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1、Respiratory system,Anatomy,鼻,咽,喉,环状软骨,气管,支气管,肺,上呼吸道,下呼吸道,Rapid gas exchange Ventilation Perfusion Diffusion Cleaning the air Alveoli(300 million alveoli in two adult lungs, provide a surface area of some 160 meters square ) Surporting structure Elastic recoil,Structure and function General Considera
2、tions,(1) the conducting airways (dead air space),(2) the gas exchange portions,气管,粘膜层,粘膜下层,外膜,上皮 ( 纤毛柱状 ),固有膜,Ciliated cell,Mucous cell,sIgA,纤毛粘液排送系统,Mucous, serous and mixed glands,Cartilaginous,肺,导气部 ：,呼吸部 ：,肺内支气管,Bronchiole,Terminal bronchiole,(软骨消失),Respiratory bronchiole,（纤毛消失）,Alveolar duct,A
3、lveolar sac,Alveoli,(SMC消失),68,1518,Alveoli,I 型 （90%）,II 型,Surfactant, repair I,肺间质、肺泡间隔 ：cap. , f, M,Cohn 孔相互沟通,Histology of the Airways,Mucosa,Submucosa,Cartilage,Muscles,Components Functions,Bronchi are distinguished from bronchioles primarily by the presence of cartilage in their walls. Bronchio
4、les also lack submucosal glands.,Epithelium,Pseudostratified ciliated columnar cells Mucous (goblet) cells,Bronchial Submucosal Glands,Histology of the Alveolar walls,Alveoli,Capillaries Pores of Kohn,Simple squamous Stretchy Permeable to O2 and CO2 Easily injured Do not divide,Reserve cells Cuboida
5、l Produce and process surfactant Divide and differentiate to type I pneumocytes,Section 1 Chronic obstructive pulmonary disease,Chronic Obstructive Pulmonary Disease (COPD),不可逆气道阻塞Irreversible airflow obstruction 慢支和肺气肿Chronic Bronchitis and Emphysema 常常伴发Frequently occur together 与空气污染和吸烟有关Strongly
6、 correlated with air pollution and smoking 男多于女More common in men than in women 社会经济影响Socioeconomic impact,COPD represents a growing global public health problem.,In one population based study conducted at multiple international sites, approximately 10% of participants 40 years of age or older were
7、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. Lancet 2007;370:741-50. ),我国国家“十五”课题最新统计数据（2005年公布）
8、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 Chronic bronchitis,Clinical diagnostic criteria,慢性咳嗽、咳痰 每年个月 连续年,Chronic bronchitis Endoscopic image,Pathogenesis,感染 吸烟气候空气污染等,大气道病变 Large airway disease,咳嗽、咳痰Cough and sputum production Histological changes 杯状细
9、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 inflammation,Reid index,inner perichondrium,basal lamina,鳞化 Squamous metaplasia,Chronic inflammation Hyperemia,小气道病变 Small airway disease,呼气性呼吸困难 Decrease in m
10、aximum forced expiratory flow Histological 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 inflammation,luminal and mucus,chronic inflammation,Pathologic changes,起始于大支气管累及小 、细支气管, 粘膜上皮的损伤和修复,纤毛倒伏、脱失 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 （ 4 5 ：1 2 ：1 ）,慢性非特异性炎,
11、 腺体变化,粘液腺肥大、增生 浆液腺化生为粘液腺, 管壁病变,充血、水肿，炎细胞浸润 平滑肌束断裂，软骨变性萎缩,小细支气管炎,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 features,支气管粘膜炎症、粘液分泌旺盛,咳,痰,支气管痉挛，渗出物阻塞,喘,晚期表现 Late stage menifestation,血氧饱和度低 insufficient oxygenation of blood (hypoxemia) 呼吸困难 labored breathing (hypoventilation) 右心衰 right-sided h
12、eart failure (cor pulmonale),Treatment,不能根治 No cure 控制症状 relieving symptoms 防止并发症 preventing complications,二、肺气肿Pulmonary emphysema,呼吸性细支气管至肺泡的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，间隔断裂致肺泡互相融合，肺容积胀大的病理状态。,Abnormal permanent enlargement of airspaces distal to the terminal bronchiole, accompanied by the de
13、struction of their walls. (morphologically defined),Inadequate ventilation Less perfusion Narrowed bronchiole,Pathogenesis,蛋白酶和抗蛋白酶水平失衡 Imbalance between proteases and anti-proteases (alpha-1 antitrypsin) in the lung Cigarette smoking 募集粒细胞和巨噬细胞 Recruits neutrophils and macrophages 氧自由基抑制抗胰蛋白酶 Oxida
14、nts and free radicals inhibit the alpha-1-antitrypsin circulating in the lung 慢支和反复感染 Chronic bronchitis and repeated infections 缺乏 Alpha-1 antitrypsin deficiency (1%),Who destroy the alveoli wall?,肺气肿类型 Types of emphysema,中央性肺气肿 Centriacinar (centrilobular) emphysema 常见 主要累及部位 respiratory bronchiol
15、e 上叶更常见 见于吸烟者,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 Types of emphysema,隔旁肺气肿 Distal acinar (paraseptal) emphysema或小叶周围性肺气肿 远端 The distal respiratory acinus is expanded 主要部位：上叶近胸膜或隔旁,肺气肿类型 Types of em
16、physema,Centriacinar (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 pattern is typical for smokers,Centriacinar (cent
