺激所产生的一种以防御为主的病理反应，是一种具有血管系统的活体组织对损伤因子的防御性反应。血管反应是炎症过程的中心环节。在炎症过程中，一方面损伤因子直接或间接造成组织和细胞的破坏，另一方面通过炎症充血和渗出反应，以稀释、杀伤和包围损伤因子。同时通过实质和间质细胞的再生使受损的组织得以修复和愈合。因此可以说炎症是损伤和抗损伤的统一过程。炎症以局部血管为中心，典型特征是红、肿、热、痛和功能障碍，炎症可参与清除异物和修补组织等。（一）根据持续时间不同分为急性和慢性。急性炎症以发红、肿胀、疼痛等为主要征候，即以血管系统的反应为主所构成的炎症。局部血管扩张，血液缓慢，血浆及中性白细胞等血液成分渗出到组织内，渗出主要是以静脉为中心，但象蛋白质等高分子物质的渗出仅仅用血管内外的压差和胶体渗透压的压差是不能予以说明的，这里能够增强血管透性的种种物质的作用受到重视。这种物质主要有：（1）组织胺、5-羟色胺等胺类物质可导致炎症刺激后所出现的即时反应。（2）以舒缓激肽（bradykinin）、赖氨酰舒缓激肽（kallidin）、甲硫氨酰-赖氨酰-舒缓激肽（methio－nyl－lysyl－bradykinin）为代表的多肽类。其共同的特征是可使血管透性亢进、平滑肌收缩、血管扩张，促进白细胞游走。（3）血纤维溶解酶（plasmin）、激肽释放酶（kallikrein）、球蛋白透性因子（globulin－PF）等蛋白酶（protease），其本身并不能成为血管透性的作用物质。但可使激肽原（kininoge）变为激肽（kinin）而发挥作用。然而上述这些物质作用于血管的那个部位以及作用机制多属不明。在组织学上可以看到发生急性炎症时出现的血管渗出反应和修复过程混杂在一起的反应。并可见有巨噬细胞、淋巴细胞、浆细胞的浸润和成纤维细胞的增生。 （二）从炎症的主要的组织变化可分类如下：（1）变质性炎症。（2）渗出性炎症（浆液性炎、纤维素性炎、化脓性炎、出血性炎、坏死性炎、卡他性炎）。（3）增生性炎症。（4）特异性炎症。 二、炎症的成因：（一）感染性：细菌毒素病毒等病原微生物感染，如呼吸道、消化道感染，创面感染等。严重的如胸腔内、腹腔内感染、胆道感染等。 （1）被病原体入侵所激活的中性粒细胞在吞噬活动时耗氧量增加，其摄入O2的70-90%在NADPH 氧化酶和NADH氧化酶的催化下接受电子形成氧自由基，用于杀灭病原微生物。氧化应激引起高凝状态组织缺血激活补体系统，或产生多种具有趋化活性的物质，如C3片段、白三烯等，吸引、激活中性粒细胞。再灌注期组织重新获得O2供应，氧自由基爆发。 （2）病原体入侵机体后，机体处于应激状态，如《伤寒论》：“太阳之为病，脉浮、头项强痛而恶寒”脉浮，是由交感兴奋引起，儿茶酚胺增加释放，由于儿茶酚胺的自氧化，可以产生大量的
Crohn病唾液中炎症因子的研究
Crohn病唾液中炎症因子的研究 目的：分析炎症因子白细胞介素1β（Interleukin 1β，IL-1β）、白细胞介素6（Interleukin 6，IL-6）、肿瘤坏死因子α（Tumor necrosis factor α，TNF-α）与活动期CD患者相关性，为疾病的诊断提供检测指标。 方法：选取本院2011-2013年克罗恩病（Crohn’s disease，CD）患者，其中48例为活动期CD组患者和42例非活动期CD组患者，并选择45例正常健康人作为正常对照组，所有患者抽取静脉血进行血细胞计数和CRP检测，采用R&D SYSTEMS检测唾液中IL-1β、IL-6和TNF-α浓度，比较分析三组患者的差异。