1、Respiratory system Anatomy 鼻鼻咽咽喉喉环状软骨环状软骨气管气管支气管支气管肺肺上呼吸道上呼吸道下呼吸道下呼吸道v Rapid gas exchange Ventilation Perfusion Diffusion v Cleaning the air v Alveoli(300 million alveoli in two adult lungs,provide a surface area of some 160 meters square)v Surporting structure Elastic recoilStructure and function G
2、eneral Considerations(1)the conducting airways (dead air space)(2)the gas exchange portions气气管管粘膜层粘膜层粘膜下层粘膜下层外膜外膜上皮上皮(纤毛柱状纤毛柱状)固有膜固有膜Ciliated cellMucous cellsIgA纤毛粘液排送系统纤毛粘液排送系统Mucous,serous and mixed glandsCartilaginous 肺肺导气部导气部：呼吸部呼吸部：肺内支气管肺内支气管Bronchiole Terminal bronchiole(软骨消失软骨消失)Respiratory b
3、ronchiole（纤毛消失）（纤毛消失）Alveolar ductAlveolar sacAlveoli(SMC消失消失)681518Alveoli I 型型 （90%）II 型型Surfactant,repair I肺间质、肺泡间隔肺间质、肺泡间隔：cap.,f,MCohn 孔相互沟通孔相互沟通Histology of the Airways MucosaSubmucosaCartilageMusclesl Components l Functions Bronchi are distinguished from bronchioles primarily by the presence
4、of cartilage in their walls.Bronchioles also lack submucosal glands.Epithelium l Pseudostratified ciliated columnar cells l Mucous(goblet)cells Bronchial Submucosal Glands Histology of the Alveolar walls Alveoli Capillaries Pores of KohnSimple squamous StretchyPermeable to O2 and CO2Easily injuredDo
5、 not divide Reserve cellsCuboidalProduce and process surfactantDivide and differentiate to type I pneumocytes Section 1 Chronic obstructive pulmonary disease Chronic Obstructive Pulmonary Disease(COPD)u不可逆气道阻塞不可逆气道阻塞Irreversible airflow obstructionu慢支和肺气肿Chronic Bronchitis and Emphysema u常常伴发常常伴发Fre
6、quently occur together u与空气污染和吸烟有关与空气污染和吸烟有关Strongly correlated with air pollution and smoking u男多于女男多于女More common in men than in women u社会经济影响社会经济影响Socioeconomic impactCOPD represents a growing global public health problem.vIn one population based study conducted at multiple international sites,ap
7、proximately 10%of participants 40 years of age or older were found to have airflow obstruction of at least moderate severity according to spirometric criteria.(Buist AS,McBurnie MA,Vollmer WM,et al.International variation in the prevalence of COPD(the BOLD Study):a population-based prevalence study.
8、Lancet 2007;370:741-50.)我国国家“十五”课题最新统计数据（2005年公布）显示40岁以上人口COPD患病率为8%。估计全国有2500万人罹患此病，每年因COPD死亡的人数达100万，致残人数达5001000万，COPD居我国疾病负担的首位。一、慢支一、慢支 Chronic bronchitisClinical diagnostic criteria慢性咳嗽、咳痰慢性咳嗽、咳痰每年个月每年个月连续年连续年Chronic bronchitis Endoscopic imagePathogenesis感染感染吸烟气候空气污染等吸烟气候空气污染等 大气道病变 Large air
9、way disease v咳嗽、咳痰咳嗽、咳痰Cough and sputum production vHistological changes 杯状细胞数量增加 increased numbers of goblet cells in the epithelium 粘液腺数量增加 increased volume of the submucosal mucus glands 慢性炎症a component of chronic inflammationReid indexinner perichondriumbasal lamina鳞化鳞化 Squamous metaplasiaChroni
10、c inflammationHyperemia小气道病变 Small airway diseasev呼气性呼吸困难呼气性呼吸困难 Decrease in maximum forced expiratory flow vHistological changes 杯状细胞数量增加 presence of goblet cells in the lining epithelium 慢性炎症 a component of chronic inflammationluminal and mucuschronic inflammationPathologic changes起始于大支气管累及起始于大支气管