17、rilobular) emphysema,Emphysema loss of alveolar walls,镜下 ： 肺泡壁、肺泡间隔 萎缩、消失、破坏， 互相融合,其它,瘢痕旁肺气肿 Emphysema with irregular distribution related to scars (obstruction / traction),代偿性肺气肿 Compensatory emphysema,Caused by removal or collapse of adjacent pulmonary parenchyma,肺大泡,肺尖、胸膜下局灶性肺泡间隔破坏， 形成 2cm (D) 囊泡
18、,间质性肺气肿,儿童多见 ，肺泡壁、细支气管壁急性破裂 ， 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 Late stage manifestation,气短 Short of breath, wheezling 咳嗽 Cough with or without mucous 疲劳 Fatigue Weight loss 下肢水肿 Ankle feet leg swelling 肺感染 lung infections,Co
19、mplications,Respiratory infections Respiratory failure Cor pulmanale,患者，女性，60岁。因反复咳嗽、咳痰11年，伴气促、心悸3年，下肢水肿2年，腹胀3月入院。11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，反复加重。3年来，在劳动或爬坡后常感心悸、呼吸困难。2年前开始反复下肢凹陷性水肿。3月前受凉后发热、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。,病例分析,体格检查： 体温37.4，脉搏98次/min，呼吸28次/min，血压102/79mmHg。慢性病容，端坐呼吸，嗜睡
20、，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，叩诊呈过清音，双肺散在干湿啰音。心率98次/min，心律齐，心浊音界缩小。腹部膨隆，大量腹水征，肝在肋下7.5cm，较硬，双下肢凹陷性水肿。,实验室检查： 血常规：血红蛋白98g/L，白细胞6.7109/L，其中嗜中性粒细胞占0.89，淋巴细胞0.11。入院后病人突然抽搐，极度烦躁不安，继之神志不清，心率增到156次/min，抢救无效死亡。,1根据主要临床表现作出诊断，并说明诊断依据。,尸检摘要 左右胸腔积液各200m1，腹腔积液2000ml呈淡黄色，透明，比重1.012。双肺各重750g，体积增大，极度充气膨
21、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；,支气管黏膜上皮内杯状细胞增多，部分鳞状上皮化生，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300g，右心室壁厚0.35cm，右心腔明显扩张，肉柱及乳头肌增粗变扁，肺动脉圆锥膨隆，左心及各瓣膜未见明显病变。心源性肝硬化。其他脏器变性、淤血。,2说明该患者的疾病的发生发展过程。 3请
22、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，下肢凹陷性水肿，腹胀 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，桶状胸，双肺散在干湿啰音，大量腹水征， 肝大、较硬,A 67-year-old man presents with a history of dyspnea, which has progressed for the past several years. He began smoking cigarettes at 15 years of age and continues to smoke one pack per day. Wo
23、rsening breathlessness forced him to retire as a laborer, and he has sought emergency care for what he calls bronchitis twice in the past year. His physical examination is notable for diminished breath sounds on auscultation, with a prolonged expiratory phase. Spirometry reveals severe airflow obstr
24、uction,The sentinel clinical feature of severe chronic obstructive pulmonary disease (COPD) is dyspnea on exertion. Its onset is usually insidious, and it may progress to severe disability over a period of years or decades. Other common symptoms include cough, sputum production, wheezing, and chest
25、congestion.,The principal pathophysiological features of COPD,Patients with severe COPD often have exacerbations that result in medical visits and hospitalizations. Chronic hypoxemia and hypercapnia may cause pulmonary hypertension and cor pulmonale. Patients with severe COPD are also at increased r
26、isk 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 of chronic obstructive pulmonary disease. Eur Respir J 2003;21:347-60.),Alpha1-Antitrypsin Deficiency,A 60-yea
27、r-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 disease (COPD). There is no family history of COPD. Severe airflow obstruction is seen on spirometry肺量测定法, with a
28、 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 his case be managed?,The Clinical Problem,AAT deficiency increases the risk of COPD, liver disease, an
29、d 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 relatively common in populations of European ancestry始祖, with an estimated prevalence of 1 case per 3000
30、to 5000 persons in the United States. The incidence of AAT deficiency in white newborns is similar to that of cystic fibrosis. AAT is a serine protease inhibitor encoded by SERPINA1 (also known as PI). AAT is a highly effective inhibitor of neutrophil elastase; an imbalance between levels of AAT and
31、 this elastase increases the risk of emphysema (Fig. 1A).,Figure 1. Pathogenesis of Alpha1-Antitrypsin (AAT) Deficiency. Panel A shows a simplified representation of the mechanism for the development of emphysema in patients with AAT deficiency. Gross pathological examination often reveals basilar p
32、anacinar emphysema, with alveolar septal destruction and airspace enlargement seen on light microscopy. Panel B provides an overview of liver disease in patients with AAT deficiency. The liver has hepatocytes containing cytoplasmic globules, which are made up of polymerized AAT molecules. The accumu