结果：与正常对照组比较，活动期CD组与缓解期CD组患者的BMI、RBC 和Hb减低，而WBC、CRP和PLT增高，比较差异均有统计学意义（P＜0.05）；活动期CD组和缓解期CD组患者的相关指标比较，差异均有统计学意义（P＜0.05）。活动期CD组患者IL-1β（282.3±52.1）pg/mL；IL-6（13.1±4.3）pg/mL；TNF-α（32.9±8.6）pg/mL。缓解期CD组患者IL-1β（192.1±42.1）pg/mL；IL-6（7.1±3.1）pg/mL；TNF-α（10.3±6.2）pg/mL；正常对照组IL-1β（180.0±37.1）pg/mL； IL-6（6.2±1.2）pg/mL；TNF-α（8.6±2.9）pg/mL。活动期CD组患者唾液中IL-1β，IL-6和TNF-α比缓解期CD组患者和正常对照组显著升高，差异均有统计学意义（P＜0.01）；但是缓解期CD组患者与正常对照组比较差异无统计学意义（P>0.05）。结论：活动期CD组患者口腔特异性损害与血红蛋白、血小板、CRP、BMI相关，唾液IL-6和TNF-α与特异性口腔损伤有关，这些炎症因子可作为活动期CD患者的检测指标。 克罗恩病（Crohn’s disease，CD）是肠道全层的慢性肉芽肿炎症疾病，病因尚不明确，临床可表现为腹痛、腹泻、发热、体重下降和其他肠外表现，并可累及口腔，如口疮、溃疡、舌炎，且病情反复发作，经久不愈[1-2]。由于克罗恩病临床表现多样，缺乏特异性，因此其早期诊断率非常低。虽然目前有许多检测手段，但均不能很好地解决克罗恩病的诊断问题。由此可见，寻找对克罗恩病早期、快速、准确的诊断方法具有重要意义。近年来对口腔唾液的检测逐渐增高，由于口腔唾液检测简单易行，为非侵入性，特别适用于儿童，并且能反映口腔和胃肠道的分泌功能，因此应用于CD[3-4]。研究发现在炎症性疾病里，唾液中许多细胞因子会升高，如IL-6，可能是口腔也参与了整个胃肠道的炎症反应[5]。本文研究了CD患者中的白细胞介素1β（Interleukin 1β，IL-1β）、白细胞介素6（Interleukin 6 ，IL-6）肿瘤坏死因子α（Tumor necrosis factor α，TNF-α）水平，并探索了CD的活动性和口腔损伤的相互关系。 1 资料与方法 1.1 一般资料选取本院消化内科2011-2013年90例CD患者，同时选取45例非CD患者作为对照组。CD的诊断符合临床、放射、内镜和组织学标准。根据疾病活动指数（Clinical disease activityindex，CDAI）将CD分为活动期和缓解
人体内的一把双刃剑——自由基
人体内的一把双刃剑——自由基 一、自由基的定义 自由基(free radical)是指能独立存在，含有未成对电子的原子，原子团、分子或离子。如含有不成对电子的氧则称为氧自由基(oxygen free radical，OFR)；自由基具有不成对电子的原子或分子。含有基数电子或不配对电子的原子、原子团和分子。具有很强的反应性。 自由基，化学上也称为“游离基”，是含有一个不成对电子的原子团。由于原子形成分子时，化学键中电子必须成对出现，因此自由基就到处夺取其他物质的一个电子，使自己形成稳定的物质。在化学中，这种现象称为“氧化”。我们生物体系主要遇到的是氧自由基，例如超氧阴离子自由基、羟自由基、脂氧自由基、二氧化氮和一氧化氮自由基。加上过氧化氢、单线态氧和臭氧，通称活性氧。体内活性氧自由基具有一定的功能，如免疫和信号传导过程。但过多的活性氧自由基就会有破坏行为，导致人体正常细胞和组织的损坏，从而引起多种疾病。如心脏病、老年痴呆症、帕金森病和肿瘤。此外，外界环境中的阳光辐射、空气污染、吸烟、农药等都会使人体产生更多活性氧自由基，使核酸突变，这是人类衰老和患病的根源。 