11、累及小小、细、细支气管支气管 粘膜上皮的损伤和修复粘膜上皮的损伤和修复纤毛倒伏、脱失纤毛倒伏、脱失上皮细胞变性、坏死脱落，可鳞化上皮细胞变性、坏死脱落，可鳞化上皮再生，杯状细胞大量增生上皮再生，杯状细胞大量增生 （4 5 ：1 2 ：1 ）慢性非特异性炎慢性非特异性炎 腺体变化腺体变化粘液腺肥大、增生粘液腺肥大、增生浆液腺化生为粘液腺浆液腺化生为粘液腺 管壁病变管壁病变充血、水肿，炎细胞浸润充血、水肿，炎细胞浸润平滑肌束断裂，软骨变性萎缩平滑肌束断裂，软骨变性萎缩v 小细小细支气管炎支气管炎晚期病变向小支气管和细支气管及管壁周围组织扩展，形成细支气管周围炎；管壁增厚管腔闭塞Clinical f
12、eatures支气管粘膜炎症、粘液分泌旺盛支气管粘膜炎症、粘液分泌旺盛咳咳痰痰支气管痉挛，渗出物阻塞支气管痉挛，渗出物阻塞喘喘晚期表现晚期表现 Late stage menifestationu血氧饱和度低血氧饱和度低 insufficient oxygenation of blood(hypoxemia)u呼吸困难呼吸困难 labored breathing(hypoventilation)u右心衰右心衰 right-sided heart failure(cor pulmonale)Treatment u不能根治不能根治 No cureu控制症状控制症状 relieving symptom
13、s u防止并发症防止并发症 preventing complications 二、肺气肿二、肺气肿Pulmonary emphysema 呼吸性细支气管呼吸性细支气管至肺泡的至肺泡的末梢肺组织因持续性含气量增末梢肺组织因持续性含气量增加而呈过度膨胀，伴有肺泡壁弹力组织破坏，间隔断裂致肺加而呈过度膨胀，伴有肺泡壁弹力组织破坏，间隔断裂致肺泡互相融合，肺容积胀大的病理状态。泡互相融合，肺容积胀大的病理状态。l Abnormal permanent enlargement of airspaces distal to the terminal bronchiole,accompanied by th
14、e destruction of their walls.(morphologically defined)l Inadequate ventilation l Less perfusionl Narrowed bronchiolePathogenesis u蛋白酶和抗蛋白酶水平失衡蛋白酶和抗蛋白酶水平失衡 Imbalance between proteases and anti-proteases(alpha-1 antitrypsin)in the lunguCigarette smoking u募集粒细胞和巨噬细胞 Recruits neutrophils and macrophages
15、u氧自由基抑制抗胰蛋白酶 Oxidants and free radicals inhibit the alpha-1-antitrypsin circulating in the lungu慢支和反复感染 Chronic bronchitis and repeated infectionsu缺乏 Alpha-1 antitrypsin deficiency(1%)Who destroy the alveoli wall?肺气肿类型肺气肿类型 Types of emphysemau中央性肺气肿中央性肺气肿 Centriacinar(centrilobular)emphysemau常见u主要累及
16、部位 respiratory bronchiole u上叶更常见u见于吸烟者v全小叶性肺气肿全小叶性肺气肿Penacinar(panlobular)emphysema 累及整个腺泡 下叶常见 1/20 as common as centriacinar emphysema.Seen in alpha-1-antitrypsin deficiency 肺气肿类型肺气肿类型 Types of emphysemav隔旁肺气肿隔旁肺气肿 Distal acinar(paraseptal)emphysema或小叶周或小叶周围性肺气肿围性肺气肿 远端 The distal respiratory acin
17、us is expanded 主要部位：上叶近胸膜或隔旁 肺气肿类型肺气肿类型 Types of emphysemaCentriacinar(centrilobular)emphysema Centrilobular emphysema in which there are dirty holes that appear focally where the central portions of lung acini have lost lung parenchyma while collecting anthracotic pigment at the same time.This patt
18、ern is typical for smokers Centriacinar(centrilobular)emphysemaEmphysema loss of alveolar walls镜下镜下：肺泡壁、肺泡间隔肺泡壁、肺泡间隔 萎缩、消失、破坏，萎缩、消失、破坏，互相融合互相融合其它其它瘢痕旁肺气肿瘢痕旁肺气肿 Emphysema with irregular distribution related to scars (obstruction/traction)代偿性肺气肿代偿性肺气肿 Compensatory emphysema Caused by removal or collap
19、se of adjacent pulmonary parenchyma 肺大泡肺大泡肺尖、胸膜下局灶性肺泡间隔破坏，肺尖、胸膜下局灶性肺泡间隔破坏，形成形成 2cm(D)囊泡囊泡 间质性肺气肿间质性肺气肿儿童多见儿童多见，肺泡壁、细支气管壁急性破裂，肺泡壁、细支气管壁急性破裂，空气进入肺间质空气进入肺间质Numerous large bullae apparent on the surface of the lungs in a patient dying with emphysema.临床病理联系临床病理联系 Late stage manifestationv气短气短 Short of br
20、eath,wheezlingv咳嗽咳嗽 Cough with or without mucousv疲劳疲劳 FatiguevWeight lossv下肢水肿下肢水肿 Ankle feet leg swellingv肺感染肺感染 lung infections Complications l Respiratory infectionsl Respiratory failurel Cor pulmanale 患者，女性，患者，女性，6060岁。因反复咳嗽、咳痰岁。因反复咳嗽、咳痰1111年年，伴气促、心悸伴气促、心悸3 3年，下肢水肿年，下肢水肿2 2年，腹胀年，腹胀3 3月月入院。入院。111