33、lation of these molecules appears to damage the liver, but there is no consensus regarding the specific mechanisms of this injury.,Most persons with AAT deficiency inherit two copies of the PI*Z allele (Table 1). Persons who inherit one of the heterogeneous group of PI*Null alleles, which result in
34、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 with the PI ZZ and PI ZNull genotypes are often clustered together as havin
35、g the Z protein phenotype. 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 bloodstream. Patients with the Z protein phenotype have approximately 15% of normal
36、 AAT levels. The accumulated AAT protein in hepatocytes appears to underlie the liver disease associated with AAT deficiency (Fig. 1B). The genetic, biochemical, and pathogenetic features of AAT deficiency have been reviewed previously.,The natural history of AAT deficiency in adulthood remains poor
37、ly 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. The diagnosis of AAT deficiency is generally made after the identification of COPD or liver disease or after the deficiency has b
38、een diagnosed in a family member. 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 the Z protein phenotype. Other risk factors for COPD in such patien
39、ts are male sex and asthma. Genetic modifiers of lung and liver disease probably exist, although they remain largely undefined.,The classic pulmonary presentation of AAT deficiency is severe, early-onset panacinar emphysema with a basilar predominance in adults (Fig. 1A and Fig. 2). However, emphyse
40、ma may also occur in a diffuse distribution or predominantly in the upper lobes. Bronchiectasis, with or without concomitant伴发的emphysema, is less common. Dyspnea is generally the prominent symptom, but chronic cough or wheezing may also occur. The majority of children with AAT deficiency with the Z
41、protein phenotype who are identified through newborn screening have abnormal liver function tests at some point during their first year of life. Approximately 10% of infants with the Z protein phenotype have prolonged obstructive jaundice, and about 2% present in childhood with liver failure requiri
42、ng transplantation. As these children age, there is an increasing risk of liver disease, including cirrhosis and hepatocellular carcinoma. A postmortem study in Sweden suggested that adults with the Z protein phenotype who died from causes unrelated to AAT deficiency often had asymptomatic cirrhosis
43、, and this risk increased with age,Figure 2. Variability of Radiographic Findings in Patients with Alpha1-Antitrypsin (AAT) Deficiency. Computed tomography of the chest in patients with AAT deficiency shows a broad range of manifestations. AAT deficiency has classically been associated with the deve
44、lopment of basilar-predominant panacinar emphysema (Panel A). However, upper-lobe-predominant emphysema (Panel B) and bronchiectasis (Panel C) can also be observed, and sometimes the lungs are normal (Panel D).,Most persons inherit two copies of the PI*M allele, which is associated with normal AAT l
45、evels. 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 liver disease, but this association has
46、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 Evidence,Diagnosis AAT deficiency remains undiagnosed in many
47、 patients, and there are often long delays between the onset of respiratory symptoms and diagnosis. Approximately 1% of patients with COPD have AAT deficiency, and the condition is frequently not diagnosed. In some cases, the underdiagnosis诊断不足of AAT deficiency may relate to perceived认知risks associa
48、ted with testing for a genetic condition. It is recommended that patients be informed about risks of testing for AAT deficiency, including potential genetic discrimination, before testing is performed. The lack of studies demonstrating that increased AAT detection leads to improved health outcomes h
49、as led to varying approaches to AAT testing, but testing has been recommended for all patients with COPD, asthma with irreversible airflow obstruction, unexplained liver disease, or necrotizing panniculitis脂膜炎,Three strategies are commonly used to diagnose AAT deficiency: measurement of the serum or plasma protein level, AAT protein phenotyping of serum or plasma, and AAT genotyping (Table 1). The measurement of AAT levels is accurately performed in many laboratories and is a reasonable initial test, bu