二、自由基的来源与形成 自由基的来源 自由基在生物体内来源有二：一是细胞正常生理过程产生；二是化学毒物在体内代谢过程产生。在人体和环境中持续形成的自由基来自人体正常新陈代谢过程，大量体育运动、吸烟、食用脂肪和腌熏烤肉、发生炎症、某些抗癌药物、安眠药、射线、农药、有机物腐烂、塑料用品制造过程、油漆干燥、石棉、空气污染、化学致癌物、大气中的臭氧等也都能产生自由基。已知自由基可损伤蛋白质，可使蛋白质的转换增加；损害DNA可导致细胞突变；作用于－SH可使某些酶的活性降低或丧失；攻击未饱和脂肪酸可引起脂质过氧化，其氧化产物可引起－SH氧化、酶失活、膜功能受损、干扰膜的运送功能等。另外，由燃料废气、香烟和一些粉尘造成的大气污染，使大气上空的自由基占分子污染物总量的1％～10％，因此环境污染中的自由基反应也是不可忽视的。 自由基有两个来源：一是来自体外，如环境污染、紫外线照射、室内外废气、烟尘、细菌等等，它们会直接导致自由基的产生；二是来自体内，人体内也会自然形成自由基，这是人体代谢过程的正常产物，十分活跃又极不稳定，它们会附着于健康细胞之上，再慢慢瓦解健康细胞，而被破坏的细胞又转而侵害更多健康的细胞，如此恶性循环从而导致肌体的早衰现象。 过量运动在《抗氧化革命》一书中，肯尼斯-库珀医生强调，过量的运动可以明显增加我们身体产生的自由基的数量。 《抗氧化革命》一书在结尾处忠告读者，过量运动实际上是有害健康的，尤其是在我们多年持续过量运动的情况下。库珀医生建议我们每个人都应适量运动，他还建议我们每人在进行营养补充时都应服用抗氧化剂。只有真正的运动员才应该进行艰苦的训练，而且他们也应该补充大量的抗氧化剂来抵消这种侵害。空气污染环境对我们提内形成的自由基的数量影响巨大。空气污染是导致我们肺部和体内氧化压力的主要原因之一。现在当你开车进入任何一个大城市时，你不仅能够看到空气中厚重的烟雾，甚至能够用舌头尝得出来。在石棉中添加含铁纤维能够产生更多的自由基。吸烟香烟的烟雾含有多种毒素，它们联合在一起使肺部和身体各部分的自由基数量增加。食物和水源污染我们的水
自由基与疾病
自由基与疾病 自由基作为一类化学实体在20世纪初就已被人们所认识，生物体系中的自由基的存在，在20世纪50年代才得以确认。随着分析方法特别是近代生物物理检测技术的发展，许多生命现象的自由基机制逐渐被揭示，目前已形成了自由基医学和自由基生物学等新兴学科。自由基理论已渗入到临床诸多学科，为疾病的病因，发病机制提供了新的理论依据，为许多疾病的诊断与防治开辟了新的途径与前景。 第一节自由基的生化基础 一、自由基的概念与种类 自由基(free radical)是指能独立存在，含有未成对电子的原子，原子团、分子或离子。如含有不成对电子的氧则称为氧自由基(oxygen free radical，OFR), 占机体内自由基的95%以上。一般在自由基前面或后面(也可在右上角)用一个圆点"·"表示未成对电子。自由基的不成对电子具有配对趋向，夺取或失去一个电子构成配对电子。因此自由基十分活泼，极易与周围分子发生反应，它存在的时间极短，其半寿期以毫秒或毫微秒计。 自由基在生物体内普遍存在，按其化学结构自由基可为分为三种类型：①半醌类自由基，如黄素类半醌自由基；②氧中心自由基，简称氧自由基，包括超氧阴离子自由基(O2 )、羟自由基(·OH)、烷氧自由基(RO·)、烷过氧自由基(ROO·)、氢过氧自由基(HOO·)。近年来研究较多的活性氮自由基(NO和NO2－)也可算作氧自由基。③其他碳、氮、硫中心自由基。