21、1年前感冒后发热、咳嗽、咳脓痰。以后年前感冒后发热、咳嗽、咳脓痰。以后每逢冬春季常咳嗽、咳白色泡沫痰，有时为脓痰，每逢冬春季常咳嗽、咳白色泡沫痰，有时为脓痰，反复加重。反复加重。3 3年来，在劳动或爬坡后常感心悸、年来，在劳动或爬坡后常感心悸、呼吸困难。呼吸困难。2 2年前开始反复下肢凹陷性水肿。年前开始反复下肢凹陷性水肿。3 3月月前受凉后发热、咳嗽加重，咳脓痰，心悸气促加前受凉后发热、咳嗽加重，咳脓痰，心悸气促加剧并出现腹胀，不能平卧，急诊入院。剧并出现腹胀，不能平卧，急诊入院。病例分析病例分析体格检查体格检查：体温体温37.437.4，脉搏，脉搏9898次次/min/min，呼吸呼吸28
22、28次次/min/min，血压血压102/79mmHg102/79mmHg。慢性病容，端坐呼吸，嗜睡，慢性病容，端坐呼吸，嗜睡，唇及皮肤明显发绀，颈静脉怒张，吸气时胸骨唇及皮肤明显发绀，颈静脉怒张，吸气时胸骨及锁骨上窝明显凹陷，桶状胸，呼吸动度降低，及锁骨上窝明显凹陷，桶状胸，呼吸动度降低，叩诊呈过清音，双肺散在干湿叩诊呈过清音，双肺散在干湿啰啰音。心率音。心率9898次次/min/min，心律齐，心浊音界缩小。腹部膨隆，大心律齐，心浊音界缩小。腹部膨隆，大量腹水征，肝在肋下量腹水征，肝在肋下7.5cm7.5cm，较硬，双下肢凹较硬，双下肢凹陷性水肿陷性水肿。实验室检查实验室检查：血常规：血红
23、蛋白血常规：血红蛋白98g/L98g/L，白细胞白细胞6.76.710109 9/L/L，其中嗜中性粒细胞占其中嗜中性粒细胞占0.890.89，淋巴细胞淋巴细胞0.110.11。入院后病人突然抽搐，。入院后病人突然抽搐，极度烦躁不安，继之神志不清，心率增极度烦躁不安，继之神志不清，心率增到到156156次次/min/min，抢救无效死亡。抢救无效死亡。1 1根据主要临床表现作出诊断，并说明诊断依据。根据主要临床表现作出诊断，并说明诊断依据。尸检摘要尸检摘要左右胸腔积液各左右胸腔积液各200m1200m1，腹腔积液腹腔积液2000ml2000ml呈淡黄呈淡黄色，透明，比重色，透明，比重1.012
24、1.012。双肺各重。双肺各重750g750g，体积增体积增大，极度充气膨胀，切面见双肺散在灶性实变，大，极度充气膨胀，切面见双肺散在灶性实变，呈灰白色，部分呈灰白与暗红相间，且以双肺下呈灰白色，部分呈灰白与暗红相间，且以双肺下叶为甚。镜下见双肺末稍肺组织过度充气、扩张，叶为甚。镜下见双肺末稍肺组织过度充气、扩张，肺泡壁变薄、部分壁断裂；灶性实变区见充血，肺泡壁变薄、部分壁断裂；灶性实变区见充血，肺泡内及细支气管腔内有浆液、嗜中性粒细胞充肺泡内及细支气管腔内有浆液、嗜中性粒细胞充填，部分上皮细胞坏死脱落；填，部分上皮细胞坏死脱落；支气管黏膜上皮内杯状细胞增多，部分鳞状支气管黏膜上皮内杯状细胞增
25、多，部分鳞状上皮化生，个别管腔内见黏液或渗出物形成上皮化生，个别管腔内见黏液或渗出物形成的栓子，管壁黏液腺增多并肥大，管壁软骨的栓子，管壁黏液腺增多并肥大，管壁软骨灶性钙化及纤维化，纤维组织增生，淋巴细灶性钙化及纤维化，纤维组织增生，淋巴细胞和少量嗜中性粒细胞浸润。心脏重胞和少量嗜中性粒细胞浸润。心脏重300g300g，右心室壁厚右心室壁厚0.35cm0.35cm，右心腔明显扩张，肉柱右心腔明显扩张，肉柱及乳头肌增粗变扁，肺动脉圆锥膨隆，左心及乳头肌增粗变扁，肺动脉圆锥膨隆，左心及各瓣膜未见明显病变。及各瓣膜未见明显病变。心源性肝硬化。其心源性肝硬化。其他脏器变性、淤血。他脏器变性、淤血。2
26、2说明该患者的疾病的发生发展过程。说明该患者的疾病的发生发展过程。3 3请用尸检发现解释患者的症状和体征。请用尸检发现解释患者的症状和体征。咳嗽、咳痰，脓痰，劳动后心悸呼吸困难，咳嗽、咳痰，脓痰，劳动后心悸呼吸困难，下肢凹陷性水肿，腹胀下肢凹陷性水肿，腹胀端坐呼吸，嗜睡，唇及皮肤发绀，颈静脉端坐呼吸，嗜睡，唇及皮肤发绀，颈静脉怒张，吸气时胸骨及锁骨上窝凹陷，桶状怒张，吸气时胸骨及锁骨上窝凹陷，桶状胸，双肺散在干湿胸，双肺散在干湿啰啰音，大量腹水征，音，大量腹水征，肝肝大、较硬大、较硬vA 67-year-old man presents with a history of dyspnea,wh
27、ich has progressed for the past several years.He began smoking cigarettes at 15 years of age and continues to smoke one pack per day.Worsening breathlessness forced him to retire as a laborer,and he has sought emergency care for what he calls bronchitis twice in the past year.vHis physical examinati
28、on is notable for diminished breath sounds on auscultation,with a prolonged expiratory phase.Spirometry reveals severe airflow obstructionvThe sentinel clinical feature of severe chronic obstructive pulmonary disease(COPD)is dyspnea on exertion.Its onset is usually insidious,and it may progress to s
29、evere disability over a period of years or decades.Other common symptoms include cough,sputum production,wheezing,and chest congestion.The principal pathophysiologicalfeatures of COPDvPatients with severe COPD often have exacerbations that result in medical visits and hospitalizations.Chronic hypoxe
30、mia and hypercapnia may cause pulmonary hypertension and cor pulmonale.vPatients with severe COPD are also at increased risk for other systemic diseases,including cardiovascular disease,osteoporosis,lung cancer,and depression.(Agust AG,Noguera A,Sauleda J,Sall a E,Pons J,Busquets X.Systemic effects