上述氧自由基及其衍生物H2O2、脂质过氧化物(LOOH)及单线态氧(1O2，singlet oxygen)等统称为活性氧(reactive oxygen species, ROS)，它是指氧的某些产物和一些反应的含氧产物，它的特点是含有氧，化学性质较氧活泼。ROS对生物机体可产生一系列的有害作用，其毒害作用称为氧的毒性。种种有害后果与许多疾病的发生密切相关，因此生物体内ROS的生成与清除的平衡对生命过程的正常进行具有重要作用。 一氧化氮(nitric oxide, NO)是20世纪80年代发现的一种自由基，它是体内重要的信使分子和效应分子，是当代医学研究的热点和前沿之一。NO的化学性质活泼，可迅速与O2、O2 、铁、铜、镁等反应，其中与O2 反应可生成过氧亚硝基阴离子(ONOO－)，后者是一强氧化剂。在生物体内，与NO有关的自由基和化合物有数十种，NO及其相关产物相互反应，在机体内生成一系列具有重要生物功用的自由基和硝基化合物，即所谓的生物活性氮。 NO在生物体内主要是由NO合酶(NO synthase, NOS)催化合成与释放的，即NOS 催化L-精氨酸和O2为底物生成NO和L-瓜氨酸。根据NO的表达与调节，NOS分成两大型：一是组成型NOS(constitutive NOS, cNOS)，其活性依赖于Ca2+和钙调蛋白，可间歇性不断表达，根据存在部位，又分为神经元型和内皮细胞型。二
炎症与修复
第六章炎症与修复 吴翠环撰写部分杨丽敏撰写部分 第一节炎症的基本病理变化第二节炎症介质 一、变质一、细胞释放的炎症介质 二、渗出（一）血管活性胺 三、增生（二）花生四烯酸代谢产物 （三）细胞因子 第三节急性炎症 一、急性炎症特点（四）血小板激活因子 二、血管反应（五）溶酶体成分 三、液体渗出（六）一氧化氮 四、炎症细胞的种类和功能二、体液产生的炎症介 质 五、急性炎症类型（一）激肽系统 （一）浆液性炎（二）补体系统 （二）纤维素性炎（三）凝血系统 （三）化脓性炎 1．脓肿第三节急性炎症 2．蜂窝织炎四、白细胞渗出3．表面化脓和积脓（一）趋化作用
（二）白细胞聚集 （三）吞噬作用（四）出血性炎第五节修复 一、慢性炎症特点一、再生 二、肉芽肿的形态学特征（一）再生的调控 三、肉芽肿性炎中有关细胞 1.细胞周期和增生 四、肉芽肿性炎的类型及其主要病理变化 2.细胞周期和细胞 分裂 （一）细菌及螺旋体感染 3.细胞生长和分化 1.结核肉芽肿二、纤维性修复 2.麻风肉芽肿（一）肉芽组织 3.梅毒树胶（二）纤维化 4.伤寒肉芽肿（三）瘢痕改建（二）寄生虫三、创伤愈合 1.血吸虫病第六节炎症与修复研究的新动向 2.丝虫病 （三）真菌 （四）尘肺 1．矽肺 2．石棉肺 3．农民肺
（五）原因不明 五、炎性息肉 六、炎性假癌 第六章炎症与修复 炎症（inflammation）是具有血管系统的活体组织对损伤因子所发生的防御反应。具有减轻机体受损程度，限制损伤因子在体内扩散和对损伤组织进行修复的作用。人类的许多疾病都属于炎症，即使动脉粥样硬化本质上也是炎症。随着人类医疗实践和科学实验的不断深入，对炎症的发生、发展的认识有了长足的进步，如新的炎症介质的不断发现，阐明了血管反应、白细胞游出和吞噬作用以及再生修复过程的分子机制也将为疾病的治疗带来新的希望。 第一节炎症的基本病理变化 任何炎症性疾病，其发病原因、发生部位可能不同，但均有它们的共同点，即局部组织的变质（alteration）、渗出（exudation）和增生（Proliferation）这一基本病理变化。在炎症过程中它们以一定的先后顺序发生，且可同时存在。一般说来变质是损伤性过程，而渗出和增生是对损伤的防御反应和修复过程。病理学家通常根据炎症局部变质、渗出和增生哪一种病变占优势，而将炎症概括地分为变质性炎、渗出性炎和增生性炎。 一、变质 炎症局部组织发生的变性和坏死称为变质。变质既可发生于实质细胞，也可见于间质。实质细胞常出现的变化为水变性、脂肪变性、凝固性
自由基的危害
自由基与消化系肿瘤1 自由基的产生与清除 自由基是具有不配对价电子(即具有奇数电子)的原子、原子团、分子或离子，包括氧分子经氧化还原反应产 生的超氧阴离子、H2O2、羟自由基(·OH)、单线态氧(1O2)，乃至对应的氧化产物、过氧化脂质等.机体内自由基主要来源于细胞生化反应，其次，紫外线照射、电离辐射和环境污染等因素也可诱发机体产生自由基.高等生物体内约有1%的氧(3O2)经呼吸链旁路反应生成氧自由基.这不仅说明自由基在生物机体内的广泛分布，也反映了在长期的生物进化过程中依然保留这些机制的生物学意义. 在生理情况下自由基不断产生，也不断被清除，使自由基浓度保持在产生与清除的动态平衡之中.生物机体内存在着有效的自由基清除剂，包括清除活性氧的酶类和一些低分子化合物.一般地，超氧化物歧化酶(superoxide dismutase, SOD)、过氧化氢酶(catalase, cAT)、谷胱甘肽过氧化物酶(glutahione peroxidase, GSH-PX)主要清除、H2O2、LOOH；而·OH、1O2等寿命短(10-5S以下)的氧自由基主要由一些低分子化合物(如维生素A、维生素E、胡萝卜素类、维生素C、维生素B1、维生素B2、维生素K、黄酮类和某些未知物质)加以清除［1］. 虽然，自由基为正常生命活动的许多重要反应所必须，它参与生物活性物质的合成(如花生四烯酸合成前列腺素)，解毒反应，吞噬细胞杀灭细菌的活动等.但是过量的氧自由基对机体的广泛损伤效应，与炎症、肿瘤、免疫性疾病及衰老等有密切关系. 2 自由基对生物大分子的损伤作用 2.1自由基对DNA的损伤作用研究证明自由基对DNA具有损伤作用［2，3］，自由基可引起细胞内DNA 的氢链断裂、碱基降解和主链解旋，所有核酸成分均可受到自由基的攻击，这种损伤可被一些特殊机制修复，但也可造成永久性损伤.所以，当细胞DNA受损伤时，可造成细胞生物学活性改变，甚至导致基因突变、肿瘤与细胞死亡.自由基攻击脱氧核糖时可导致链断裂，但这类损伤可被DNA的修复系统所修复，然而，修复过的DNA
自由基与疾病的关系
自由基与疾病的关系 自由基是人体在新陈代谢时必然产生的一种物质，它在身体的细胞中产生的最多。细胞中有很多细胞器，其中的线粒体是产生自由基的主要部位。 线粒体是产生能量的关键结构，它把蛋白质、糖类、脂类等能量物质与人体吸入的氧结合，在它这个类似于反应罐的物体中进行能量释放。细胞中有很多线粒体，有的细胞多达上千条。线粒体通过转移电子、释放氧、产生ATP（三磷酸腺苷）承载能量，并产生副产品二氧化碳。在这个过程中，有98%的氧会准确无误的分解释放能量，但也有2%的氧不能把氧原子的4对电子全部转移释放，而丢失一个电子，这个丢失了一个电子的氧原子就成了氧自由基。所以，线粒体是产生能量的结构，也是产生自由基的地方。 这个氧自由基很不稳定，它会抢劫别的氧原子上的电子来补充使自己稳定，而被抢劫了电子的氧原子又成了新的自由基。新自由基为了使自己稳定又会到另一个物体上抢夺电子，这就形成了恶性循环。因而，自由基是人体中的抢劫犯。 自由基是人体新陈代谢的必然产物，只要人体活着就不可避免。但是，它在人体中的数量不能多，不然，就会使线粒体的功能遭受破坏，使细胞提前衰老，使人体的一些部位发生类似于炎症的反应。比如关节炎，它不是细菌性的病，而是自由基破坏了关节中的液体、软骨，造成了关节类似于炎症的反应。自由基还会导致多种慢性病，并使病情加重。 据科学研究，如果线粒体的功效下降，产生的自由基就会更多。比如60岁以上的人比40岁以前的人，线粒体的功效降低40%，所以人老以后，就会出现体力下降、冬季怕冷的现象。如果年轻人相当怕冷、手脚冰凉，就是线粒体释放能量