31、of chronic obstructive pulmonary disease.Eur Respir J 2003;21:347-60.)Alpha1-Antitrypsin DeficiencyvA 60-year-old white man presents for evaluation of progressive dyspnea.He is a former smoker with a 20-pack-year smoking history and a 10-year history of diagnosed chronic obstructive pulmonary diseas
32、e(COPD).There is no family history of COPD.vSevere airflow obstruction is seen on spirometry肺量肺量测定法测定法,with a forced expiratory volume in 1 second(FEV1)that is 40%of the predicted value.Should the patient be evaluated for alpha1-antitrypsin(AAT)deficiency?If AAT deficiency is documented,how should h
33、is case be managed?The Clinical Problemv AAT deficiency increases the risk of COPD,liver disease,and several other conditions.Although various definitions have been used,we define AAT deficiency as the inheritance of two severe deficiency alleles at the locus encoding AAT.AAT deficiency is relativel
34、y common in populations of European ancestry始祖始祖,with an estimated prevalence of 1 case per 3000 to 5000 persons in the United States.The incidence of AAT deficiency in white newborns is similar to that of cystic fibrosis.v AAT is a serine protease inhibitor encoded by SERPINA1(also known as PI).AAT
35、 is a highly effective inhibitor of neutrophil elastase;an imbalance between levels of AAT and this elastase increases the risk of emphysema(Fig.1A).vFigure 1.Pathogenesis of Alpha1-Antitrypsin(AAT)Deficiency.vPanel A shows a simplified representation of the mechanism for the development of emphysem
36、a in patients with AAT deficiency.Gross pathological examination often reveals basilar panacinar emphysema,with alveolar septal destruction and airspace enlargement seen on light microscopy.vPanel B provides an overview of liver disease in patients with AAT deficiency.The liver has hepatocytes conta
37、ining cytoplasmic globules,which are made up of polymerized AAT molecules.The accumulation of these molecules appears to damage the liver,but there is no consensus regarding the specific mechanisms of this injury.v Most persons with AAT deficiency inherit two copies of the PI*Z allele(Table 1).Perso
38、ns who inherit one of the heterogeneous group of PI*Null alleles,which result in the absence of AAT production,and one PI*Z allele(i.e.,PI ZNull)are not readily distinguished from those who are homozygous for the PI*Z allele on the basis of serum AAT levels or protein phenotyping.Therefore,patients
39、with the PI ZZ and PI ZNull genotypes are often clustered together as having the Z protein phenotype.v The Z protein can form polymers that trap AAT within the rough endoplasmic reticulum of hepatocytes,the primary source of AAT synthesis,leading to reduced levels of circulating AAT in the bloodstre
40、am.Patients with the Z protein phenotype have approximately 15%of normal AAT levels.The accumulated AAT protein in hepatocytes appears to underlie the liver disease associated with AAT deficiency(Fig.1B).v The genetic,biochemical,and pathogenetic features of AAT deficiency have been reviewed previou
41、sly.v The natural history of AAT deficiency in adulthood remains poorly understood.AAT deficiency is recognized in less than 10%of persons in whom a diagnosis would be expected on the basis of screening studies in the general population.v The diagnosis of AAT deficiency is generally made after the i
42、dentification of COPD or liver disease or after the deficiency has been diagnosed in a family member.v The health status of patients with undiagnosed AAT deficiency is uncertain,but many patients may not be substantially impaired.Cigarette smoking greatly increases the risk of COPD in patients with
43、the Z protein phenotype.Other risk factors for COPD in such patients are male sex and asthma.Genetic modifiers of lung and liver disease probably exist,although they remain largely undefined.v The classic pulmonary presentation of AAT deficiency is severe,early-onset panacinar emphysema with a basil
44、ar predominance in adults(Fig.1A and Fig.2).However,emphysema may also occur in a diffuse distribution or predominantly in the upper lobes.Bronchiectasis,with or without concomitant伴发的伴发的emphysema,is less common.Dyspnea is generally the prominent symptom,but chronic cough or wheezing may also occur.
45、v The majority of children with AAT deficiency with the Z protein phenotype who are identified through newborn screening have abnormal liver function tests at some point during their first year of life.v Approximately 10%of infants with the Z protein phenotype have prolonged obstructive jaundice,and
46、 about 2%present in childhood with liver failure requiring transplantation.As these children age,there is an increasing risk of liver disease,including cirrhosis and hepatocellular carcinoma.v A postmortem study in Sweden suggested that adults with the Z protein phenotype who died from causes unrela
47、ted to AAT deficiency often had asymptomatic cirrhosis,and this risk increased with agev Figure 2.Variability of Radiographic Findings in Patients with Alpha1-Antitrypsin(AAT)Deficiency.v Computed tomography of the chest in patients with AAT deficiency shows a broad range of manifestations.AAT defic
48、iency has classically been associated with the development of basilar-predominant panacinar emphysema(Panel A).v However,upper-lobe-predominant emphysema(Panel B)and bronchiectasis(Panel C)can also be observed,and sometimes the lungs are normal(Panel D).vMost persons inherit two copies of the PI*M a
49、llele,which is associated with normal AAT levels.The PI*S allele is slightly more common than the PI*Z allele in most European populations and is associated with mildly reduced AAT levels.Available evidence suggests that patients with the PI MZ genotype may be at slightly increased risk for COPD and
50、 liver disease,but this association has not been proved.Patients with the PI SZ genotype are at increased risk for COPD,especially if they smoke,as compared with those with the PI MM genotype,but they have a lower risk than those with the Z protein phenotype.Strategies and Evidencev Diagnosisv AAT d