的能力不足。儿童大都火力旺，这是他们的线粒体功能好，产生的能量多的原因。 科学研究证明，自由基与身体的疾病有直接的联系，有70多种慢性病也叫退行性病是由自由基造成的。比如老年痴呆、帕金森症、癌症等，都是外界环境和身体内在的因素变化，使人身自由基增多造成的结果。 自由基破坏哪个器官，哪个器官就会提前衰老、就会发病，俗话说“黄鼠狼先叼病鸭子”。自由基也是先破坏身体的弱势器官，这是导致人身快速衰老的根本原因。人体衰老是不可抗拒的，但是衰老的速度是可以控制的，只要弄清自由基的来龙去脉，就能延缓衰老的进程。比同龄人有活力、有精神，看头发、看皮肤都显得年轻。 自由基增多的原因： 1.运动过量。运动需要能量，过量的运动会迫使线粒体过速工作，在这个过程中会伴随产生大量的自由基。比如运动员由于运动过度，大都会提前衰老。 2.压力过大。轻中度的精神压力，产生的自由基有轻微的增加，而压力过大，就会产生大量的自由基。 有一位38岁的小伙子患了大脑快速萎缩症，原因是他经常加班熬夜，饥饿时就吃点面包、方便面等垃圾食品。晚上本来是线粒体休息的时间，而他却让线粒体加倍工作，因而患病。目前年轻人的精神压力对健康是最大的威胁。如果不注意减压，很多病都会发生。 3.空气污染。有毒物质进入人体，身体就要排毒、清除毒素，细胞排毒需要能量，这就使得体内的自由基增多。 4.吸烟饮酒。吸烟是自己主动吸毒，饮酒也是自己强化自由基产生。吸一支烟，相当在污染严重的城市生活了一周。
炎症反应和败血症的发生机制
炎症反应和败血症的发生机制 1991年美国胸科医生学会与危重感染急救医学(ACCP/SCCM)在芝加哥 联合召开的讨论会上进一步确认全身炎症反应综合征(SIRS)的概念［1］。SIRS是由感染或非感染因素刺激宿主触发炎症过度反应的结果，这些因素刺激宿主免疫系统，释放体液和细胞因子，对血管张力和渗 透性产生影响，导致微循环障碍、休克或器官衰竭，即多器官功能障 碍综合征(MODS)。SIRS是MODS的必经之路，而MODS是SIRS的必然发展结果。 细胞因子是全身炎症反应综合征的重要介质［2］ 在SIRS和败血症以及继发组织损伤时，释放一些不能控制的细胞因 子进入循环，引起血液动力学不稳定、广泛的组织损伤，导致内脏器 官的炎症反应。在此过程中，细胞因子起信息分子作用，发出不同的 细胞反应信号，引起细胞和体液反应。从单核细胞、吞噬细胞和其它 细胞释放细胞因子后，通过与初始信号传递受体结合生成第二信息， 引起细胞间信号效应，包括重要酶的磷酸化，影响细胞行为基因产物 的表达或失活。细胞因子显示十分广泛的特性，包括能启动细胞因子 及其网络系统活化，调节受体结合水平。特别在SIRS和器官障碍的发 生机制上，细胞因子的特殊作用是多方面的，因为细胞因子显示出基 因多态性和多效性。有趣的是，SIRS也伴有释放相反作用的炎症分子、可溶性肿瘤坏死因子受体(sTNFR)、IL-1受体拮抗物(IL-1ra)和IL-10，参与调节细胞因子释放与促炎症因子和抗炎症分子的平衡，可能对炎 症反应的严重性起决定性作用。 全身炎症反应综合征和败血症的发生机制 败血症的临床特点是宿主对感染刺激过度反应的结果，即使体内防御 机制对机体是有益的，能中和侵入的微生物，清除损伤的细胞和修复 破坏组织，但过度的活化可能是有害的。近来研究表明，SIRS的关键 步骤是感染损伤：如内毒素、外毒素、革兰阳性(G+)细菌细胞壁成分、病毒和真菌；以及非感染性损伤：细胞碎片、补体成分、免疫复合物